Efficient and Convenient Protocol for the Synthesis of 3,5-Disubstituted 1,2,4-Oxadiazoles Using HClO4-SiO2 as a Heterogeneous Recyclable Catalyst

Abstract Silica-supported perchloric acid (HClO4-SiO2) was found to be a new, highly efficient, inexpensive, and reusable catalyst for a rapid and efficient synthesis of various 1,2,4-oxadiazoles with good to excellent yields under solvent-free conditions. The present methodology has been effectively utilized for the synthesis of oxolamine, an anti-inflammatory drug. GRAPHICAL ABSTRACT

In recent years, heterogeneous catalysts have gained prominence because of environmental and economic considerations. [19] They have successfully been utilized in several organic transformations to minimize undesirable waste that causes environmental pollution. To the best of our knowledge, no report on the use of silica-supported perchloric acid (HClO 4 -SiO 2 ) as a catalyst utilizing carboxylic acid anhydrides is known for the synthesis of 3,5-disubtituted 1,2,4-oxadiazoles. As a part of our ongoing research program [20] on the development of efficient and environmentally benign synthetic protocols for the synthesis of heterocycles, herein we report a simple and efficient one-pot method for the synthesis of 3,5-disubstituted 1,2,4oxadiazoles from amidoximes and acid anhydrides using silica-supported perchloric acid (HClO 4 -SiO 2 ) at 80 C under solvent-free conditions (Scheme 1).

SYNTHESIS OF 1,2,4-OXADIAZOLES
conditions. The HClO 4 -SiO 2 loading was subsequently examined (Table 1, entries 9, 12, and 13), and it was found that 5 mol% of HClO 4 -SiO 2 provides the maximum yield in the least time (Table 1, entry 9). We immediately undertook a study to examine the effects of temperature on this transformation (Table 1, entries 7, 8, 10, and 11). The results demonstrated that 80 C appeared to be the optimum temperature for this transformation. Thus, the best yield, cleanest reaction, and most facile workup were achieved by employing 5 mol% of HClO 4 -SiO 2 at 80 C under solvent-free conditions (Table 1,  entry 9).
To generate a small library of functionalized 1,2,4-oxadiazoles (5), we next utilized a variety of substrates to explore the synthetic scope and generality of this method under the optimal conditions (Table 2). Notably, a wide range of anhydrides (4a-h) and amidoximes (3a and 3b) were well tolerated and proceeded smoothly under the optimized reaction conditions. All products obtained were characterized by spectroscopic methods such as 1 H NMR, 13 C NMR, and mass spectrometry.
Next, we investigated the reusability of HClO 4 -SiO 2 . A mixture of benzamidoxime, acetic anhydride, and HClO 4 -SiO 2 was stirred at 80 C for 5 min. After the completion of the reaction (monitored by thin-layer chromatography, TLC), the reaction mixture was diluted with dichloromethane (DCM, 5 mL) and the catalyst was separated by simple filtration. The recovered catalyst was activated and reused for three consecutive times with only slight variation in the yields of the products (93%, 92%, and 90%).
Substituted oxadiazoles are present in many important pharmaceutically active molecules. Although many of the compounds in Table 2 already display drug like attributes, we wanted to demonstrate the utility of this method through the synthesis of a pharmaceutically relevant molecule oxolamine, an anti-inflammatory drug. Thus, benzamidoxime (3a) was treated with 3-chloropropanoic anhydride in the presence of HClO 4 -SiO 2 under solvent-free conditions to get compound 6. Subsequently, it was treated with commercially available Et 2 NH Á HCl in the presence of K 2 CO 3 under refluxing conditions to afford desired oxolamine (7) in 84% yield (Scheme 2).   (Continued ) The advantage of this method over previous methods could be established while comparing the results obtained with acetic anhydride as well as with hexanoic anhydride. For instance under the reaction condition with benzaldehyde and with ammonium acetate and nitroethane in acetic acid under reflux conditions to afford 5-methyl-3-phenyl-1,2,4-oxadiazole (5a) the reported yield is 50%, [21] whereas the same product could be obtained in 95% yield within 5 min under the method described on this report. On the other hand, the reaction of benzamidoxime with hexanoic anhydride in water under reflux conditions resulted in 53% yield of the 5-pentyl-3-phenyl-1,2,4-oxadiazole (5g) in 12 h, [22] whereas the present method affords 96% yield of the corresponding product in 4 min.

EXPERIMENTAL
General Experimental Procedure for 5-Methyl-3-phenyl 1,2,4-oxadiazole ( Table 2, 5a) A mixture of benzamidoxime (1.47 mmol), acetic anhydride (1.77 mmol), and HClO 4 -SiO 2 (5 mol%) was stirred at 80 C for the specified time (Table 2). After completion of the reaction as indicated by TLC, the mixture was cooled to room temperature and diluted with DCM, and the catalyst was allowed to settle down.

CONCLUSIONS
In summary, we have developed a simple, efficient, and ecofriendly method for the synthesis of 3,5-diubstituted 1,2,4-oxadiazoles using HClO 4 -SiO 2 . The protocol uses amidoximes and acid anhydrides as starting materials, and the corresponding products were obtained in fair to excellent yields at 80 C under solvent-free conditions. The HClO 4 -SiO 2 catalyst was reused for three consecutive times with only a slight variation in yields of the products. The present methodology has been effectively utilized for the synthesis of oxolamine, an anti-inflammatory drug.