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.

Based on our previous works on reactions of cinnamides [24] and 5-styryl-2H-tetrazoles [25] with arenes under superelectrophilic activation with Brønsted or Lewis superacids, we turned our attention towards the hydroarylation of the C=C double bond in 5-styryl-substituted oxadiazoles, such as (E)-5-(2-arylethenyl)-3-aryl-1,2,4-oxadiazoles 1 (Scheme 1). The main goals of the current work were to investigate the reactions of oxadiazoles 1 with different arenes under the conditions of superelectrophilic activation and to study protonated forms of the oxadiazoles as reactive intermediates by means of NMR and DFT calculations.
It should be noted, that the metal-catalyzed hydroarylation of C=C bonds is widely used in organic synthesis [26,27]. The most efficient catalysts for these purposes are complexes of the transition metals Pt [28], Au [29], Ru [30], Rh [31][32][33], Ni [34], Pd [35], and Pd/Ag [36]. However, a metal-free hydroarylation variant of C=C bonds under the action of Brønsted or Lewis superacids has been developed [37,38] and we were able to extend the scope of this reaction [24,25].
The expected reaction products, oxadiazoles 2 (Scheme 1) are structurally close to many biologically active compounds and drugs [39][40][41][42][43][44][45][46][47][48][49], which contain a chain of three carbon atoms, two aryl rings on one end of this chain, and further functional groups on the other end of it ( Figure 2, compare also with libexin in Figure 1). One may suppose that compounds of type 2 having the same structural fragments, i.e., three carbon atoms (one of them part of the oxadiazole moiety), two aryl groups, and the four remaining atoms of the oxadiazole ring, as a functional group, may also show biological activity. Thus, the synthesis of these particular 5-(2,2-diarylethyl)-substituted oxadiazoles 2 may be interesting for medicinal chemistry.

