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.

Organometal-Free Arylation and Arylation/Trifluoroacetylation of Quinolines by Their Reaction with CF3-ynones and Base-Induced Rearrangement.

The reaction of quinolines with CF3-ynones resulted in the formation of 1,3-oxazinoquinolines. Subsequent treatment of the reaction mixture with a base initiated deep structural transformation of primary products. Both steps proceed in very high yield. As a result, unusual rearrangement of 1,3-oxazinoquinolines to form either 2-arylquinolines or 2-aryl-3-trifluoroacetylquinolines was discovered. The decisive role of the base in the reaction direction was shown. Using these reactions, highly efficient pathways to 2-arylquinolines and 2-aryl-3-trifluoroacetylquinolines were elaborated to provide the corresponding compounds in high yields using a simple one-pot procedure. The possible mechanism of rearrangement is discussed.

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.

Electrophilic halogenation of hydrazones of CF3-ynones. Regioselective synthesis of 4-halo-substituted 3-CF3-pyrazoles.

An efficient approach for the synthesis of 4-halo-3-CF3-pyrazoles was elaborated using the cyclization of hydrazones of CF3-ynones induced by electrophilic halogenation. This method can be used for the regioselective synthesis of 3-CF3-pyrazoles substituted at the 4-position with any halogen (I, Br or Cl). The high (up to quantitative) yields, mild conditions and simplicity of the reaction protocol are the advantages of the proposed method. It was demonstrated that cross-coupling with 4-iodo-3-CF3-pyrazoles can be used for the synthesis of a broad family of tetrasubstituted pyrazoles. Moreover, it was found that this method is suitable for the synthesis of 4-substituted derivatives of Celebrex and SC-560.

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.

Radical Nitration-Debromination of α-Bromo-α-fluoroalkenes as a Stereoselective Route to Aromatic α-Fluoronitroalkenes-Functionalized Fluorinated Building Blocks for Organic Synthesis.

A new highly efficient method for the synthesis of 2-fluoro-2-nitrostyrenes was described. Radical nitration of readily available 2-bromo-2-fluorostyrenes with Fe(NO3)3·9H2O resulted in the formation of the corresponding α-fluoro-nitroalkenes in isolated yields up to 92%. The reaction proceeded as a nitration-debromination sequence to highly stereoselectively give α-fluoro-nitroalkenes as Z-isomers only. The broad scope of this method was demonstrated. Prepared monofluorinated alkenes were shown to be versatile building blocks for the synthesis of various fluorinated products.

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.

Reactions of CF3-enones with arenes under superelectrophilic activation: a pathway to trans-1,3-diaryl-1-CF3-indanes, new cannabinoid receptor ligands.

4-Aryl-1,1,1-trifluorobut-3-en-2-ones ArCH[double bond, length as m-dash]CHCOCF3 (CF3-enones) react with arenes in excess of Brønsted superacids (TfOH, FSO3H) to give, stereoselectively, trans-1,3-diaryl-1-trifluoromethyl indanes in 35-85% yields. The reaction intermediates, the O-protonated ArCH[double bond, length as m-dash]CHC(OH(+))CF3 and the O,C-diprotonated ArHC(+)CH2C(OH(+))CF3 species, have been studied by means of (1)H, (13)C, (19)F NMR, and DFT calculations. Both types of the cations may participate in the reaction, depending on their electrophilicity and electron-donating properties of the arenes. The formation of CF3-indanes is a result of cascade reaction of protonated CF3-enones to form chemo-, regio- and stereoselectively three new C-C bonds. The obtained trans-1,3-diaryl-1-trifluoromethyl indanes were investigated as potential ligands for cannabinoid receptors CB1 and CB2 types. The most potent compound showed sub-micromolar affinity for both receptor subtypes with a 6-fold selectivity toward the CB2 receptor with no appreciable cytotoxicity toward SHSY5Y cells.

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.

Fragmentation of trifluoromethylated alkenes and acetylenes by N,N-binucleophiles. Synthesis of imidazolines or imidazolidines (oxazolidines) controlled by substituent.

The reaction of beta-halogeno-beta-polyfluoromethylstyrenes with N,N- or N,O-binucleophiles leads to unexpected fragmentation products (imidazolines) or to heterocyclization giving CF(3)-substituted imidazolidines (N,N-) and oxazolidines (N,O-) depending on aryl substituent. The scope and the reaction mechanism are discussed.