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.

Based on our previous works on the chemistry of 1,2,4-oxadiazoles in superacids [24,25], we undertook this study on further investigation of the transformations of these heterocyclic compounds in electrophilic media. The main goals of this work were the synthesis of 5-arylacetylenyl-1,2,4-oxadiazoles and the study of their reactions with/without arenes under the conditions of superelectrophilic activation by the Brønsted superacid CF 3 SO 3 H (TfOH), the strong Lewis acids AlX 3 (X = Cl, Br), or the acidic zeolite CBV-720.

Results and Discussion
The synthesis of 5-arylethynyl-1,2,4-oxadiazoles 3 was based on transformations of the corresponding 5-styryloxadiazoles, i.e., 5-(2-arylethenyl)-3-aryl-1,2,4-oxadiazoles 1a-g (Scheme 1). Bromination of the side chain carbon-carbon double bond in oxadiazoles 1a-g led to pairs of diastereomers of dibromo derivatives 2a-g. Then, several bases were tested for the di-dehydrobromination of compounds 2a-g. However, treatment of 2a-g in the following systems, KOH-EtOH (reflux, 2 h), BuLi-THF (−40 °C, 2 h), t-BuOK-THF (reflux, 2 h), or LiN(iPr) 2 -THF (−40 °C, 2 h), afforded complex mixtures of reaction products without desired acetylenyloxadiazoles 3. We succeeded to get compounds 3a-e by the reaction of 2a-e with sodium amide in liquid ammonia [NaNH 2 -NH 3 (liq.)] only at low temperature −70 to −60 °C (Scheme 1). However, the yields of target compounds were moderate 32-54% (for 3a-c,e) or even low 9% (for 3d). Running this reaction at higher temperature -50 to -40 °C led to a decrease of the yields of compounds 3. Apart from that, compounds 2f,g containing a 3-para-bromophenyl moiety in the heterocyclic core gave no corresponding 5-acetylenyloxadiazoles 3 in the system NaNH 2 -NH 3 (liq.), only mixtures of oligomeric materials were formed. Moreover, compound 3e was obtained as an inseparable mixture with styryloxadiazole 1e. The latter may be formed from 3e under the reduction by the solution that contained NaNH 2 . All these data point out the instability of 5-acetylenyloxadiazoles 3 in strong basic and nucleophilic media. Oxadiazoles 3, which were initially formed from compounds 2 in the system NaNH 2 -NH 3 (liq.), underwent further secondary transformations under nucleophilic reaction conditions, even at very low temperature -70 to -60 °C, that resulted in low to moderate yields of the target acetylene derivatives.
Then, electrophilic reactions of 5-acetylenyloxadiazoles 3a-d in different acids were studied. In our recent study on the electrophilic activation of 5-styryl-1,2,4-oxadiazoles 1 [24], it was shown by means of NMR spectroscopy and DFT calculation that the protonation of these oxadiazoles in Brønsted superacids Table 1: Selected electronic characteristics for cations Aa-d and Ba-d calculated by DFT from protonation of oxadiazoles 3a-d.

Species
E HOMO , eV TfOH and FSO 3 H gave reactive N,C-diprotonated species. The protonation of oxadiazoles 1 takes place at the nitrogen N4 and the α-carbon of the side chain C=C bond. One would expect the formation of similar dications at the protonation of acetylenyloxadiazoles 3 in Brønsted superacids (see Table 1). Table 1 contains data on DFT calculations of cations Aa-d (N-protonated forms) and Ba-d (N,C-diprotonated forms) derived at the protonation of oxadiazoles 3a-d. Charge delocalization, contribution of atomic orbital into LUMO, global electrophilicity indices ω [26,27], and Gibbs free energies of protonation reactions with hydroxonium ion (H 3 O + ) ΔG 298 were calculated.
Big negative values of ΔG 298 (−86.6 to −79.2 kJ/mol) of the first protonation step show that the formation of N-protonated  A and B), the capture of the diaction B by a nucleophile is likely to be very exergonic and this can drive the reaction through to the products. Calculated electronic characteristic of these dications reveal their high electrophilicity, the indexes ω are 6.1-8.4 eV. Carbon C β bears a large positive charge (0.40-0.47 e) and gives a big contribution into LUMO (16.7-30%), pointing out that this carbon is a reactive electrophilic center by charge and orbital factors.
Thus, according our previous data on reactions of 5-styryl-1,2,4-oxadiazoles 1 [24] and results of the DFT calculations for protonation of 5-acetylenyl-1,2,4-oxadiazoles 3 (Table 1) We also checked the reaction of oxadiazole 3a with benzene under the action of Lewis acids AlCl 3 , AlBr 3 and acidic zeolite CBV-720 (Table 2). However, these Lewis acids showed unsatisfactory results leading to oligomeric materials ( Table 2, entries 1 and 2). Probably, due to some secondary reactions of the formed compound 5a with AlCl 3 , AlBr 3 . The yield of target compound 5a in the reaction with zeolite was lower than in the same reaction in TfOH (compare entry 3 in Table 2 with data shown in Scheme 5). Thus, among the tested acidic reagents, TfOH showed better results for the hydroarylation of compounds 3.
Additionally, the reaction of oxadiazole 3a with benzene in TfOH (rt, 1 h) in the presence of cyclohexane, as a hydride ion source, was conducted to achieve the ionic hydrogenation of intermediate cationic species. However, no products of ionic hydrogenation were obtained, only the product of the hydrophenylation of the acetylene bond 5a was quantitatively isolated (compare with data shown in Scheme 5).