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.


Results and Discussion
Protonation of CCl3-enone 1 in various Brønsted acids (CH3COOH, CF3COOH, H2SO4, CF3SO3H) was initially investigated by means of NMR. According to 1 H and 13 C NMR data, CCl3-enone 1 gives stable O-protonated form A in these acids at room temperature (Table 1, see original spectra in Supplementary Materials). Upon increasing the acidity in the row CH3COOH→CF3COOH→H2SO4→CF3SO3H [1], signals of protons H 3 , H 4 and carbons C 2 , C 4 are shifted more and more downfield. The corresponding differences in chemical shifts (∆δ = δacid-δCDCl3) for atoms H 3 , H 4 and C 2 , C 4 are gradually increased (Table 1). These data reveal that the positive charge is mainly localized on carbons C 2 and C 4 in cation A, and both these atoms may act as reactive electrophilic centers in consequent interactions with aromatic nucleophiles. Notes. а CH2Cl2 was used as internal standard. b ∆δ = δacid -δCDCl3.
Based on our recent studies on superelectrophilic activation of electron deficient alkenes [19][20][21], we undertook this study on electrophilic activation of E-5,5,5-trichloropent-3-en-2-one 1 (CCl 3 -enone). The presence of two electron withdrawing groups, COMe and CCl 3 , at the carbon-carbon double bond increases its electrophilicity, especially under protonation of the carbonyl oxygen-resulting O-protonated species A (Scheme 1b). The second protonation of C=C bond in cation A may be hampered due to the strong acceptor characteristics of substituents C(OH + )Me and CCl 3 . However, species A possesses enough electrophilicity to react with aromatic nucleophiles.
The main goals of this study were to investigate the protonation of E-5,5,5-trichloropent-3-en-2-one 1 by NMR and DFT calculations and study its reactions with arenes under the action of strong Brønsted and Lewis acids.

Results and Discussion
Protonation of CCl 3 -enone 1 in various Brønsted acids (CH 3 COOH, CF 3 COOH, H 2 SO 4 , CF 3 SO 3 H) was initially investigated by means of NMR. According to 1 H and 13 C NMR data, CCl 3 -enone 1 gives stable O-protonated form A in these acids at room temperature (Table 1, see original spectra in Supplementary Materials). Upon increasing the acidity in the row CH 3 COOH→CF 3 COOH→H 2 SO 4 →CF 3 SO 3 H [1], signals of protons H 3 , H 4 and carbons C 2 , C 4 are shifted more and more downfield. The corresponding differences in chemical shifts (∆δ = δ acid -δ CDCl3 ) for atoms H 3 , H 4 and C 2 , C 4 are gradually increased (Table 1). These data reveal that the positive charge is mainly localized on carbons C 2 and C 4 in cation A, and both these atoms may act as reactive electrophilic centers in consequent interactions with aromatic nucleophiles. NMR data, CCl3-enone 1 gives stable O-protonated form A in these acids at room temperature (Table 1, see original spectra in Supplementary Materials). Upon increasing the acidity in the row CH3COOH→CF3COOH→H2SO4→CF3SO3H [1], signals of protons H 3 , H 4 and carbons C 2 , C 4 are shifted more and more downfield. The corresponding differences in chemical shifts (∆δ = δacid-δCDCl3) for atoms H 3 , H 4 and C 2 , C 4 are gradually increased (Table 1). These data reveal that the positive charge is mainly localized on carbons C 2 and C 4 in cation A, and both these atoms may act as reactive electrophilic centers in consequent interactions with aromatic nucleophiles. H2SO4, CF3SO3H) was initially investigated by means of NMR. According to H and C NMR data, CCl3-enone 1 gives stable O-protonated form A in these acids at room temperature (Table 1, see original spectra in Supplementary Materials). Upon increasing the acidity in the row CH3COOH→CF3COOH→H2SO4→CF3SO3H [1], signals of protons H 3 , H 4 and carbons C 2 , C 4 are shifted more and more downfield. The corresponding differences in chemical shifts (∆δ = δacid-δCDCl3) for atoms H 3 , H 4 and C 2 , C 4 are gradually increased (Table 1). These data reveal that the positive charge is mainly localized on carbons C 2 and C 4 in cation A, and both these atoms may act as reactive electrophilic centers in consequent interactions with aromatic nucleophiles. Notes. a CH 2 Cl 2 was used as internal standard Then, DFT calculations of cations A-C derived from the protonation of CCl 3 -enone 1 have been carried out. The thermodynamics of their formation, such as Gibbs energies ∆G 298 of protonation reactions, energies of HOMO/LUMO, electrophilicity indices ω [22,23], charge distribution, and contribution of atomic orbital into LUMO of species A-C have been estimated (Table 2, see full data in Supplementary Materials).
