Lanthanide Nitrates as Lewis Acids in the One-Pot Synthesis of 1,2,4-Oxadiazole Derivatives

Lanthanide compounds have been extensively used as Lewis acids in the different reactions including asymmetric catalysis. The most important compounds include the use of chlorides, triflates, p-toluenesulphonates, dithiocarbamates complexes, alkoxides and others. On the other hand, the oxadiazole group is a key element of a number of biological activity such as ligands of benzodiazepine receptor, inhibidor of protein tyrosine phosphatase, agonists of muscarinic receptors, antiinflammatory agents, antiviral agents, cardiovascular and other medicinal activity. Also, 1,2,4-oxadiazole compounds have been applied as ligands of metal complexes and liquid crystalline materials. Synthesis of 1,2,4-oxadiazole derivatives by using ketones, nitriles and nitric acid as starting materials and Fe(NO3)3 as catalyst has been reported by Itoh et al. 17 However, this method has the disadvantage of low reaction rates and drastic conditions, resulting in low reaction yields. Recently, yttrium triflate [Y(OTf)3] 18 was applied instead of Fe(NO3)3 by using the same reaction condition in the synthesis of various 1,2,4-oxadiazole with low reaction times and good yields. Nonetheless, neither of these methodologies could be successfully applied in the synthesis of 1,2,4-oxadiazole contained electron-donating. In the present work, we have proposed a simple methodology for the one-pot synthesis of 1,2,4-oxadiazole derivates, by using lanthanide nitrates prepared in situ as Lewis acids. We have investigated the rule of different ions on the reaction.


Introduction
Lanthanide compounds have been extensively used as Lewis acids in the different reactions including asymmetric catalysis.The most important compounds include the use of chlorides, 1 triflates, 2 p-toluenesulphonates, 3 dithiocarbamates complexes, 4 alkoxides 5 and others. 6On the other hand, the oxadiazole group is a key element of a number of biological activity such as ligands of benzodiazepine receptor, 7 inhibidor of protein tyrosine phosphatase, 8 agonists of muscarinic receptors, 9 antiinflammatory agents, 10 antiviral agents, 11 cardiovascular 12 and other medicinal activity. 13Also, 1,2,4-oxadiazole compounds have been applied as ligands of metal complexes 14 and liquid crystalline materials. 15,16ynthesis of 1,2,4-oxadiazole derivatives by using ketones, nitriles and nitric acid as starting materials and Fe(NO 3 ) 3 as catalyst has been reported by Itoh et al. 17 However, this method has the disadvantage of low reaction rates and drastic conditions, resulting in low reaction yields.Recently, yttrium triflate [Y(OTf) 3 ] 18 was applied instead of Fe(NO 3 ) 3 by using the same reaction condition in the synthesis of various 1,2,4-oxadiazole with low reaction times and good yields.Nonetheless, neither of these methodologies could be successfully applied in the synthesis of 1,2,4-oxadiazole contained electron-donating.
In the present work, we have proposed a simple methodology for the one-pot synthesis of 1,2,4-oxadiazole derivates, by using lanthanide nitrates prepared in situ as Lewis acids.We have investigated the rule of different ions on the reaction.

General
All reagents were commercially available and used without any purification. 1H and 13 C NMR spectra were recorded on a Varian 300-MHz spectrometer.Mass spectrometer spectra were recorded on a Shimadzu GC-MS-QP 5000 gas chromatograph-mass spectrometer equipped with a 30 m × 0.25 mm × 0.25 mm capillary column of fused silica, Supelco Simplicity 1 TM .All reactions were monitored by TLC.Flash column chromatography was carried out using 200-300 mesh silica gel at increased pressure.

Results and Discussion
In a preliminary screening, we carried out the reaction of benzonitrile, using europium nitrate prepared in situ from europium oxide or from europium dithiocarbamate with nitric acid and 4-chloroacetophenone at 80 o C. The results are compared with those obtained from the europium triflate and were shown in Table 1.
All of the three europium compounds gave similar yields; however, the reactions with europium nitrate and europium ditiocarbamate were faster than those with europium triflate.The similarity between the results for the three Lewis acids indicates that same intermediate is formed in all of the three reactions.Probably the europium nitrate formed in situ acts as Lewis acid in the enolization of the ketones in all of the cases.
The lanthanide nitrates is a salt of easy preparation from available lanthanide oxides, cheaper and more stable than others salts and lanthanide compounds.We have prepared and applied on the reaction described above nitrates of different metals, in order to investigate their role upon the reaction.The results are summarized on Table 2.
As it can be seen on Table 2, the use of 10 mol% of lanthanide catalyst (entry 1-6) promoted the reaction between 4-chloroacetophenone and benzonitrile in the presence of nitric acid to give 3-(4-chlorobenzoyl)-5phenyl-1,2,4-oxadiazole (1) in good yield.Ytterbium catalyst proved to be the most effective (Table 2, entry 6).The product was obtained in 86% in just 1.5 h at 80 o C. The quantity of nitric acid was controlled to avoid the formation of benzoic acid from hydrolysis of benzonitrile.
Due to the excellent result obtained with Yb(NO 3 ) 3 , it was applied for the synthesis of several 1,2,4-oxadiazole derivatives contained electron-withdrawing and electrondonating substituents in the aromatic ring of ketones.The results are given in the Table 3.
As it was shown in Table 3, a large variety of ketones can be converted into the corresponding 1,2,4-oxadiazole compounds with good to excellent yields.All yields with Yb(NO 3 ) 3 were higher than those obtained using Fe(NO 3 ) 3 as catalyst and short time reaction than those obtained by use Y(OTf) 3 . 18The reactivity of benzonitrile was higher than the acetonitrile in terms of reaction time and isolated yield (compared compounds (1, 8), (4, 9) and (5, 10)).Furthermore, the reaction occurred with ketones with electron-withdrawing and electron-donating at aromatic ring (Table 3, entries 4, 5 and 9) and with unsubstituted ring (Table 3, entries 3 and 8).This is the first time that 3-benzoyl-and 3-acetyl-1,2,4-oxadiazole derivates with electron donor substituent is synthesized one-pot.

Conclusions
In conclusion, we have demonstrated the effectiveness of the use of lanthanide nitrates as catalyst in the one-pot synthesis of 3-acetyl-and 3-benzoyl-1,2,4-oxadiazole derivates in good yield and short reaction times, when compared with other reported methodologies.Additionally, the reaction was efficient for aromatic ketones substituted with electron-donating and electron-withdrawing groups in the aromatic ring.