Cyclization of 1-aryl-4,4,4-trichlorobut-2-en-1-ones into 3-trichloromethylindan-1-ones in triflic acid.

Trichloromethyl-substituted enones (1-aryl-4,4,4-trichlorobut-2-en-1-ones, ArCOCH=CHCCl3, CCl3-enones) undergo intramolecular transformation into 3-trichloromethylindan-1-ones (CCl3-indanones) in Brønsted superacid CF3SO3H (triflic acid, TfOH) at 80 °C within 2-10 h in yields up to 92%. Protonation of the carbonyl oxygen of the starting CCl3-enones by TfOH affords the key reactive intermediates, the O-protonated forms ArC(=OH+)CH=CHCCl3, which are then cyclized into the target CCl3-indanones. These cations have been studied experimentally by means of NMR spectroscopy in TfOH and theoretically by DFT calculations. Under the same superacidic conditions in TfOH, CCl3-hydroxy ketones (1-aryl-4,4,4-trichloro-3-hydroxybutan-1-ones; ArCOCH2CH(OH)CCl3) undergo dehydration to the corresponding CCl3-enones, which are further cyclized into CCl3-indanones. The yields of CCl3-indanones starting from CCl3-hydroxy ketones are up to 86% in TfOH at 80 °C within 3-18 h.

Synthesis of α-(Trifluoromethyl)styrenes and 1,3-Di(trifluoromethyl)indanes via Electrophilic Activation of TMS Ethers of (Trifluoromethyl)benzyl Alcohols in Brønsted Acids.

TMS ethers of CF3-benzyl alcohols (and their heterocyclic analogues) undergo elimination of TMSOH molecule with the formation of α-(trifluoromethyl)styrenes in yields of up to 90% under the action of strong Brønsted acids TfOH or H2SO4. Under the acidic conditions upon prolongation of the reaction, the α-(trifluoromethyl)styrenes are further dimerized into cis-/trans-1,3-di(trifluoromethyl)indanes in yields of up to 100%. Plausible reaction mechanisms of these electrophilic transformations including the intermediate formation of CF3-benzyl carbocations are discussed.

5,5,5-Trichloropent-3-en-one as a Precursor of 1,3-Bi-centered Electrophile in Reactions with Arenes in Brønsted Superacid CF3SO3H. Synthesis of 3-Methyl-1-trichloromethylindenes.

Reactions of 5,5,5-trichloropent-3-en-2-one Cl3CCH=CHC(=O)Me with arenes in Brønsted superacid CF3SO3H at room temperature for 2 h-5 days afford 3-methyl-1-trichloromethylindenes, a novel class of indene derivatives. The key reactive intermediate, O-protonated form of starting compound Cl3CCH=CHC(=OH+)Me, has been studied experimentally by NMR in CF3SO3H and theoretically by DFT calculations. The reaction proceeds through initial hydroarylation of the carbon-carbon double bond of starting CCl3-enone, followed by cyclization onto the O-protonated carbonyl group, leading to target indenes. In general, 5,5,5-trichloropent-3-en-2-one in CF3SO3H acts as a 1,3-bi-centered electrophile.

Synthesis of 3-Aryl-3-(Furan-2-yl)Propanoic Acid Derivatives, and Study of Their Antimicrobial Activity.

Reactions of 3-(furan-2-yl)propenoic acids and their esters with arenes in Brønsted superacid TfOH affords products of hydroarylation of the carbon-carbon double bond, 3-aryl-3-(furan-2-yl)propenoic acid derivatives. According to NMR and DFT studies, the corresponding O,C-diprotonated forms of the starting furan acids and esters should be reactive electrophilic species in these transformations. Starting compounds and their hydroarylation products, at a concentration of 64 µg/mL, demonstrate good antimicrobial activity against yeast-like fungi Candida albicans. Apart from that, these compounds suppress Escherichia coli and Staphylococcus aureus.

Michael Addition of 3-Oxo-3-phenylpropanenitrile to Linear Conjugated Enynones: Approach to Polyfunctional δ-Diketones as Precursors for Heterocycle Synthesis.