The formation of O-protonated species A is very favorable, as the ∆G 298 value of the protonation is negative (−35 kJ/mol). Secondly, the protonation of the C=C bond, both onto carbons C 3 and C 4 , which leads to dications B and C, is, correspondingly, extremely unfavorable, due to the very high positive values of protonation Gibbs energies (Table 2). Thus, the generation of O,C-diprotonated species B and C from CCl 3 -enone 1 is very unlikely; that is, in accordance with NMR data (Table 1). Apart from that, it has been found that dication B is extremely unstable. It is spontaneously rearranged into species B1 via a shift of a chlorine atom.
Calculations show that the largest part of positive charge in species A is localized on atom C 2 (0.66 e). Apart from that, this carbon atom contributes significantly to LUMO by 28%. There are similarities between the charge and orbital factors of the electrophilic properties of carbon C 2 . Contrary to that, carbon C 4 bears no positive charge (−0.06 e), but it contributes significantly into LUMO by 21% (see LUMO visualization of cation A in Table 2). Electrophilic properties of atom C 4 can be mainly explained by orbital factors.
Reactions of CCl 3 -enone 1 with benzene under the action of various Brønsted and Lewis acids have also been conducted ( Table 3). The use of strong Lewis acids AlCl 3 or AlBr 3 yields complex mixtures of oligomeric materials (entries 1-3). Reaction in H 2 SO 4 results in the formation of alcohol 3 as a product of hydration of the carbon-carbon double bond; no reaction with benzene occurs (entry 4). Reaction in Brønsted superacid CF 3 SO 3 H (triflic acid, TfOH) at room temperature for 5 days affords indene 2a in yields 29% (entry 7). Under other conditions (temperature and time) in CF 3 SO 3 H, the formation of 2a is unsatisfactory (entries 5, 6,8,9), as is the reaction in stronger acid FSO 3 H at a low temperature of −78 • C (entry 10). In weaker acids, CH 3 CO 2 H and CH 3 CO 2 H, the reaction does not take place (entries [11][12][13][14]. These data reveal that the formation of indene 2a in CF 3 SO 3 H is accompanied by cationic oligomerization processes, which leads to a decrease in the yield of the target compound. The formation of indene 2a points out that the starting compound 1 in CF 3 SO 3 H behaves as a precursor of the bi-centered electrophile, with reactive cationic centers on carbons C 2 and C 4 . Calculations show that the largest part of positive charge in species A is localized on atom C 2 (0.66 e). Apart from that, this carbon atom contributes significantly to LUMO by 28%. There are similarities between the charge and orbital factors of the electrophilic properties of carbon C 2 . Contrary to that, carbon C 4 bears no positive charge (−0.06 e), but it contributes significantly into LUMO by 21% (see LUMO visualization of cation A in Table  2). Electrophilic properties of atom C 4 can be mainly explained by orbital factors.  atom C 2 (0.66 e). Apart from that, this carbon atom contributes significantly to LUMO by 28%. There are similarities between the charge and orbital factors of the electrophilic properties of carbon C 2 . Contrary to that, carbon C 4 bears no positive charge (−0.06 e), but it contributes significantly into LUMO by 21% (see LUMO visualization of cation A in Table  2). Electrophilic properties of atom C 4 can be mainly explained by orbital factors.  carbons C 3 and C 4 , which leads to dications B and C, is, correspondingly, extremely unfavorable, due to the very high positive values of protonation Gibbs energies (Table 2). Thus, the generation of O,C-diprotonated species B and C from CCl3-enone 1 is very unlikely; that is, in accordance with NMR data (Table 1). Apart from that, it has been found that dication B is extremely unstable. It is spontaneously rearranged into species B1 via a shift of a chlorine atom. Calculations show that the largest part of positive charge in species A is localized on atom C 2 (0.66 e). Apart from that, this carbon atom contributes significantly to LUMO by 28%. There are similarities between the charge and orbital factors of the electrophilic properties of carbon C 2 . Contrary to that, carbon C 4 bears no positive charge (−0.06 e), but it contributes significantly into LUMO by 21% (see LUMO visualization of cation A in Table  2). Electrophilic properties of atom C 4 can be mainly explained by orbital factors.  