Results and Discussion
According to literature data [50,51] the protonation of a 1,2,4oxadiazole ring takes place mainly at the N 4 nitrogen. However, also the N 2 nitrogen may be protonated depending on the substituents attached to the heterocyclic system [50]. To investigate this issue in more detail we undertook a theoretical study on the protonation of 5-(2-phenylethenyl)-3-phenyl-1,2,4-oxadiazole (1a) by quantum-chemical calculations. Table 1 contains data obtained by DFT calculations for the different possible mono-, di-and tricationic species A-F derived from the protonation of 1a. Charge distributions, contributions of the atomic orbital into LUMO, global electrophilicity indices ω [52,53], Species Negative values for ΔG 298 of the first protonation step show that this reaction is energetically favorable at both N 2 (formation of species A) and N 4 (formation of species C). A further protonation may occur at the second nitrogen atom of the oxadiazole system (formation of dication E) or at the carbon C α of the side chain C=C double bond (formation of dications B or D). Finally, the third protonation giving rise to trication F is rather high in energy (ΔG 298 121 kJ/mol for E→F) and therefore highly unlikely. Also the outlined route leading to species species E had an imaginary frequency revealing that it may be a transition state rather than an intermediate species.
Thus, from a thermodynamic point of view, the first protonation of 5-styryl-substituted 1,2,4-oxadiazoles takes place at the N 4 nitrogen atom leading to cation C (ΔG 298 of this reaction has the lowest value of −59.2 kJ/mol) and the most probable dicationic species, obtained through protonation of species C, should be N 4 ,C-diprotonated form D.
The calculated electronic characteristics of species A-F revealed that the dication D has the highest electrophilicity index ω (7.48 eV) among the other cationic species, even including trication F (Table 1). Therefore, dication D is expected to be an extremely reactive electrophile. Moreover, it has a large portion of the positive charge (0.18 e) located at the C β carbon atom and a high contribution to the LUMO (37.3%), thus making this carbon atom a reactive electrophilic center through charge and orbital control. One may not exclude that N 2 -and N 4 -monoprotonated forms A and C, respectively, also may behave as electrophiles. However, the calculated negative charges on the C β carbon atoms may prevent a chemical transformation on them.
Summarizing the calculation results, one may conclude that the most probable reactive electrophilic species, derived through the protonation of 5-styryl-substituted 1,2,4-oxadiazoles, is the N 4 ,C-diprotonated species D from both the thermodynamic and electronic point of view.
Next, we carried out an NMR study of the protonation of oxadiazoles 1a and 1m in the superacid FSO 3 H at low temperature (−80 °C). The spectra are shown in Supporting Information File 1. Upon dissolving compounds 1a and 1m in fluorosulfonic acid, FSO 3 H in an NMR tube at −80 °C, the formation of N 4 -protonated species Ca and Cm, respectively, was detected ( Figure 3). The proton bounded to nitrogen N 4 resonates at δ ≈ 12.5-13 ppm at this temperature whereas at higher temperature (above −40 °C) this signal disappeared due to fast proton exchange with the superacidic medium (see Supporting Information File 1). The addition of the proton at the N 4 position, rather than at N 2 , was proved by the NOESY correlation between this proton and the vinyl proton H α (Figure 3). In the case of a protonation at N 2 , there should not be any correlation between the proton attached to N 2 and H α . The assignment of all signals in the 1 H and 13 C NMR spectra of cations Ca and Cm was undertaken on the basis of 1 H-13 C HSQC and 1 H-15 N HSQC spectra (see spectra in Supporting Information File 1). According to the NMR study and preparative experiments, the increasing reaction temperature in trifluoromethanesulfonic acid (TfOH, to 60 °C for 1a, and to room temperature for 1m) led to the formation of oligomeric material. Most likely, at higher temperature the second protonation at the C=C bond takes place giving rise to the corresponding unstable highly reactive dications D, which were not detected by NMR.
Thus, the NMR data reveal that the protonation of 5-styrylsubstituted 1,2,4-oxadiazoles in superacids results in the formation of their relatively stable N 4 -protonated forms. However, these species do not react with aromatic π-nucleophiles (vide infra). Most probably, those reactive intermediates, generated under the protonation of substrates 1, are N 4 ,C-diprotonated species D.
The experimental results from the hydroarylation reactions of the side chain C=C double bond of oxadiazoles 1a-n with various arenes under the action of different acidic reagents leading to oxadiazoles 2a-za are shown in Table 2 (see also X-ray structures of 2a and 2m in Figure 4). First, it should be emphasized that no reaction is observed under the conditions of generation of monoprotonated species C (see Table 1, and Figure 3). Thus, in FSO 3 H at low temperature (−80 to −60 °C) compounds 1e (Table 2, entries 14 and 15) and 1m ( Table 2, entry 29) do not react with benzene. At higher temperature, fluorosulfonation of the aromatic ring is observed, especially with donating arenes (see example of this reaction in our work [24]). On the other hand, compounds 1e and 1m readily react with benzene in TfOH at room temperature (see Table 2, entries 16 and 28). Presumably, at higher temperatures the second protonation takes place at the C=C double bond giving rise to reactive dications D. The acidity of H 2 SO 4 , which is lower than that of FSO 3 H and TfOH, is not sufficient to promote this reaction. Thus, the protonation of the C=C bond of 1a in H 2 SO 4 does not take place even at elevated temperature (75 °C, see Table 2, entry 1). Also, Lewis acids such as AlCl 3 and AlBr 3 are not effective in this transformation ( Table 2, entries 2 and 3). The best results were obtained in neat TfOH.
The substituents present in the aromatic ring of the styryl group of oxadiazoles 1 play a crucial role for the protonation and reactivity of these compounds. Thus, styryl-substituted oxadiazoles     double bond, resulting in a reduced reaction time to 1-2 h at room temperature (Table 2, entries 13, 16, 27, 28, and 30).
Increasing the acidity of the reaction medium promotes the protonation of deactivated oxadiazoles. Thus, compound 1b in the system TfOH-SbF 5 (20 mol %) reacted with benzene within 0.5 h at room temperature ( Table 2, entry 9), but in less Different arenes may be involved in this reaction. The corresponding hydroarylation products were obtained by reaction with benzene, chlorobenzene, 1,2-dichlorobenzene, toluene, and anisole. Electron-rich polymethylated aromatics, such as isomeric xylenes, mesitylene, pseudocumene, or durene gave mixtures of oligomeric products. Probably, these products are formed through multiple electrophilic substitution reactions of these arenes by the reactive dication species D. When oxadiazole 1b reacted with tert-butylbenzene ( Table 2, entry 10), product 2f lacking the tert-butyl group was isolated. In this case, an ipso-substitution of the tert-butyl group by a proton under the superacidic conditions took place. Reactions with some arenes gave regioisomeric products, for instance, anisole (2o + 2p, Table 2, entry 20), 1,2-dichlorobenzene (2d + 2e, Additionally, the reactions were carried out under microwave (MW) irradiation (Table 3) analogously to our recent study on the hydroarylation of styryl tetrazoles [25]. Indeed, under MW activation the reactions in TfOH proceeded within 5-20 min at 120 °C (Table 3, entries 4-9) with formation of oxadiazoles 2 in high yields (compare the yields under thermal and MW heating in Table 3). The MW-activated process without any acid ( Table 3, entry 1) or in a weaker acid (H 2 SO 4 , Table 3, entry 2) did not proceed at all. Apart from that, the conversion of 1a in the presence of AlCl 3 was rather low (Table 3, entry 3). It should be emphasized that the oxadiazole ring is stable under the superacidic conditions and no destruction was noticed.

Supporting Information
Supporting Information File 1 Experimental part, NMR spectra and DFT calculations.