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.


Introduction
Acetylene compounds are of great importance for chemistry, biology, medicine, materials science, and other fields of science and technology [1][2][3][4][5][6][7][8][9][10][11]. Fluorinated acetylene derivatives are useful building blocks in organic synthesis for the preparation of new substances and materials with valuable practical properties. The presence of fluorine atoms in organic compounds gives the compounds unique characteristics, such as high lipophilicity and biological activity, heat resistance, nonlinear optical and liquid crystal properties, and so forth [12][13][14][15][16]. Synthesis of new organofluorine derivatives is an actual goal of modern organic chemistry.
Based on our work on the electrophilic activation of unsaturated compounds (alkynes, alkenes, allenes) [36], we undertook a special study on the transformation of To estimate the electronic characteristics of the initial intermediates A and B of these reactions, DFT (density functional theory) calculations of species Aa and Ba (B′a↔B″a) derived at the protonation of alcohol 1a were carried out ( Table 1). Energies of the HOMO (highest occupied molecular orbital) and LUMO (lowest unoccupied molecular orbital), charge distribution, the contribution of the atomic orbitals into the molecular orbital, and the global electrophilicity index ω [37,38] were calculated. The calculations show that species Ba should be a rather active electrophile, Scheme 1. Plausible mechanisms of acid-promoted reactions of CF 3 -alcohols 1 with arenes.
Another reaction pathway is the reaction of the arene with species B onto its electrophilic carbon C 4 , which affords allene 2. Protonation of the latter gives the mesomeric allyl cation C ↔C . Species C Molecules 2018, 23, 3079 3 of 21 may be cyclized into both rings Ar and Ar, leading to indenes 4 and 5, respectively (way b). One more possible pathway for this allyl cation is cyclization through its resonance form C , giving rise to indene 6 (way c).
To estimate the electronic characteristics of the initial intermediates A and B of these reactions, DFT (density functional theory) calculations of species Aa and Ba (B a↔B a) derived at the protonation of alcohol 1a were carried out ( Table 1). Energies of the HOMO (highest occupied molecular orbital) and LUMO (lowest unoccupied molecular orbital), charge distribution, the contribution of the atomic orbitals into the molecular orbital, and the global electrophilicity index ω [37,38] were calculated. The calculations show that species Ba should be a rather active electrophile, since it is characterized by a large value of the electrophilicity index ω, of 7.59 e, compared to species Aa, with ω of 3.92 e. The cation Aa has a large positive charge of 1.00 e on carbon C 2 . This carbon gives a large contribution into the LUMO of 13.2%. This proves that carbon C 2 in the species Aa is an electrophilic reactive center according to both charge and orbital factors. To estimate the electronic characteristics of the initial intermediates A and B of these reactions, DFT (density functional theory) calculations of species Aa and Ba (B′a↔B″a) derived at the protonation of alcohol 1a were carried out ( Table 1). Energies of the HOMO (highest occupied molecular orbital) and LUMO (lowest unoccupied molecular orbital), charge distribution, the contribution of the atomic orbitals into the molecular orbital, and the global electrophilicity index ω [37,38] were calculated. The calculations show that species Ba should be a rather active electrophile, since it is characterized by a large value of the electrophilicity index ω, of 7.59 e, compared to species Aa, with ω of 3.92 e. The cation Aa has a large positive charge of 1.00 e on carbon C 2 . This carbon gives a large contribution into the LUMO of 13.2%. This proves that carbon C 2 in the species Aa is an electrophilic reactive center according to both charge and orbital factors.
Contrary to that, the cation Ba has a larger positive charge, of 0.23, on carbon C 4 . However, carbon C 2 gives a larger contribution into the LUMO, of 28.5%. This suggests that in this species, the electrophilic reactivity of the atom C 4 is ruled under charge control, but the reactivity of the atom C 2 may be explained by orbital control.  To estimate the electronic characteristics of the initial intermediates A and B of these reactions, DFT (density functional theory) calculations of species Aa and Ba (B′a↔B″a) derived at the protonation of alcohol 1a were carried out ( Table 1). Energies of the HOMO (highest occupied molecular orbital) and LUMO (lowest unoccupied molecular orbital), charge distribution, the contribution of the atomic orbitals into the molecular orbital, and the global electrophilicity index ω [37,38] were calculated. The calculations show that species Ba should be a rather active electrophile, since it is characterized by a large value of the electrophilicity index ω, of 7.59 e, compared to species Aa, with ω of 3.92 e. The cation Aa has a large positive charge of 1.00 e on carbon C 2 . This carbon gives a large contribution into the LUMO of 13.2%. This proves that carbon C 2 in the species Aa is an electrophilic reactive center according to both charge and orbital factors.