protonation is negative (−35 kJ/mol). Secondly, the protonation of the C=C bond, both onto carbons C 3 and C 4 , which leads to dications B and C, is, correspondingly, extremely unfavorable, due to the very high positive values of protonation Gibbs energies (Table 2). Thus, the generation of O,C-diprotonated species B and C from CCl3-enone 1 is very unlikely; that is, in accordance with NMR data (Table 1). Apart from that, it has been found that dication B is extremely unstable. It is spontaneously rearranged into species B1 via a shift of a chlorine atom. Calculations show that the largest part of positive charge in species A is localized on atom C 2 (0.66 e). Apart from that, this carbon atom contributes significantly to LUMO by 28%. There are similarities between the charge and orbital factors of the electrophilic properties of carbon C 2 . Contrary to that, carbon C 4 bears no positive charge (−0.06 e), but it contributes significantly into LUMO by 21% (see LUMO visualization of cation A in Table  2). Electrophilic properties of atom C 4 can be mainly explained by orbital factors.  protonation is negative (−35 kJ/mol). Secondly, the protonation of the C=C bond, both onto carbons C 3 and C 4 , which leads to dications B and C, is, correspondingly, extremely unfavorable, due to the very high positive values of protonation Gibbs energies (Table 2). Thus, the generation of O,C-diprotonated species B and C from CCl3-enone 1 is very unlikely; that is, in accordance with NMR data (Table 1). Apart from that, it has been found that dication B is extremely unstable. It is spontaneously rearranged into species B1 via a shift of a chlorine atom. Calculations show that the largest part of positive charge in species A is localized on atom C 2 (0.66 e). Apart from that, this carbon atom contributes significantly to LUMO by 28%. There are similarities between the charge and orbital factors of the electrophilic properties of carbon C 2 . Contrary to that, carbon C 4 bears no positive charge (−0.06 e), but it contributes significantly into LUMO by 21% (see LUMO visualization of cation A in Table  2). Electrophilic properties of atom C 4 can be mainly explained by orbital factors.  Reactions of CCl3-enone 1 with benzene under the action of various Brønsted and Lewis acids have also been conducted ( Table 3). The use of strong Lewis acids AlCl3 or AlBr3 yields complex mixtures of oligomeric materials (entries 1-3). Reaction in H2SO4 results in the formation of alcohol 3 as a product of hydration of the carbon-carbon double bond; no reaction with benzene occurs (entry 4). Reaction in Brønsted superacid CF3SO3H (triflic acid, TfOH) at room temperature for 5 days affords indene 2a in yields 29% (entry 7). Under other conditions (temperature and time) in CF3SO3H, the formation of 2a is unsatisfactory (entries 5,6,8,9), as is the reaction in stronger acid FSO3H at a low temperature of −78 C (entry 10). In weaker acids, CH3CO2H and CH3CO2H, the reaction does not take place (entries [11][12][13][14]. These data reveal that the formation of indene 2a in CF3SO3H is accompanied by cationic oligomerization processes, which leads to a decrease in the yield of the target compound. The formation of indene 2a points out that the starting compound 1 in CF3SO3H behaves as a precursor of the bi-centered electrophile, with reactive cationic centers on carbons C 2 and C 4 . Notes. a Global electrophilicity index ω = (E HOMO + E LUMO ) 2 /8(E LUMO − E HOMO ). b Natural charges. c Contribution of atomic orbital into the molecular orbital. d Gibbs energy of protonation reactions. Reactions of CCl3-enone 1 with benzene under the action of various Brønsted Lewis acids have also been conducted ( Table 3). The use of strong Lewis acids AlCl AlBr3 yields complex mixtures of oligomeric materials (entries 1-3). Reaction in H2 results in the formation of alcohol 3 as a product of hydration of the carbon-carbon dou bond; no reaction with benzene occurs (entry 4). Reaction in Brønsted superacid CF3SO (triflic acid, TfOH) at room temperature for 5 days affords indene 2a in yields 29% (en 7). Under other conditions (temperature and time) in CF3SO3H, the formation of 2a is satisfactory (entries 5, 6,8,9), as is the reaction in stronger acid FSO3H at a low temp ture of −78 C (entry 10). In weaker acids, CH3CO2H and CH3CO2H, the reaction does take place (entries [11][12][13][14]. These data reveal that the formation of indene 2a in CF3SO3H accompanied by cationic oligomerization processes, which leads to a decrease in the y of the target compound. The formation of indene 2a points out that the starting compou 1 in CF3SO3H behaves as a precursor of the bi-centered electrophile, with reactive catio centers on carbons C 2 and C 4 .  