New efficient synthesis of bis-1,2,4-oxadiazole derivatives via subsequent Staudinger/aza-Wittig reaction

A convenient route for the synthesis of bis-1,2,4-oxadiazoles is described. One-pot reaction of diazidoglyoxime esters and triphenylphosphine produced bis-1,2,4-oxadiazole derivatives in good overall yields by subsequent Staudinger/aza-Wittig reaction. All compounds were characterized by IR, 1 HNMR, 13 CNMR and HRMS and the structure of key product was unequivocally confirmed by X-ray diffraction analysis

The Staudinger reaction 25 is between azides and triphenylphosphine (Ph3P) to give iminophosphoranes(P=N).The aza-Wittig reactions of iminophosphoranes with aldehydes, ketones and esters provide an important tool for the construction of C=N double bond under mild and neutral conditions [25][26] .Especially the intramolecular version of the aza-Wittig reaction has been applied widely in the synthesis of nitrogen containing heterocyclic compounds [27][28] .In addition, Catalytic aza-Wittig reaction has also become a new method to construct some new heterocycles [29][30] .Recently we have been interested in the synthesis of various heterocycles via aza-Wittig reaction [31][32][33][34][35] .In this work, we developed a new simple and efficient method for the synthesis of bis-1,2,4-oxadiazole derivatives from diazidoglyoxime esters via subsequent Staudinger and aza-Wittig reaction (Scheme 1).

Results and Discussion
Initially diazidoglyoxime 1 was obtained through the direct nucleophilic substitution reaction using dichloroglyoxime and sodium azide as the starting substrate in DMF, and the reaction was successfully carried out in high yield according to the literature 37 .Diazidoglyoxime 1 is unstable and needs to be stored in a refrigerator at low temperature.And diazidoglyoxime 1 was treated with various aromatic acyl chlorides to obtain diazidoglyoxime esters 2a-2j in high yield using dichloromethane as solvent in the ice-water bath.The reaction was promoted by using triethylamine as acid acceptor, the reaction was completed in about half an hour.(Scheme 2) Diazidoglyoxime esters 2 are also unstable because they contain an azide group.They should be reacted as soon as possible or stored at low temperature.R 1 =R 2 or R 1 ≠R 2 Scheme 2. Preparation methods of diazidoglyoxime esters 2a-2j.
Diazidoglyoxime esters 2 and triphenylphosphine underwent Staudinger reaction in anhydrous toluene at room temperature to give the key intermediate iminophosphoranes 3, which were not to be isolated.Subsequently the reaction system was heated at reflux (115℃), and the bis-1,2,4-oxadiazoles 4a-4h were obtained by intramolecular aza-Wittig reaction without catalyst.
With this information of these successful reactions in hand, we attempted to expand this methodology to the synthesis of bis-1,2,4-oxadiazoles with asymmetric substituent groups.When two different acyl chlorides were added to the reaction system in batches, the reaction was successful; diazidoglyme esters 2i and 2j with asymmetric substituent groups were obtained.Asymmetric bis-1,2,4-oxadiazoles 4i and 4j were successfully obtained by intramolecular aza-Wittig reaction when applying asymmetric diazidoglyme esters 2i and 2j.
Bis-1,2,4-oxadiazole 4a, white crystals, was synthesized as the first example of this type of compound.The structure of 4a was identified by IR, 1 HNMR, 13 CNMR and HRMS.The IR of the reaction product showed aromatic C=N at 1608 cm -1 and the characteristic peaks of benzene ring can also be found at the corresponding positions.The 1 H NMR showed it can be found the signal for the aromatic protons at d 7.51-8.31ppm.Furthermore, their structures were supported by 13 C NMR.In addition, a single crystal of 5,5'-diphenyl-3,3'-bi(1,2,4-oxadiazole) 4a was obtained from the CH2Cl2/petroleum ether solution of 4a, and X-ray structure analysis verified the proposed structure (Figure 1).The preparation and characterization of other compounds 4b-4k were described in detail in this paper.(Table 2) Melting point(℃) Yield(%) [a] 2a [a] Isolated yields.

Conclusions
In conclusion, we described a new efficient synthesis of fully substituted bis-1,2,4-oxadiazoles, which are of considerable interest as potential biological active compounds or functional explosive materials.This new procedure has the advantages of available starting material, simple operation, and mild reaction conditions.