Reaction of linear conjugated enynones, 1,5-diarylpent-2-en-4-yn-1-ones [Ar1C≡CCH=CHC(=O)Ar2], with 3-oxo-3-phenylpropanenitrile (NCCH2COPh) in the presence of sodium methoxide MeONa as a base in MeOH at room temperature for 4-26 h affords polyfunctional δ-diketones as a product of regioselective Michael addition to the double carbon-carbon bond of starting enynones. The δ-diketones have been formed as mixtures of two diastereomers in a ratio of 2.5:1 in good general yields of 53-98%. A synthetic potential of the obtained δ-diketones has been demonstrated by heterocyclization with hydrazine into substututed 5,6-dihydro-4H-1,2-diazepine.

AlBr3-Promoted stereoselective anti-hydroarylation of the acetylene bond in 3-arylpropynenitriles by electron-rich arenes: synthesis of 3,3-diarylpropenenitriles.

Reactions of 3-arylpropynenitriles (ArC≡CCN) with electron-rich arenes (Ar'H, benzene and its polymethylated derivatives) under the action of aluminum bromide (AlBr3, 6 equiv) at room temperature for 0.5-2 h result in the stereoselective formation of 3,3-diarylpropenenitriles (Ar(Ar')C=CHCN) in yields of 20-64%, as products of mainly anti-hydroarylation of the acetylene bond. The obtained 3,3-diarylpropenenitriles in triflic acid CF3SO3H (TfOH) at room temperature for 1 h are cyclized into 3-arylindenones in yields of 55-70%.

Synthesis of 5-arylacetylenyl-1,2,4-oxadiazoles and their transformations under superelectrophilic activation conditions.

Acetylene derivatives of 1,2,4-oxadiazoles, i.e., 5-(2-arylethynyl)-3-aryl-1,2,4-oxadiazoles, have been obtained, for the first time reported, from 5-(2-arylethenyl)-3-aryl-1,2,4-oxadiazoles by their bromination at the carbon-carbon double bond followed by di-dehydrobromination with NaNH2 in liquid NH3. The reaction of the acetylenyl-1,2,4-oxadiazoles with arenes in neat triflic acid TfOH (CF3SO3H) at room temperature for 1 h resulted in the formation of E/Z-5-(2,2-diarylethenyl)-3-aryl-1,2,4-oxadiazoles as products of regioselective hydroarylation of the acetylene bond. The addition of TfOH to the acetylene bond of these oxadiazoles quantitatively resulted in E/Z-vinyl triflates. The reactions of the cationic intermediates have been studied by DFT calculations and the reaction mechanisms are discussed.

TfOH-Promoted Reactions of TMS-Ethers of CF3-Pentenynoles with Arenes. Synthesis of CF3-Substituted Pentenynes, Indenes, and Other Carbocyclic Structures.

Trimethylsilyl ethers of 1,5-diaryl-3-(trifluoromethyl)-pent-1-en-4-yn-3-oles [Ar-C≡C-C(CF3)(OSiMe3)-CH═CH-Ar'] in the superacid TfOH give rise to reactive conjugated CF3-allylic-propargylic cations [Ar-C≡C-C+(CF3)-CH═CH-Ar']. These species react with arenes in the presence of 1.5 equiv of TfOH forming regio- and stereoselectively E-1,1,5-triaryl-3-(trifluoromethyl)-pent-2-en-4-ynes [Ar-C≡C-C(CF3)═CH-CHAr'(Ar″)] in good yields. In the excess of TfOH, these CF3-pentenynes are further intramolecularly cyclized into CF3-bicyclic dihydroanthracene derivatives ("helicopter"-like molecules). The CF3-pentenynes may also react with arenes, as external nucleophiles, leading to CF3-indenes. These two main reaction pathways depend on internal nucleophilicity of aryl substituents in CF3-pentenynes and external nucleophilicity of aromatic molecules. Plausible cationic reaction mechanisms have been discussed. CF3-bicyclic dihydroanthracene derivatives have been studied regarding their cytotoxicity and virus-inhibiting activity against influenza virus A/Puerto Rico/8/34 (H1N1) in MDCK cell line.