Contrary to that, the cation Ba has a larger positive charge, of 0.23, on carbon C 4 . However, carbon C 2 gives a larger contribution into the LUMO, of 28.5%. This suggests that in this species, the electrophilic reactivity of the atom C 4 is ruled under charge control, but the reactivity of the atom C 2 may be explained by orbital control. Thus, there are three main pathways, a, b, and c, for the reactions of CF3-propargyl alcohols with arenes, proceeding through various cationic intermediates which may lead to various CF3-indenes Contrary to that, the cation Ba has a larger positive charge, of 0.23, on carbon C 4 . However, carbon C 2 gives a larger contribution into the LUMO, of 28.5%. This suggests that in this species, the electrophilic reactivity of the atom C 4 is ruled under charge control, but the reactivity of the atom C 2 may be explained by orbital control.
Thus, there are three main pathways, a, b, and c, for the reactions of CF 3 -propargyl alcohols with arenes, proceeding through various cationic intermediates which may lead to various CF 3 -indenes (Scheme 1). A key point in this reaction mechanism is a possible dual reactivity of propargyl cations B (B ↔B ), which may finally lead to different indene structures.
To determine the dependence of the reaction pathway on the substituents in the aromatic rings in alcohols 1 and arenes, starting substrates containing various donor and acceptor substituents in aryl moieties were investigated in these reactions.
First, we conducted reactions of alcohol 1a with benzene under the action of different Brønsted and Lewis acids (Table 2). In all cases, indene 4aa was obtained. However, a better result with the highest yield of 4aa was achieved for the reaction with the use of 1.5 equivalents of trifluoromethanesulfonic acid CF 3 SO 3 H (triflic acid, TfOH) at room temperature for 1 h (entry 3, Table 2). Table 2. Acid-promoted reaction of 1a with benzene.
In principle, the structures of the target indenes 4, 5, and 6 reveal the reaction pathway of their formation (ways a, b, c in Scheme 1) and key intermediates of these transformations (A, B, C, and D in Scheme 1). These data are shown in Tables 3-7 for every reaction. In some cases, it is not possible to unequivocally distinguish the reaction pathways based only on the structures of the compounds obtained. However, many reactions clearly point out the mechanism of the formation of the final products.
In almost all cases for the reactions of alcohols 1 with p-xylene, indenes of the general structure4b were obtained (Table 4). These compounds may be formed bywaya through the vinyl cation D or wayb through the cation C′ (Scheme 1).  In almost all cases for the reactions of alcohols 1 with p-xylene, indenes of the general structure4b were obtained (Table 4). These compounds may be formed bywaya through the vinyl cation D or wayb through the cation C′ (Scheme 1). Table 4.TfOH-promoted reaction of 1 with p-xylene; reaction conditions: TfOH, CH2Cl2, molar ratio of 1:p-xylene:TfOH = 1:1.1:1.5, room temperature, 1 h. In almost all cases for the reactions of alcohols 1 with p-xylene, indenes of the general structure4b were obtained (Table 4). These compounds may be formed bywaya through the vinyl cation D or wayb through the cation C′ (Scheme 1). Table 4.TfOH-promoted reaction of 1 with p-xylene; reaction conditions: TfOH, CH2Cl2, molar ratio of 1:p-xylene:TfOH = 1:1.1:1.5, room temperature, 1 h.    Based on the structure of the reaction products 4c and 5c obtained from alcohols 1 and m-xylene (Table 5),one may assume that in all cases, them-xylene lecule is attacked by the electrophilic center C 4 of species B″, which leads to the formation of the corresponding indenes in wayb (Scheme 1). The presence of tron-withdrawing substituents in the aryl ring at the atom C 4 prevents electrophilic substitution into this ring, and only indenes 4ci-4cm were isolated (entries 12, 15, 16). Based on the structure of the reaction products 4c and 5c obtained from alcohols 1 and m-xylene (Table 5),one may assume that in all cases, them-xylene olecule is attacked by the electrophilic center C 4 of species B″, which leads to the formation