Experimental Section
General.All reagents used in the reaction are commercial chemical pure or analytical pure; N,Ndimethylformamide (DMF) was dried with anhydrous magnesium sulfate for one week, triethylamine (Et3N) was dried with calcium hydride and then distilled under atmospheric pressure, and toluene (C6H5CH3) was dried with anhydrous calcium chloride for one week; Dichloroglyoxime, benzoyl chloride, sodium azide, triphenylphosphine, anhydrous sodium sulfate and the common solvents are commercially available analytical purity and can be used directly without purification.
All melting points were determined on a X-4 model melting point apparatus and were uncorrected previously. 1 H NMR and 13 C NMR spectra were obtained with AVANCE NEO 500M spectrometer and resonances relative to TMS.Infrared spectra were recorded on a Perkin Elmer-Spectrum One spectrometer as KBr pellets and were reported in cm -1 .High-resolution mass spectra (HRMS) were recorded by an Agilent 6224 TOF LC/MS spectrometer.Silica gel (HSGF254) was used for TLC and Silica gel (200-300 mesh) was used for short column chromatography.
Synthesis of diazidoglyoxime.Sodium azide (1.26 g, 19.38 mmol) was added to a solution of dichloroglyoxime (1.5 g, 9.56 mmol) in DMF (20 mL).The reaction mixture was stirred at room temperature for 3 h and was then poured into 100 mL of cold water.The aqueous suspension was mixed continually for about 10 minutes until a large amount of white solid was precipitated from the solution.The crude product was collected by filtration and washed with petroleum ether and fully dried to yield diazidoglyoxime (1.44g, 89%) as white solid, mp 159 ℃.
General procedure for synthesis of diazidoglyoxime esters (2a-2h, 2k).Diazidoglyoxime (0.51 g, 3mmol) was dissolved in anhydrous CH2Cl2 (10 mL) and aromatic acyl chlorides (6.3 mmol) were added.The reaction mixture was stirred in the ice-water bath for 5 minutes, a solution of redistilled triethylamine (0.67 g，6.6 mmol) and CH2Cl2 (2 mL) was added drop wise into the system, and then after dropping the reaction system was stirred at room temperature for about 0.5-1 hours.When the starting materials were consumed, the mixture was poured into 100 mL of cold water and extracted three times with dichloromethane (20 mL×3), the extracted solution was washed once with saturated salt water.The combined organic layers were dried by Na2SO4, the solvent was evaporated under reduced pressure and the residue was purified by column chromatography (Petroleum ether/AcOEt v/v=7:1) to give diazidoglyoxime esters.Compound 2a-2h used in this study were prepared by the above procedure.Diazidoglyoxime ester 2k was prepared by the previously reported method 38 .
General procedure for synthesis of asymmetric diazidoglyoxime esters (2i, 2j).One of aromatic acyl chlorides (3 mmol) was added drop by drop to diazidoglyoxime (0.51 g, 3 mmol) in anhydrous CH2Cl2 (10 mL) at 0 ℃, a solution of redistilled triethylamine (0.67 g，6.6 mmol) and CH2Cl2 (2 mL) was added into the system drop by drop.When the aromatic acyl chloride was consumed, another aromatic acyl chloride(3 mmol) was added drop by drop to the reaction solution.When the depletion of the starting material diazidoglyoxime was observed by TLC, the mixture was poured into 100 mL of cold water, and extracted three times with dichloromethane (20 mL×3), the extracted solution was washed once with saturated salt water.The combined organic layers were dried by Na2SO4, the solvent was evaporated under reduced pressure and the residue was purified by column chromatography (Petroleum ether/AcOEt v/v=7:1) to give diazidoglyoxime esters 2i or 2j.The carbon spectra of diazidoglyoxime esters 2c, 2f, 2g, 2i and 2j are missing due to poor solubility in the solvents deuterated chloroform, deuterated DMSO and deuterated DMF.  13 C NMR (125 MHz, CDCl3) δ 160.8, 143.9, 135.6 (JC-F = 32.5 Hz), 130.5 (JC-F = 7.5 Hz), 125.9 (JC-F = 10.0 Hz), 124.4,122.3.

General procedure for synthesis of bis-1,2,4-oxadiazole derivatives (4a-4k).
To a well stirred solution of diazidoglyoxime esters(2 mmol) in anhydrous toluene (15 mL) was added triphenylphosphine (1.10 g, 4.19 mmol), large numbers of bubbles were formed and stirring was continued at room temperature (25°C).When the depletion of the starting material and the formation of iminophosphorane were observed by TLC, the reaction mixture was continuously heated to 115°C for 8-12h, the solvent was evaporated under reduced pressure and the dark red residue was purified by column chromatography (Petroleum ether/AcOEt mixtures as eluent v/v=8:1) to give the corresponding product.