Stereoselective Synthesis of Multisubstituted Cyclohexanes by Reaction of Conjugated Enynones with Malononitrile in the Presence of LDA.

Reaction of linear conjugated enynones, 1,5-diarylpent-2-en-4-yn-1-ones, with malononitrile in the presence of lithium diisopropylamide LDA, as a base, in THF at room temperature for 3-7 h resulted in the formation of the product of dimerization, multisubstituted polyfunctional cyclohexanes, 4-aryl-2,6-bis(arylethynyl)-3-(aryloxomethyl)-4-hydroxycyclohexane-1,1-dicarbonitriles, in yields up to 60%. Varying the reaction conditions by decreasing time and temperature and changing the ratio of starting compounds (enynone and malononitrile) allowed isolating some intermediate compounds, which confirmed a plausible reaction mechanism. The relative stability of possible stereoisomers of such cyclohexanes was estimated by quantum chemical calculations (DFT method). The obtained cyclohexanes were found to possess photoluminescent properties.

Generation and NMR Study of Short-Lived and Reactive Trifluoroalkyl Carbocations of the α-Halogenothiophene Series in Brønsted Superacids: Reactions of the Cations with Arenes.

Protonation of oxygen in the side chain of the Me3SiO group (followed by the elimination of Me3SiOH) and protonation of the thiophene ring in 2-chloro(or bromo)-5-(1'-Me3SiO-1'-trifluoromethyl-alkyl)thiophenes in Brønsted superacids (CF3SO3H, FSO3H) gave rise to short-lived and reactive trifluoroalkyl carbocations of the thiophene series. These cations were studied by low-temperature NMR spectroscopy in the superacids, which shed light on their reactivity and reaction mechanisms. The cations may react with (hetero)aromatic π-nucleophiles in various directions, depending on their structures as well as the reaction temperature and time. These transformations resulted in the formation of novel fluoro-organics of the thiophene family, namely, products of arylation of both the thiophene system and its side chain, hydrodehalogenation of halothiophenes, or electrophilic "dimerization".

Reactions of 2-carbonyl- and 2-hydroxy(or methoxy)alkyl-substituted benzimidazoles with arenes in the superacid CF3SO3H. NMR and DFT studies of dicationic electrophilic species.

Reactions of 2-carbonyl- and 2-hydroxy(or methoxy)alkylbenzimidazoles with arenes in the Brønsted superacid TfOH resulted in the formation of the corresponding Friedel-Crafts reaction products, 2-diarylmethyl and 2-arylmethyl-substituted benzimidazoles, in yields up to 90%. The reaction intermediates, protonated species derived from starting benzimidazoles in TfOH, were thoroughly studied by means of NMR and DFT calculations and plausible reaction mechanisms are discussed.

Different reactivity of phosphorylallenes under the action of Brønsted or Lewis acids: a crucial role of involvement of the P=O group in intra- or intermolecular interactions at the formation of cationic intermediates.

3-Methylbuta-1,2-dien-1-ylphosphonic acid derivatives (phosphorylallenes) [X2(O=)P-CR=C=CMe2, X = Cl, OMe, NR2, or SAr] undergo intramolecular cyclization into the corresponding 1,2-oxaphospholium ions in the Brønsted superacid TfOH. These cations have been thoroughly studied by means of NMR spectroscopy. The hydrolysis of superacidic solutions of these species afforded cyclic phosphonic acids and other phosphorus-containing compounds. Contrary to Brønsted acids, 3-methylbuta-1,2-dien-1-ylphosphonic dichloride [Cl2(O=)P-HC=C=CMe2] reacted with the Lewis acid AlCl3 in an intermolecular way forming noncyclic intermediates, which were investigated by NMR spectroscopy and DFT calculations. Hydrolysis of these species resulted in the formation of phosphoryl-substituted allyl alcohols and 1,3-butadienes. A strong coordination of the oxygen of the P=O group with AlCl3 prevented the formation of cyclic 1,2-oxaphospholium ions and played a crucial role in the different reactivity of such phosphorylallenes under the action of Brønsted or Lewis acids. Apart from that, the reaction of dichlorophosphorylallenes with arenes and AlCl3 led to products of hydroarylation of the allene system, phosphoryl-substituted alkenes and/or indanes. This is the first example of a Lewis acid-promoted intermolecular hydroarylation of allenes bearing electron-withdrawing substituents. Plausible reaction mechanisms have been proposed on the basis of the investigated reactions, and NMR analysis and DFT studies of the intermediate cationic species.