of the corresponding indenes in wayb (Scheme 1). The presence of lectron-withdrawing substituents in the aryl ring at the atom C 4 prevents electrophilic substitution into this ring, and only indenes 4ci-4cm were isolated (entries 0-12, 15, 16). Based on the structure of the reaction products 4c and 5c obtained from alcohols 1 and m-xylene (Table 5),one may assume that in all cases, them-xylene lecule is attacked by the electrophilic center C 4 of species B″, which leads to the formation of the corresponding indenes in wayb (Scheme 1). The presence of tron-withdrawing substituents in the aryl ring at the atom C 4 prevents electrophilic substitution into this ring, and only indenes 4ci-4cm were isolated (entries 12, 15, 16). Based on the structure of the reaction products 4c and 5c obtained from alcohols 1 and m-xylene (Table 5),one may assume that in all cases, them-xylene olecule is attacked by the electrophilic center C 4 of species B″, which leads to the formation of the corresponding indenes in wayb (Scheme 1). The presence of lectron-withdrawing substituents in the aryl ring at the atom C 4 prevents electrophilic substitution into this ring, and only indenes 4ci-4cm were isolated (entries 0-12, 15, 16).      actions of alcohols 1 with electron-rich pseudocumene afforded two types of indene structures,4d and 4e, formed by electrophilic substitution onto the cumene moiety only (Table 6). Taking into account that the most active position for electrophilic attack in the pseudocumene molecule is the atom C 5  Reactions of alcohols 1 with electron-rich pseudocumene afforded two types of indene structures,4d and 4e, formed by electrophilic substitution onto the documene moiety only (Table 6). Taking into account that the most active position for electrophilic attack in the pseudocumene molecule is the atom C 5 and the first reaction occurs in this particular position, one may propose that indenes 4da-do are formed in wayb through cations B″ and C′, and indenes 4ea-4eoin through cations A (or B′)and D (see Scheme 1). The structures of compounds 4d and 4e and positions of the methyl groups in the indene core were rmined by H,H and H,F NOESY correlations between the methyl substituents, CF3 group, and aromatic indene protons (see theSupporting Information). actions of alcohols 1 with electron-rich pseudocumene afforded two types of indene structures,4d and 4e, formed by electrophilic substitution onto the cumene moiety only (Table 6). Taking into account that the most active position for electrophilic attack in the pseudocumene molecule is the atom C 5  Reactions of alcohols 1 with electron-rich pseudocumene afforded two types of indene structures,4d and 4e, formed by electrophilic substitution onto the udocumene moiety only (Table 6). Taking into account that the most active position for electrophilic attack in the pseudocumene molecule is the atom C 5 and t the first reaction occurs in this particular position, one may propose that indenes 4da-do are formed in wayb through cations B″ and C′, and indenes 4ea-4eoin ya through cations A (or B′)and D (see Scheme 1). The structures of compounds 4d and 4e and positions of the methyl groups in the indene core were ermined by H,H and H,F NOESY correlations between the methyl substituents, CF3 group, and aromatic indene protons (see theSupporting Information). actions of alcohols 1 with electron-rich pseudocumene afforded two types of indene structures,4d and 4e, formed by electrophilic substitution onto the cumene moiety only (Table 6). Taking into account that the most active position for electrophilic attack in the pseudocumene molecule is the atom C 5 and first reaction occurs in this particular position, one may propose that indenes 4da-do are formed in wayb through cations B″ and C′, and indenes 4ea-4eoin hrough cations A (or B′)and D (see Scheme 1). The structures of compounds 4d and 4e and positions of the methyl groups in the indene core were ined by H,H and H,F NOESY correlations between the methyl substituents, CF3 group, and aromatic indene protons (see theSupporting Information). Reactions of alcohols 1 with electron-rich pseudocumene afforded two types of indene