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

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.

Sukach V. A.; Tkachuk V. M.; Shoba V. M.; Pirozhenko V. V.; Rusanov E. B.; Chekotilo A. A.; Röschenthaler G. V.; Vovk M. V.
Eur. J. Org. Chem. 2014, (7), 1452-1460
DOI: 10.1002/ejoc.201301542