Synthesis of 1,2,4-Oxadiazoles by Tandem Reaction of Nitroalkenes with Arenes and Nitriles in the Superacid TfOH.

The tandem reaction of nitroalkenes with arenes and nitriles in the superacid CF3SO3H (TfOH) results in the formation of 1,2,4-oxadiazole derivatives in yields up to 96%. This reaction proceeds via the consequent interaction of arenes and nitriles, as nucleophiles, with intermediate cationic species derived by the protonation of nitroalkenes in TfOH. This is novel and general synthesis of 1,2,4-oxadiazoles, which are very important compounds for medicinal chemistry.

HUSY zeolite-promoted reactions of trifluoromethylated propargyl alcohols with arenes: synthesis of CF3-indenes and DFT study of intermediate carbocations.

The reaction of CF3-propargyl alcohols [ArC[triple bond, length as m-dash]CCH(OH)CF3] with arenes under the action of acidic HUSY zeolite CBV-720 was investigated. It was found that the reaction at 100 °C for 1 h gave rise to 3-aryl-1-CF3-indenes in up to 83% yield. Electronic characteristics of the reaction key intermediates, mesomeric CF3-propargyl-allenyl cations [ArC[triple bond, length as m-dash]C-HC+(CF3) ↔ ArC+[double bond, length as m-dash]C[double bond, length as m-dash]CH(CF3)], were studied by DFT calculations. A plausible cationic reaction mechanism is discussed.

Generation of 1,2-oxathiolium ions from (arysulfonyl)- and (arylsulfinyl)allenes in Brønsted acids. NMR and DFT study of these cations and their reactions.

In strong Brønsted acids (CF3SO3H, FSO3H, D2SO4), (arysulfonyl)allenes (ArSO2-CR1=C=CR2R3) and (arylsulfinyl)allenes (ArSO-CR1=C=CR2R3) undergo cyclization into the corresponding stable 1,2-oxathiolium ions, which were studied by means of NMR and DFT calculations. Quenching of solutions of these cations with low nucleophilic media, aqueous HCl, leads to their deprotonation with a stereoselective formation of (arysulfonyl)butadienes (for instance, ArSO2-CR1=C-C(Me)=CH2, for R2 = R3 = Me, yields of 87-98%). Reactions of (arysulfonyl)allenes in the system TfOH (0.1 equiv)-HFIP (hexafluoropropan-2-ol) followed by hydrolysis give rise to allyl alcohols (ArSO2-CR1=CH-C(OH)R2R3, yields of 78-99%). Reflux of solutions of (arysulfonyl)allenes in the presence of TfOH (1 equiv) in 1,2-dichlorobenzene leads to the cyclization into thiochromene 1,1-dioxides in high yields. Under the action of TfOH or AlX3 (X = Cl, Br) followed by hydrolysis of reaction mixtures, (arylsulfinyl)allenes give allyl alcohols (ArSO2-CR1=CH-C(OH)R2R3). Plausible reaction mechanisms have been proposed for all studied reactions.

TfOH-Promoted Reaction of 2,4-Diaryl-1,1,1-Trifluorobut-3-yn-2-oles with Arenes: Synthesis of 1,3-Diaryl-1-CF3-Indenes and Versatility of the Reaction Mechanisms.

