Synthesis of 5-arylacetylene 1,2,4-oxadiazoles and their transformations under superelectrophilic activation conditions

Acetylene derivatives of 1,2,4-oxadiazoles, 5-(2-arylethynyl)-3-aryl-1,2,4-oxadiazoles, have been obtained, for the first time, 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. Reaction of the acetylene 1,2,4-oxadiazoles with arenes in neat triflic acid TfOH (CF3SO3H) at room temperature for 1 h result in the formation of E-/Z-5-(2,2-diarylethenyl)-3-aryl-1,2,4oxadiazoles as products of regioselective hydroarylation of the acetylene bond. Addition of TfOH to acetylene bond of these oxadiazoles gives rise quantitatively to E-/Z-vinyl triflates. Reaction cationic intermediates have been studied by DFT calculations. The reaction mechanisms have been discussed.

Based on our previous works on chemistry of 1,2,4-oxadiazoles in superacids [26, 27], we undertook this study on further investigation of transformations of these heterocyclic compounds in electrophilic media. The main goals of this work were synthesis of 5-arylacetylene 1,2,4oxadiazoles and study of their reactions with/without arenes under the conditions of superelectrophilic activation by Brønsted superacid CF3SO3H (TfOH), strong Lewis acids AlX3 (X = Cl, Br), or acidic zeolite CBV-720.
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 didehydrobromination 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(i-Pr)2-THF (-40C, 2 h), afforded complex mixtures of reaction products without desired acetylene oxadiazoles 3. We succeeded to get compounds 3a-e by the reaction of 2a-e with sodium amide in the liquid ammonia [NaNH2-NH3(liq.)] only at low temperature -70 --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 --40C led to a decrease of the yields of compounds 3. Apart from that, compounds 2f,g containing 3-para-bromophenyl ring in the heterocyclic core gave no corresponding acetylene oxadiazoles 3 in the system NaNH2-NH3(liq.), only mixtures of oligomeric materials were formed. Moreover, compound 3e was obtained as an inseparable mixture with styryl oxadiazole 1e. The latter may be formed from 3e under the basic reaction conditions by reduction under the action of NaNH2. All these data point out instability of acetylene oxadiazoles 3 in strong basic and nucleophilic media. Oxadiazoles 3, which were initially formed from compounds 2 in the system NaNH2-NH3(liq.), underwent further secondary transformations under the nucleophilic reaction conditions, even at very low temperature -70 --60C, that resulted in low-moderate yields of the target acetylene derivatives.
Then, electrophilic reactions of acetylene oxadiazoles 3a-d in different acids were studied. In  Table 1). Table 1    It should be noted that attempts of chromatographic separation of triflates 4a-c into individual Eand Z-isomers on silica gel led to a decrease of their yields and a change in E-/Z-ratio. That reveals instability of these compounds on silica gel.
In the same reaction in H2SO4, oxadiazole 3a gave product of hydration of acetylene bond 4d (yield of 65%) existing in solution as equilibrium between ketone and enole forms in a ratio of 1.2 : 1 according to NMR data (see Supporting Information). We also checked reaction of oxadiazole 3a with benzene under the action of Lewis acids AlCl3, AlBr3 and acidic zeolite CBV-720 (Scheme 6). However, these Lewis acids showed unsatisfactory results leading to olygomeric materials. A yield of target compound 5a in reaction with zeolite was lower than in the same reaction in TfOH (compare with data in Scheme 5). Thus, among the tested acidic reagents, TfOH showed better results for hydroarylation of compounds 3.
Additionally reaction of oxadiazole 3a with benzene in TfOH (r.t., 1 h) in the presence of cyclohexane, as a hydride ion source, was conducted to achieve ionic hydrogenation of intermediate cationic species. However, no products of ionic hydrogenation were obtained, only product of hydrophenylation of acetylene bond 5a was quantitatively isolated (compare with data on Scheme 5).