Science of Synthesis

Chebanov, V. A.; Gorobets, N. Yu.; Sedash, Yu. V., Science of Synthesis: Multicomponent Reactions, (2014) 1, 36.

The isolation of an intermediate of type ‌7‌ (see ‌Scheme 3‌) has been reported.[‌28‌] Treatment of ethyl 4,4,4-trifluoro-3-oxobutanoate with benzaldehyde and urea under classical Biginelli conditions produces hexahydropyrimidine ‌9‌ (R1 = OEt; R2 = CF3; X = O) in diastereomerically pure form as the only isolable product (‌Scheme 6‌). A detailed structural study including X-ray crystallographic analysis confirmed the suggested structure of this intermediate including its stereochemical aspects.[‌63‌] Interestingly, even under prolonged exposure to the above-mentioned acidic reaction conditions, transformation of ‌9‌ (R1 = OEt; R2 = CF3; X = O) into the 3,4-dihydropyrimidin-2(1H)-one ‌10‌ is not observed. Only treatment with 4-toluenesulfonic acid in refluxing toluene with azeotropic removal of water leads to the formation of 1,2,3,4-tetrahydropyrimidine ‌10‌ (R1 = OEt; R2 = CF3; X = O). Further work has shown that different 1,3-dicarbonyl compounds containing partially or completely fluorinated substituents react to form such hexahydropyrimidine derivatives ‌9‌ in a diastereoselective fashion (‌Scheme 6‌).[‌64‌] The formation of stable hydrated heterocycles due to the presence of a strongly electron-withdrawing group is typical for the reactions of fluorinated 1,3-dicarbonyl compounds with nucleophilic reagents.[‌64‌]

‌Meeeee 8‌ Meøeeeee Meee Meeeeeeee Meeeeeeee Meeeeeeee Meeee Meeeeeeeeee β-Meeeeeeeee Meeeeeeee[‌88‌,‌88‌]

‌Meeeeeeeeee 8‌

Me eeeeee ee eeeee eeee eeeee eeeee[‌88‌,‌88‌] eeeeeeeeee eeeeeeeeeee ee eeeeeeeeeee β-eeeeeeeeee eeeeeeeee ee eeeeeee Meeeeeeee eeeeeeeee eeeeeeee eee eeeeeeee eeeeeeeeeeeee ee eee ee8 eeeeee eeeeeee eee eeeeeeeeeeeeeee eee eeeeeee eeeeee ee eee eeeeeeee ‌8‌, eeeeeeee eeeeeee eeeeeeeeee eeeeeeee.

Meeeeeeeeeee Meeeeeeee

Meeee (8M*,8M*,8M*)-8-Meeeeee-8-eee-8-eeeeee-8-(eeeeeeeeeeeeeee)eeeeeeeeeeeeeeeeeee-8-eeeeeeeeeee (‌8‌, M8 = MMe; M8 = MM8; M = M); Meeeeee Meeeeeeee:[‌88‌,‌88‌]

M eeeeeee ee MeMMM (888 ee, 8.8 eeee), eeeee 8,8,8-eeeeeeeee-8-eeeeeeeeeeee (888 ee, 8.8 eeee), eeee (888 ee, 8.8 eeee), eee MeMM (8 eM) eeeeeeeeee eeeee MMe (8 eeeee) eee eeeeee eeeee eeeeee eee 8 e. Meeee eeeeeeee eeeeeeeee ee 8 °M, eee eeeeeeeeeeee eeeee eee eeeeeeeee ee eeeeeeeeee eee eeeeee eeee eeee MeMM; eeeee: 888 ee (88%); ee 888 °M (MeMM).

Meeee 8-Mee-8-eeeeee-8-(eeeeeeeeeeeeeee)-8,8,8,8-eeeeeeeeeeeeeeeeeeee-8-eeeeeeeeeee (‌88‌, M8 = MMe; M8 = MM8; M = M); Meeeeee Meeeeeeee:[‌88‌]

M eeee ee eeeee (8M*,8M*,8M*)-8-eeeeeee-8-eee-8-eeeeee-8-(eeeeeeeeeeeeeee)eeeeeeeeeeeeeeeeeee-8-eeeeeeeeeee (‌8‌, M8 = MMe; M8 = MM8; M = M; 8.88 e, 8.88 eeee) ee eeeee eeeeeee (88 eM) eeeeeeeeee MeMM (8.8 e) eee eeeeeeee eee 8 e eeee eeeeeeeeeee eeeeeeeeee eeeeeee ee M8M. Meeee eee eeeeeee eee eeee eeeeee ee ee, ee eee eeeeeeee eee eeeeeeeeeeee eeeee eeeeeee eeeeeeee. Mee eeeeeeeee eee eee eeeeeeee ee eeeee eeeeee eeeeeeeeeeeeee (eeeeee eee, MMMe8/eeeeeee 8:8) ee eeee eee eeeeeee ee e eeeeeeeee eeeee; eeeee: 888 ee (88%); ee 888 °M (MeMM). Mee eeeee eeeeeeeeeee ‌88‌,[‌88‌] eee eeeeeee eee eeeeee ee ee eee eee eeeee eeeeeeee eee eeeeeeeee ee eeeeeeeeee eee eeee eeeeeeeeeeeeee eeee MeMM/M8M ee eeee eee eeeeeeee.

References