structures,4d and 4e, formed by electrophilic substitution onto the udocumene moiety only (Table 6). Taking into account that the most active position for electrophilic attack in the pseudocumene molecule is the atom C 5 and t the first reaction occurs in this particular position, one may propose that indenes 4da-do are formed in wayb through cations B″ and C′, and indenes 4ea-4eoin ya through cations A (or B′)and D (see Scheme 1). The structures of compounds 4d and 4e and positions of the methyl groups in the indene core were ermined by H,H and H,F NOESY correlations between the methyl substituents, CF3 group, and aromatic indene protons (see theSupporting Information).                  Summarizing the data obtained on the TfOH-promoted reactions of CF3-propargyl alcohols 1 with different arenes, leading to CF3-indenes (Tables 3-7), one may conclude that these indenes may be formed in several reaction pathways (Scheme 1), depending on the structures of the starting alcohol 1 and the nucleophilicity of the arene. Key intermediates of these reactions are o-protonated forms A of the alcohols and the mesomeric propargyl cations B (B′↔B″) generated from alcohols 1 in acidic media (see Scheme 1). Most probably, reactions with electron-rich arenes, pseudocumene (Table 6), and veratrole (Table 7) may proceed through cations A (waya in Scheme 1), which are sufficientlyelectrophilic (see data on DFT calculations in Table 2) to react with such donating arenes. Reactions with other less nucleophilic arenes, benzene, and xylenes (Tables 3-5) may go both in waya and b (Scheme 1) due to the dual reactivity of the propargyl cation B. However, wayb through the allenyl resonance form B″ may be more preferable; see the reactions with m-xylene that proceed mainly in this way ( Table 5). Construction of the indene core at the final stages of the reaction depends on the nucleophilicity of the aryl rings Ar, Ar′, and Ar″ in the intermediate species C and D. Electrophilic cyclization takes place in the more-donating aromatic moiety. In almost all cases for the reactions of alcohols 1 with p-xylene, indenes of the general structure4b were obtained (Table 4). These compounds may be formed bywaya through the vinyl cation D or wayb through the cation C′ (Scheme 1). Table 4.TfOH-promoted reaction of 1 with p-xylene; reaction conditions: TfOH, CH2Cl2, molar ratio of 1:p-xylene:TfOH = 1:1.1:1.5, room temperature, 1 h. In principle, the structures of the target indenes 4, 5, and 6 reveal the reaction pathway of their formation (ways a, b, c in Scheme 1) and key intermediates of these transformations (A, B, C, and D in Scheme 1). These data are shown in Tables 3-7 for every reaction. In some cases, it is not possible to unequivocally distinguish the reaction pathways based only on the structures of the compounds obtained. However, many reactions clearly point out the mechanism of the formation of the final products.
The data in Table 3 show that for alcohols 1 having phenyl or aryl rings with acceptor groups at the acetylene bond, the only reaction products are indenes of the general structure 4a, obtained as a result of cyclization into a phenyl ring (entries 1-3, 5-8, 12-14, 17, and 18). These compounds may be formed via pathway a or b (Scheme 1).
Alcohols 1 bearing donor methyl groups in the aryl substituent at the triple bond react with benzene to form a mixture of indenes of types of 4a and 5a. The latter is the main reaction product (entries 9-11). Compounds 5a are formed at the cyclization into the electron-rich aryl ring (not into the phenyl one) at carbon C 4 in cations C (way a, Scheme 1).
Alcohol 1d, with a 3,4-dimethylphenyl ring at carbon C 2 , additionally gave indenes 6a and 6b, which were formed by way c only (see Scheme 1).
Alcohol 1a in reaction with o-xylene afforded indene 5ac (Scheme 2). Again, one may propose two possible directions for the formation of this compound: way a or b (see Scheme 1).
In almost all cases for the reactions of alcohols 1 with p-xylene, indenes of the general structure 4b were obtained (Table 4). These compounds may be formed by way a through the vinyl cation D or way b through the cation C (Scheme 1).
