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.

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.

Catalyst-free synthesis of substituted pyridin-2-yl, quinolin-2-yl, and isoquinolin-1-yl carbamates from the corresponding hetaryl ureas and alcohols.

A novel catalyst-free synthesis of N-pyridin-2-yl, N-quinolin-2-yl, and N-isoquinolin-1-yl carbamates utilizes easily accessible N-hetaryl ureas and alcohols. The proposed environmentally friendly technique is suitable for the good-to-high yielding synthesis of a wide range of N-pyridin-2-yl or N-quinolin-2-yl substituted carbamates featuring electron-donating and electron-withdrawing groups in the azine rings and containing various primary, secondary, and even tertiary alkyl substituents at the oxygen atom (48-94%; 31 examples). The DFT calculation and experimental study showed that the reaction proceeds through the intermediate formation of hetaryl isocyanates. The method can be applied to obtain N-isoquinolin-1-yl carbamates, although in lower yields, and ethyl benzo[h]quinolin-2-yl carbamate has also been successfully synthesized (68%).

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.

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.

Synthesis and Properties of 6-Aryl-4-azidocinnolines and 6-Aryl-4-(1,2,3-1H-triazol-1-yl)cinnolines.

An efficient approach towards the synthesis of 6-aryl-4-azidocinnolines was developed with the aim of exploring the photophysical properties of 6-aryl-4-azidocinnolines and their click reaction products with alkynes, 6-aryl-4-(1,2,3-1H-triazol-1-yl)cinnolines. The synthetic route is based on the Richter-type cyclization of 2-ethynyl-4-aryltriazenes with the formation of 4-bromo-6-arylcinnolines and nucleophilic substitution of a bromine atom with an azide functional group. The developed synthetic approach is tolerant to variations of functional groups on the aryl moiety. The resulting azidocinnolines were found to be reactive in both CuAAC with terminal alkynes and SPAAC with diazacyclononyne, yielding 4-triazolylcinnolines. It was found that 4-azido-6-arylcinnolines possess weak fluorescent properties, while conversion of the azido function into a triazole ring led to complete fluorescence quenching. The lack of fluorescence in triazoles could be explained by the non-planar structure of triazolylcinnolines and a possible photoinduced electron transfer (PET) mechanism. Among the series of 4-triazolylcinnoline derivatives a compound bearing hydroxyalkyl substituent at triazole ring was found to be cytotoxic to HeLa cells.

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.

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%).

Ligation-Enhanced π-Hole···π Interactions Involving Isocyanides: Effect of π-Hole···π Noncovalent Bonding on Conformational Stabilization of Acyclic Diaminocarbene Ligands.

The reaction of cis-[PdCl2(CNXyl)2] (Xyl = 2,6-Me2C6H3) with the aminoazoles [1 H-imidazol-2-amine (1), 4 H-1,2,4-triazol-3-amine (2), 1 H-tetrazol-5-amine (3), 1 H-benzimidazol-2-amine (4), 1-alkyl-1 H-benzimidazol-2-amines, where alkyl = Me (5), Et (6)] in a 2:1 ratio in the presence of a base in CHCl3 at RT proceeds regioselectively and leads to the binuclear diaminocarbene complexes [(ClPdCNXyl)2{µ-C(N-azolyl)N(Xyl)C═NXyl}] (7-12; 73-91%). Compounds 7-12 were characterized by C, H, N elemental analyses, high-resolution ESI+-MS, Fourier transform infrared spectroscopy, 1D (1H, 13C) and 2D (1H,1H-COSY, 1H,1H-NOESY, 1H,13C-HSQC, 1H,13C-HMBC) NMR spectroscopies, and X-ray diffraction (XRDn). Inspection of the XRDn data and results of the Hirshfeld surface analysis suggest the presence in all six structures of intramolecular π-holeisocyanide···πarene interactions between the electrophilic C atom of the isocyanide moiety and the neighboring arene ring. These interactions also result in distortion of the Pd-C≡N-Xyl fragment from the linearity. Results of density functional theory calculations [M06/MWB28 (Pd) and 6-31G* (other atoms) level of theory] for model structures of 7-9 followed by the topological analysis of the electron density distribution within the framework of Bader's theory (QTAIM method) reveal the presence of these weak interactions also in a CHCl3 solution, and their calculated strength is 1.9-2.2 kcal/mol. The natural bond orbital analysis of 7-9 revealed that π(C-C)Xyl → π*(C-N)isocyanide charge transfer (CT) takes place along with the intramolecular π-holeisocyanide···πarene interactions. The observed π(C-C)Xyl → π*(C-N)isocyanide CT is due to ligation of the isocyanide to the metal center, whereas in the cases of the uncomplexed p-CNC6H4NC and CNXyl species, the effects of CT are negligible. Available CCDC data were processed from the perspective of isocyanide-involving π-hole···π interactions, disclosed the role of metal coordination in the π-hole donor ability of isocyanides, and verified the π-holeisocyanide···πarene interaction effect on the stabilization of the in-conformation in metal-bound acyclic diaminocarbenes.

