Regioselective Synthesis of New Family of 2-Substituted 1,2,3-Triazoles and Study of Their Fluorescent Properties.

Modification of 5-aryl-4-trifluoroacetyltriazoles at the NH-moiety was investigated. Screening of the alkylation conditions revealed that using Na2CO3 as a base and DMF as a solvent of 2-substituted triazoles can be preferentially prepared in up to 86% yield. In the best cases, the amount of minor 1-alkyl isomer was less than 6%. SNAr reaction of the 5-aryl-4-trifluoroacetyltriazoles with aryl halides having electron-withdrawing groups led to regiospecific formation of 2-aryltriazoles isolated in good-to-high yields. Chan-Lam reaction of the 5-aryl-4-trifluoroacetyltriazoles with boronic acids afforded 2-aryltriazoles as single isomers in up to 89% yield. The subsequent reaction of the prepared 2-aryltriazoles with primary and secondary amines gave a set of amides of 4-(2,5-diaryltriazolyl)carboxylic acid. The fluorescent properties of the prepared 2-substituted derivatives of triazoles were investigated to demonstrate their utility as new efficient luminophores having more than 60% quantum yields.

Acid-Switchable Synthesis of Trifluoromethylated Triazoles and Isoxazoles via Reaction of CF3-Ynones with NaN3: DFT Study of the Reaction Mechanism.

A detailed study of the reaction of CF3-ynones with NaN3 was performed. It was found that the reaction permits the selective synthesis of either 4-trifluoroacetyltriazoles or 5-CF3-isoxazoles. The chemoselectivity of the reaction was switchable via acid catalysis. The reaction of CF3-ynones with NaN3 in EtOH produced high yields of 4-trifluoroacetyltriazoles. In contrast, the formation of 5-CF3-isoxazoles was observed under catalysis by acids. This acid-switchable procedure can be performed at sub-gram scale. The possible reaction mechanism was supported by DFT calculations. The synthetic utility of the prepared 4-trifluoroacetyltriazoles was demonstrated.

Synthesis and Reactions of 3-Halogenated 2-CF3-Indoles.

Halogenation of 2-trifluoromethylindole afforded 3-chloro-, 3-bromo- and 3-iodo derivatives in up to 98% yield. Methyl-, benzyl- and tosyl-groups can be installed at the nitrogen atom of prepared indoles in high yields by base catalyzed reaction with the corresponding alkylating (sulfonylating) reagents. A high synthetic utility of the prepared haloindoles in the reaction with various nucleophilies was shown. The reaction with 4-methylthiophenol and copper cyanide afforded the corresponding sulfides and nitriles in high yield. Palladium catalyzed cross-coupling with phenyl boronic acid and phenylacetylene gave the corresponding 3-phenyl-2-CF3-indoles and acetylenic derivatives in 72-98% yield.

An Efficient Approach to 2-CF3-Indoles Based on ortho-Nitrobenzaldehydes.

The catalytic olefination reaction of 2-nitrobenzaldehydes with CF3CCl3 afforded stereoselectively trifluoromethylated ortho-nitrostyrenes in up to 88% yield. The reaction of these alkenes with pyrrolidine permits preparation of α-CF3-ß-(2-nitroaryl) enamines. Subsequent one pot reduction of nitro-group by Fe-AcOH-H2O system initiated intramolecular cyclization to afford 2-CF3-indoles. Target products can be prepared in up to 85% yields. Broad synthetic scope of the reaction was shown as well as some followed up transformations of 2- CF3-indole.

An Efficient Synthesis of 2-CF3-3-Benzylindoles.

The reaction of α-CF3-ß-(2-nitroaryl) enamines with benzaldehydes afforded effectively α,ß-diaryl-CF3-enones having nitro group. Subsequent reduction of nitro group by NH4HCO2-Pd/C system initiated intramolecular cyclization to give 2-CF3-3-benzylindoles. Target products can be prepared in up to quantitative yields. Broad synthetic scope of the reaction was shown. Probable mechanism of indole formation is proposed.

Modular Construction of Functionalized 2-CF3-Indoles.

The reaction of α-CF3-ß-(2-nitroaryl)enamines with benzaldehydes led to nitro-substituted α,ß-diaryl-CF3-enones in high yield. Subsequent reduction of the nitro-group to the amino moiety by the Pd/C-NH4HCO2 system resulted in intramolecular cyclization to form a 5-membered hemiaminal which is stabilized by the presence of a CF3-group. The reaction of this hemiaminal with various nucleophiles afforded functionalized 2-CF3-indoles isolated in up to quantitative yields. High efficiency and broad synthetic scope of all steps of the sequence were demonstrated. A possible mechanism of the reaction is discussed.

Synthesis of 2-trifluoromethylated quinolines from CF3-alkenes.

α-CF3-enamines can be prepared by the reaction of pyrrolidine with the corresponding haloalkenes. The prepared enamines react with 2-nitrobenzaldehydes to give ortho-nitro-substituted α,ß-diaryl-CF3-enones highly stereoselectively in up to 88% yield. Subsequent reduction of the nitro-group by an Fe-AcOH system promotes intramolecular cyclization to afford 2-CF3-3-arylquinolines in up to 99% isolated yield. High synthetic utility of all synthetic steps of the sequence was shown. A one-pot procedure was developed to give the target trifluoromethylated quinolines directly from enamines or haloalkenes.

α,ß-Disubstituted CF3-Enones as a Trifluoromethyl Building Block: Regioselective Preparation of Totally Substituted 3-CF3-Pyrazoles.

An efficient pathway toward a novel class of trifluoromethyl building blocks was elaborated. The reaction of α-CF3-enamines with arylaldehydes resulted in direct synthesis of α,ß-diaryl-CF3-enones isolated in up to 93% yield as E-isomers. The possible reaction mechanism was proposed using the Zimmerman-Traxler model. The reaction of α,ß-diaryl-CF3-enones with hydrazines opens a novel pathway to trifluoromethylated pyrazolines. Oxidation of pyrazolines with DDQ opened access to totally regioselective preparation of 3-CF3-pyrazoles isolated in high yield. Using this strategy, 4-arylated derivatives of known drugs Celebrex, Mavacoxib, and SC-560 can be synthesized.

One-Pot Metal-Free Synthesis of 3-CF3-1,3-Oxazinopyridines by Reaction of Pyridines with CF3CO-Acetylenes.

The reaction of pyridines with trifluoroacetylated acetylenes was investigated. It was found that the reaction of various pyridines with two molecules of CF3CO-acetylenes proceeds under mild metal-free conditions. As a result, efficient stereoselective synthesis of 3-arylethynyl-3-trifluoromethyl-1,3-oxazinopyridines was elaborated. Target heterocycles can be prepared in up to quantitative yields.