Reactions of CCl 3 -enone 1 with other arenes (o-, m-, p-xylenes, pseudocumene, and veratrole) in CF 3 SO 3 H, leading to indenes 2b-f, are presented in Scheme 2. These reactions with electron donating arenes take much less time (2 h only) at room temperature compared to the reaction with benzene (5 days, However, the same reactions with anisole (methoxybenzene) and 1,3-dimethoxy zene at room temperature for 2 h furnish compounds 4a,b as products of hydroaryla of the carbon-carbon double bond of starting CCl3-enone 1 (Scheme 3). Running thes actions at the higher temperature of 60 C does not lead to the consequent cyclizatio compounds 4a,b into the corresponding indenes 2. However, the same reactions with anisole (methoxybenzene) and 1,3-dimethoxybenzene at room temperature for 2 h furnish compounds 4a,b as products of hydroarylation of the carbon-carbon double bond of starting CCl 3 -enone 1 (Scheme 3). Running these reactions at the higher temperature of 60 • C does not lead to the consequent cyclization of compounds 4a,b into the corresponding indenes 2.

Visualization of LUMO of cation
Scheme 2. Reactions of CCl3-enone 1 with arenes in CF3SO3H leading to indenes 2b-f. However, the same reactions with anisole (methoxybenzene) and 1,3-dimethoxybenzene at room temperature for 2 h furnish compounds 4a,b as products of hydroarylation of the carbon-carbon double bond of starting CCl3-enone 1 (Scheme 3). Running these reactions at the higher temperature of 60 C does not lead to the consequent cyclization of compounds 4a,b into the corresponding indenes 2. The data obtained allow proposing plausible reaction mechanisms for transformations of CCl3-enone 1 in Brønsted acids (Scheme 4). The formation of compounds 4 reveals that the first interaction of arenes with cation A occurs at carbon C 4 of the latter, leading to species D. Hydrolysis of these cations affords compounds 4 (Scheme 3). In the case of electron donating aryl groups, cations D undergo intramolecular cyclization into species E. At this stage of the reaction, carbon C 2 acts as an electrophilic center. Finally, dehydration of E gives rise to indenes 2. Another reaction pathway takes place in H2SO4. The interaction of cation A with hydrosulfate anion HSO4 − affords species F, which is hydrolyzed into alcohol 3. We additionally examined the reaction of alcohol 3 with benzene in TfOH to obtain indene 2a. However, only a mixture of oligomeric materials was obtained, with no target indene 2a. In general, upon the formation of indenes 2, starting CCl3-enone 1 in CF3SO3H behaves as a precursor of 1,3-bi-centered electrophilic synthon. The data obtained allow proposing plausible reaction mechanisms for transformations of CCl 3 -enone 1 in Brønsted acids (Scheme 4). The formation of compounds 4 reveals that the first interaction of arenes with cation A occurs at carbon C 4 of the latter, leading to species D. Hydrolysis of these cations affords compounds 4 (Scheme 3). In the case of electron donating aryl groups, cations D undergo intramolecular cyclization into species E. At this stage of the reaction, carbon C 2 acts as an electrophilic center. Finally, dehydration of E gives rise to indenes 2. Another reaction pathway takes place in H 2 SO 4 . The interaction of cation A with hydrosulfate anion HSO 4 − affords species F, which is hydrolyzed into alcohol 3. We additionally examined the reaction of alcohol 3 with benzene in TfOH to obtain indene 2a. However, only a mixture of oligomeric materials was obtained, with no target indene 2a. In general, upon the formation of indenes 2, starting CCl 3 -enone 1 in CF 3 SO 3 H behaves as a precursor of 1,3-bi-centered electrophilic synthon. It should be especially emphasized that the development of routes for the synthesis of novel indene derivatives such as compounds 2 is a highly important goal for organic chemistry. Indenes are valuable molecules for medicinal uses [24][25][26]. They are widely exploited as ligands in organometallic chemistry [27][28][29][30][31], as structural units in molecular machines [32] and organic photovoltaics [33]. It should be especially emphasized that the development of routes for the synthesis of novel indene derivatives such as compounds 2 is a highly important goal for organic chemistry. Indenes are valuable molecules for medicinal uses [24][25][26]. They are widely exploited as ligands in organometallic chemistry [27][28][29][30][31], as structural units in molecular machines [32] and organic photovoltaics [33].

