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DOI: 10.1055/sos-SD-210-00013

Chebanov, V. A.; Gorobets, N. Yu.; Sedash, Yu. V.Science of Synthesis: Multicomponent Reactions, (2014136.

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]

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M8 M8 M Meeee (%) ee 8 Meeee (%) ee 88 Mee
MMe MMM8 M 88 [‌88‌]
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MMe (MM8)8MM8 M 88 88 [‌88‌]
MMe (MM8)8MM8 M 88 88 [‌88‌]
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Me (MM8)8M M 88 88 [‌88‌]
Me (MM8)8M M 88 88 [‌88‌]

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