Silica-Supported Dichlorophosphate : a Recoverable Cyclodehydrant for the Eco-Friendly Synthesis of 2 , 5-Disubstituted 1 , 3 , 4-Oxadiazoles under Solvent-Free and Microwave Irradiation Conditions

Uma série de compostos simétricos e assimétricos de 2,5-dissubstituídos 1,3,4-oxadiazol foram sintetizados eficientemente a partir do ciclodesidratação das diacilhidrazinas, usando a sílica suportada com o diclorofosfato, como recuperador do ciclodesidratação sem solvente e sob irradiação por microondas. Este processo tem vantagens de ser não corrosivo e nem poluente, apresenta ainda velocidade acelerada, alto rendimento e simples procedimento experimental.

][29] Microwave energy has also developed into a useful technique for a variety of applications in organic synthesis, [30][31][32] especially for the solvent-free reactions 33,34 since the solvent-free MW-assisted reactions can provide an opportunity to work with open vessels thus avoiding the risk of high pressure development and increasing the potential of such reaction to upscale, and has advantage of rapid reaction rate, high yield and simple work-up procedure.
In this paper, we describe an eco-friendly new method that utilizes silica-supported dichlorophosphate as a recoverable cyclodehydrant for the synthesis of 2,5-disubstituted 1,3,4-oxadiazoles from 1,2-diacylhydrazines under solventfree and microwave irradiation condition.

Experimental
IR spectra were recorded using KBr pellets on a Digilab FTS 3000 FTIR spectrophotometer and 1 H NMR spectra on a Mercury Plus-400 instrument using CDCl 3 as solvent and Me 4 Si as internal standard.Elemental analyses were performed on a Vario El Elemental Analysis instrument.Melting points were observed in an electrothermal melting point apparatus, and the values are uncorrected.Microwave reactions were conducted in a modified microwave oven fitted with a condenser (LG-WP650, 2450 MHz, China).BET surface area of silica-supported dichlorophosphate was determined from N 2 adsorption-desorption isotherms using a Surface Area Analyzer (BET, Quantachrome Instruments Nova 2000 series, USA).1,2-Diacylhydrazines were prepared according to literature procedure. 15

Preparation of silica-supported dichlorophosphate
The suspension of silica gel (10 g, 80-200 mesh) in phosphorus oxychloride (50 mL) was refluxed for 48 h.The released HCl gas was absorbed by dilute aqueous solution of sodium hydroxide.Then the mixture was filtered in a drybox, washed with dry dichloromethane (6×10 mL) and dried in vacuum to give 13 g of product.IR (KBr): 571 (ν P-Cl ).The silica supporting capacity for POCl 2 is ca.1.92 mmol g -1 (which was calculated according to weight increase of silica).The specific surface area for the sample is ca.82 m 2 g -1 .

General procedure for preparation of 2,5-disubstituted 1,3,4-oxadiazoles
The mixture of 1,2-diacylhydrazine (0.7 mmol) and silica-supported dichlorophosphate (0.52 g, 1.0 mmol based on supported POCl 2 ) was ground in a mortar with a pestle at room temperature without any solvents for 15 min.Then the mixture was transferred into a beaker, and irradiated in a microwave oven for 2 min at 455 W of microwave power.Then the resulting mixture was extracted with 10 mL of acetone to recover the used silica-supported reagent, and the extract was evaporated off the solvent to give the crude product, which was further purified by column chromatography to afford pure product.The analytical data for represent compounds are shown below.

Results and Discussion
Silica-supported dichlorophosphate was prepared by reaction of silica gel with phosphorus oxychloride under refluxing condition (Scheme 1).The reaction could afford the desired product in excellent yield. Figure 1 shows the IR spectra of silica-supported dichlorophosphate and silica gel.Both IR spectra show the typical broad absorption peaks of Si-O-Si bond at 1103 cm -1 .Hydrogen-bonded silanol groups give bands in the region of 3300-3600 cm -1 .Especially, a new strong peak at 571 cm -1 is exhibited in the spectrum of silica-supported dichlorophosphate, which is attributable to the absorption of P-Cl.The specific surface area for the sample is ca.82 m 2 g -1 .
In order to explore the availability of silica supported dichlorophosphate as a recoverable cyclodehydrant under solvent-free and microwave irradiation, the synthesis of 2,5-diphenyl-1,3,4-oxadiazole (Table 1, 2a) from 1,2-dibenzoylhydraine was selected as a model reaction.The optimal reaction conditions including reactant ratio, reaction time, and microwave power were investigated.It was found that when the ratio of 1,2-dibenzoylhydraine to silica-supported dichlorophosphate was 1:1.4 and the microwave power was 455 W (which was determined by power adjustor of microwave oven), the reaction gave the highest yield within 2 min.Using the similar condition, a series of 2,5-disubstituted-1,3,4-oxadiazoles (Table 1, 2a-z) were synthesized in high yield.The protocol is suitable for cyclodehydrating synthesis of aryl, alkyl and heterocyclyl substituted 1,3,4-oxadiazoles.Various aryl substituted 1,3,4-oxadiazoles could be easily synthesized by this method.Different substituents (4-MeO, 2-Me, 3-Me, 2-Cl, 3-Cl, 4-Cl, 3-NO 2 and 4-NO 2 ) on the aryl rings were have no significant effect on the reaction conditions and the reaction yield.Alkyl groups, such as hexyl and heptyl, substituted 1,3,4-oxadiazoles could also be readily prepared by this route (Table 1, 2u-z).In addition, heteroaryl group, such as furyl, substituted 1,3,4-oxadiazoles could also be synthesized from this approach (Table 1, 2f and 2m).Meanwhile, this protocol was suitable to the synthesis of both symmetrical (Table 1, 2a-g) and unsymmetrical (Table 1, 2h-z) 1,3,4-oxadiazoles.After the reactions the desired products   could be easily isolated from the reaction systems only by extraction, and the used silica-supported cyclodehydrant could be recovered simply by filtration, and this efficiently avoided the corrosion and pollution caused by using liquid dehydrant, such as phosphorus oxychloride.The pure products could be readily obtained by evaporating off the solvent and purified by column chromatography.
In contrast, the selected reaction for 2a was also conducted by using oil-bath heating at the same temperature as the microwave method (140 °C), but no any product was observed after 2 min of reaction.

Conclusion
Silica-supported dichlorophosphate was found to be an efficient cyclodehydrant for the synthesis of 2,5-disubstituted 1,3,4-oxadiazoles from 1,2-diacylhydrazines in solvent-free medium under microwave irradiation.This protocol is suitable to the synthesis of alkyl, aryl and heterocyclyl substituted symmetrical and unsymmetrical 1,3,4-oxadiazoles, and has advantages of no corrosion, no environmental pollution, accelerated rate, high yield and simple work-up procedure.