General Information
The NMR spectra of solutions of compounds in CDCl 3 and in acids (CH 3 COOH, CF 3 COOH, H 2 SO 4 , CF 3 SO 3 H) were recorded on a Bruker 400 spectrometer (Billerica, MA, USA) at 25 • C at 400 and 101 MHz for 1 H and 13 C NMR spectra, respectively. The residual proton-solvent peaks CDCl 3 (δ 7.26 ppm) for 1 H NMR spectra, and the carbon signals of CDCl 3 (δ 77.0 ppm) for 13 C NMR spectra were used as references. NMR spectra in acids were referenced to the signal of CH 2 Cl 2 added as internal standard: δ 5.30 ppm for 1 H NMR spectra, and δ 53.52 ppm for 13 C NMR spectra. HRMS-APCI was carried out using the instruments Bruker maXis HRMS-ESI-QTOF (Billerica, MA, USA). Preparative TLC was performed on silica gel 5−40 µm (Merck Co., Kenilworth, NJ, USA) with petroleum ether or petroleum ether-ethyl acetate mixture elution.

DFT Calculations
All computations were carried out at the DFT/HF hybrid level of theory using hybrid exchange functional B3LYP, by using GAUSSIAN 2009 program packages [34]. The geometries optimization was performed using the 6-311+G(2d,2p) basis set (standard 6-311G basis set added with polarization (d,p) and diffuse functions). Optimizations were performed on all degrees of freedom and solvent-phase optimized structures were verified as true minima with no imaginary frequencies. The Hessian matrix was calculated analytically for the optimized structures in order to prove the location of correct minima and to estimate the thermodynamic parameters. For solvent-phase calculations, the Polarizable Continuum Model (PCM, solvent=water) was used.

Preparation and Characterization of Compounds 1-4
First, E-5,5,5-trichloropent-3-en-2-one 1 was obtained in a yield of 83% according to the procedure shown in the literature [35]. Yellow oil. 1  The general procedure for the synthesis of indenes 2, compounds 3 and 4 from E-5,5,5-trichloropent-3-en-2-one 1 and arenes in CF 3 SO 3 H. Solution of compound 1 (50 mg, 0.27 mmol) and arene (1.2 equiv., 0.320 mmol) in 2 mL of CF 3 SO 3 H involved stirring at room temperature for 2 h (or other temperature and time, see Table 3 and Scheme 3). Then, the reaction mixture was poured into water (25 mL) and extracted with CH 2 Cl 2 (3 × 20 mL). Combined extract was washed with water (20 mL), saturated aqueous solution of NaHCO 3 (10 mL), water again (20 mL), and dried over Na 2 SO 4 . The solvent was distilled off under a reduced pressure. The residue was subjected to preparative TLC using petroleum ether or petroleum ether-ethyl acetate mixtures (20:1, vol.) as eluent.
Reactions under the action of other Brønsted (H 2 SO 4 , FSO 3 H) and Lewis (AlCl 3 and AlBr 3 , 5 equiv. in 5 mL of benzene) acids were carried out in the same way (Table 1).