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.

Acid-promoted cyclization of 2,4-diaryl-1,1,1-trifluorobut-3-en-2-oles and their TMS-ethers into CF3-indenes.

2,4-Diaryl-1,1,1-trifluorobut-3-en-2-oles and their TMS-ethers in H2SO4 at room temperature in just 2 min are quantitatively cyclized into 1-aryl-3-trifluoromethyl-1H-indenes. The reaction proceeds through an intermediate formation of the corresponding CF3-allyl cations, which are cyclized regioselectively at the allyl carbon atom most remote from the CF3-group. The obtained CF3-indenes in solution of EtOAc in the presence of silica gel at room temperature over 4 h are quantitatively isomerized into 3-aryl-1-trifluoromethyl-1H-indenes.

Superelectrophilic activation of 5-hydroxymethylfurfural and 2,5-diformylfuran: organic synthesis based on biomass-derived products.

The reaction of 5-hydroxymethylfurfural (5-HMF) with arenes in superacidic trifluoromethanesulfonic acid (triflic acid, TfOH) as the solvent at room temperature for 1-24 h gives rise to 5-arylmethylfurfurals (yields of 17-91%) and 2-arylmethyl-5-(diarylmethyl)furans (yields of 10-37%). The formation of these two types of reaction products depends on the nucleophilicity of the arene. The same reactions under the action of acidic zeolites H-USY in high pressure tubes at 130 °C for 1 h result in the formation of only 5-arylmethylfurfurals (yields of 45-79%). 2,5-Diformylfuran (2,5-DFF) in the reaction with arenes under the action of AlBr3 at room temperature for 1 h leads to 5-(diarylmethyl)furfurals (yields of 51-90%). The reactive protonated species of 5-HMF and 2,5-DFF were characterized by NMR spectroscopy in TfOH and studied by DFT calculations. These reactions show possibilities of organic synthesis based on biomass-derived 5-HMF and 2,5-DFF.

Difference in Energy between Two Distinct Types of Chalcogen Bonds Drives Regioisomerization of Binuclear (Diaminocarbene)PdII Complexes.

The reaction of cis-[PdCl2(CNXyl)2] (Xyl = 2,6-Me2C6H3) with various 1,3-thiazol- and 1,3,4-thiadiazol-2-amines in chloroform gives a mixture of two regioisomeric binuclear diaminocarbene complexes. For 1,3-thiazol-2-amines the isomeric ratio depends on the reaction conditions and kinetically (KRs) or thermodynamically (TRs) controlled regioisomers were obtained at room temperature and on heating, respectively. In CHCl3 solutions, the isomers are subject to reversible isomerization accompanied by the cleavage of Pd-N and C-N bonds in the carbene fragment XylNCN(R)Xyl. Results of DFT calculations followed by the topological analysis of the electron density distribution within the formalism of Bader's theory (AIM method) reveal that in CHCl3 solution the relative stability of the regioisomers (ΔGexp = 1.2 kcal/mol; ΔGcalcd = 3.2 kcal/mol) is determined by the energy difference between two types of the intramolecular chalcogen bonds, viz. S···Cl in KRs (2.8-3.0 kcal/mol) and S···N in TRs (4.6-5.3 kcal/mol). In the case of the 1,3,4-thiadiazol-2-amines, the regioisomers are formed in approximately equal amounts and, accordingly, the energy difference between these species is only 0.1 kcal/mol in terms of ΔGexp (ΔGcalcd = 2.1 kcal/mol). The regioisomers were characterized by elemental analyses (C, H, N), HRESI+-MS and FTIR, 1D (1H, 13C{1H}) and 2D (1H,1H-COSY, 1H,1H-NOESY, 1H,13C-HSQC, 1H,13C-HMBC) NMR spectroscopies, and structures of six complexes (three KRs and three TRs) were elucidated by single-crystal X-ray diffraction.

Reactions of N,3-diarylpropiolamides with arenes under superelectrophilic activation: synthesis of 4,4-diaryl-3,4-dihydroquinolin-2(1H)-ones and their derivatives.

The reaction of 3-aryl-N-(aryl)propiolamides with arenes in TfOH at room temperature for 0.5 h led to 4,4-diaryl-3,4-dihydroquinolin-2-(1H)-ones in yields of 44-98%. The obtained dihydroquinolinones were further transformed into the corresponding N-acyl or N-formyl derivatives. For the latter, the superelectrophilic activation of the N-formyl group by TfOH in the reaction with benzene resulted in the formation of N-(diphenylmethyl)-substituted dihydroquinolinones.