Synthesis of 5-(trifluoroacetyl)imidazoles from Bromoenones and Benzimidamides via Aza-Michael Initiated Ring Closure Reaction.

INTRODUCTION: A simple method for the preparation of 5-(trifluoroacetyl)imidazoles was elaborated. METHODS: The reaction of trifluoromethyl(α-bromoalkenyl)ketones with benzimidamides was employed to afford the target heterocycles in good yields. RESULTS: The assembly of imidazole core proceeds via aza-Michael adduct formation followed by intramolecular nucleophilic substitution and spontaneous aromatization as an oxidation sequence. CONCLUSION: The yields of target imidazoles can be improved by the use of soft oxidizing agents.

Selective, Metal-Free Approach to 3- or 5-CF3-Pyrazoles: Solvent Switchable Reaction of CF3-Ynones with Hydrazines.

A detailed study of the reaction of trifluoroacetylated acetylenes and aryl (alkyl) hydrazines was performed, aimed to the regioselective synthesis of 3- or 5-trifluoromethylated pyrazoles. It was found that the regioselectivity of reaction depends dramatically on the solvent nature. Highly polar protic solvents (hexafluoroisopropanol) favor the formation of 3-trifluoromethylpyrazoles. In contrast, when the reaction was performed in polar aprotic solvents (DMSO), the formation of their 5-CF3-substituted isomers was preferentially observed. Alternatively, the regioselective assembly of 3-CF3-substituted pyrazoles can be performed via two-step one-pot procedure. The reaction of trifluoromethylated ynones with aryl (alkyl) hydrazines in the presence of acidic catalysts leads to formation of the corresponding hydrazones. The latter can be smoothly transformed into 3-CF3-pyrazoles by treatment with a base. This solvent-switchable procedure was used for the preparation of such important drugs as Celebrex and SC-560 as well as their isomers in gram scale. The possible reaction mechanism is discussed.

Domino Assembly of Trifluoromethylated N,O-Heterocycles by the Reaction of Fluorinated α-Bromoenones with Amino Alcohols.

A highly efficient method for the selective synthesis of trifluoromethylated morpholines (4-oxa-1-azabicyclo[4.1.0]heptanes) and so far unknown 1,4-oxazepanes (2,8-dioxa-5-azabicyclo[5.1.0]octanes) based on a domino reaction of fluorinated α-bromoenones with ß-amino alcohols was elaborated. The assembly of both heterocyclic systems is initiated by an aza-Michael reaction followed by intramolecular cyclization. The conditions for total control of selectivity of the reaction were found.

Experimental and Theoretical Study of an Intramolecular CF3-Group Shift in the Reactions of α-Bromoenones with 1,2-Diamines.

The reactions of trifluoromethylated 2-bromoenones and N,N'-dialkyl-1,2-diamines have been studied. Depending on the structures of the starting compounds, the formation of 2-trifluoroacetylpiperazine or 3-trifluoromethylpiperazine-2-ones was observed. The mechanism of the reaction is discussed in terms of multistep processes involving sequential substitution of bromine in the starting α-bromoenones and intramolecular cyclization of the captodative aminoenones as key intermediates to form the target heterocycles. The results of theoretical calculations are in perfect agreement with the experimental data. The unique role of the trifluoromethyl group in this reaction is demonstrated.

Reaction of α-bromo enones with 1,2-diamines. Cascade assembly of 3-(trifluoromethyl)piperazin-2-ones via rearrangement.

A facile one-pot synthesis of 3-trifluoromethylated piperazin-2-ones has been achieved by the treatment of trifluoromethyl 2-bromo enones with N,N'-disubstituted ethylenediamines in trifluoroethanol. The mechanism of this unexpected reaction is discussed in terms of multistep processes involving formation of captodative aminoenone as a key intermediate. The unique influence of trifluoromethyl group on the reaction path was demonstrated.