Additional proof for the proceeding of the reaction of alcohol 1n with p-xylene in way b was the isolation of allene 2a, which then was transformed into indene 4bm in TfOH (Scheme 3). Additional proof for the proceeding of the reaction of alcohol 1n with p-xylene in way b was the isolation of allene 2a, which then was transformed into indene 4bm in TfOH (Scheme 3). Based on the structure of the reaction products 4c and 5c obtained from alcohols 1 and m-xylene (Table 5),one may assume that in all cases, them-xylene molecule is attacked by the electrophilic center C 4 of species B″, which leads to the formation of the corresponding indenes in wayb (Scheme 1). The presence of electron-withdrawing substituents in the aryl ring at the atom C 4 prevents electrophilic substitution into this ring, and only indenes 4ci-4cm were isolated (entries 10-12, 15, 16). Based on the structure of the reaction products 4c and 5c obtained from alcohols 1 and m-xylene (Table 5), one may assume that in all cases, the m-xylene molecule is attacked by the electrophilic center C 4 of species B , which leads to the formation of the corresponding indenes in way b (Scheme 1). The presence of electron-withdrawing substituents in the aryl ring at the atom C 4 prevents electrophilic substitution into this ring, and only indenes 4ci-4cm were isolated (entries 10-12, 15, 16).
Reactions of alcohols 1 with electron-rich pseudocumene afforded two types of indene structures, 4d and 4e, formed by electrophilic substitution onto the pseudocumene moiety only (Table 6). Taking into account that the most active position for electrophilic attack in the pseudocumene molecule is the atom C 5 and that the first reaction occurs in this particular position, one may propose that indenes 4da-do are formed in way b through cations B and C , and indenes 4ea-4eo in way a through cations A (or B ) and D (see Scheme 1). The structures of compounds 4d and 4e and positions of the methyl groups in the indene core were determined by H,H and H,F NOESY correlations between the methyl substituents, CF 3 group, and aromatic indene protons (see the Supporting Information).
Surprisingly, reactions of alcohols 1 with veratrole yielded mixtures of alkyne 3 and indene 4f. Moreover, treatment of alkyne 3 with TfOH (1.5 eq.) in CH 2 Cl 2 at room temperature for 1 h gave indene 4f. This data unambiguously proves that reactions with veratrole proceed in way a with the participation of cations A (or B ) and D (see Scheme 1).
Summarizing the data obtained on the TfOH-promoted reactions of CF 3 -propargyl alcohols 1 with different arenes, leading to CF 3 -indenes (Tables 3-7), one may conclude that these indenes may be formed in several reaction pathways (Scheme 1), depending on the structures of the starting alcohol 1 and the nucleophilicity of the arene. Key intermediates of these reactions are o-protonated forms A of the alcohols and the mesomeric propargyl cations B (B ↔B ) generated from alcohols 1 in acidic media (see Scheme 1). Most probably, reactions with electron-rich arenes, pseudocumene (Table 6), and veratrole (Table 7) may proceed through cations A (way a in Scheme 1), which are sufficiently electrophilic (see data on DFT calculations in Table 2) to react with such donating arenes. Reactions with other less nucleophilic arenes, benzene, and xylenes (Tables 3-5) may go both in way a and b (Scheme 1) due to the dual reactivity of the propargyl cation B. However, way b through the allenyl resonance form B may be more preferable; see the reactions with m-xylene that proceed mainly in this way ( Table 5). Construction of the indene core at the final stages of the reaction depends on the nucleophilicity of the aryl rings Ar, Ar , and Ar" in the intermediate species C and D. Electrophilic cyclization takes place in the more-donating aromatic moiety.
It should be noted that many of the reactions studied lead to the exclusive formation of only one of CF 3 -indene 4 or 5 in good yields. Such CF 3 -indenes are rather rare substrates, and there are only a few reports on their synthesis [39][40][41][42][43][44].

Conclusions
We have studied, for the first time, reactions of diaryl-substituted CF 3 -propargyl alcohols with arenes under the action of the superacid TfOH. The reaction proceeds through the intermediate formation of several cationic species, which finally lead to the formation of the synthetically hardly available 1,3-diaryl-1-CF 3 -indenes.