The TfOH-mediated reactions of 2,4-diaryl-1,1,1-trifluorobut-3-yn-2-oles (CF3-substituted diaryl propargyl alcohols) with arenes in CH2Cl2 afford 1,3-diaryl-1-CF3-indenes in yields up to 84%. This new process for synthesis of such CF3-indenes is complete at room temperature within one hour. The synthetic potential, scope, and limitations of this reaction were illustrated by more than 70 examples. The proposed reaction mechanism invokes the formation of highly reactive CF3-propargyl cation intermediates that can be trapped at the two mesomeric positions by the intermolecular nucleophilic attack of an arene partner with a subsequent intramolecular ring closure.

Hydroarylation of unsaturated carbon-carbon bonds in cross-conjugated enynones under the action of superacid CF3SO3H or acidic zeolite HUSY. Reaction mechanism and DFT study on cationic intermediate species.

Reactions of cross-conjugated enynones,1,5-diarylpent-1-en-4-yn-3-ones, with arenes in the system TfOH-pyridine or under the action of acidic zeolite HUSY lead regioselectively to products of hydroarylation of the acetylene bond only,1,1,5-triarylpent-1,4-dien-3-ones, in yields up to 98%. These dienones add one more arene molecule to the double carbon-carbon bond in neat TfOH forming 1,1,5,5-tetraarylpent-1-en-3-ones in high yields. Cationic reaction intermediates have been studied by means of DFT calculations to elucidate plausible reaction mechanisms.

Reactions of 3,3,3-Trihalogeno-1-nitropropenes with Arenes in the Superacid CF3SO3H: Synthesis of ( Z)-3,3,3-Trihalogeno-1,2-diarylpropan-1-one Oximes and Study on the Reaction Mechanism.

3,3,3-Trihalogeno-1-nitropropenes C(Hal3)CH═CH(NO2) (Hal = F, Cl, Br) in reaction with arenes in the superacid CF3SO3H (TfOH) at room temperature in 1 h afford 3,3,3-trihalogeno-1,2-diarylpropan-1-one oximes C(Hal3)CH(Ar)-C(Ar)═NOH (CHal3-oximes) in yields of 23-99%. Such CHal3-oximes having one ortho-substituent in the aryl ring exist as atropoisomers in solutions at room temperature. Several cationic intermediates of this reaction were studied by means of NMR and DFT calculations, which proves the detailed reaction mechanism of the formation of CHal3-oximes in TfOH. CHal3-oximes (for Hal = Cl, Br) with DBU in DMF at microwave or thermal activation are cyclized into 5-halogeno-3,4-diarylisoxazoles in yields of 37-59%. CHal3-oximes under the conditions of Beckmann rearrangement with PCl5 in benzene at room temperature in 24 h are turned at first into imidoyl chlorides (yields of 94-96%), which undergo transformation into the corresponding benzamides PhCONHCHPh(CHal3) on silica gel (yields of 46-47%).

Reactions of 1,5-Diaryl-3-(trifluoromethyl)pent-1-en-4-yn-3-yl Cations with Benzene in TfOH. Synthesis of CF3-"Helicopter"-Like Molecules.

Trimethylsilyl ethers of 1,5-diaryl-3-(trifluoromethyl)pent-1-en-4-yn-3-oles in superacid CF3SO3H (TfOH) give rise to the corresponding intermediate CF3-pentenynyl cations. These species react with benzene to afford conjugated CF3-pentenynes, which undergo subsequent cyclization, first, into CF3-cycloheptadienes and, finally, into unusual CF3-"helicopter"-like bicyclic structures.

Metal-free hydroarylation of the side chain carbon-carbon double bond of 5-(2-arylethenyl)-3-aryl-1,2,4-oxadiazoles in triflic acid.

The metal-free reaction of 5-(2-arylethenyl)-3-aryl-1,2,4-oxadiazoles with arenes in neat triflic acid (TfOH, CF3SO3H), both under thermal and microwave conditions, leads to 5-(2,2-diarylethyl)-3-aryl-1,2,4-oxadiazoles. The products are formed through the regioselective hydroarylation of the side chain carbon-carbon double bond of the starting oxadiazoles in yields up to 97%. According to NMR data and DFT calculations, N4,C-diprotonated forms of oxadiazoles are the electrophilic intermediates in this reaction.