Microwave Assisted Synthesis of Two-Substituted Benzoxazoles in the Presence of Potassium Cyanide Under Mild Conditions

Various two-substituted benzoxazoles were prepared using microwave-assisted reaction of 2-aminophenol with aromatic aldehydes in the presence of one equivalent of potassium cyanide as an equimolecular catalyst. Aldehydes having either electron-donating or withdrawing groups afforded the target products. The important features of this method were high yields, short reaction times and easy work up. The structure of synthesized products was characterized by nuclear magnetic resonance (NMR) and infrared (IR).

Preparation of organic compounds could be accelerated by microwave (MW) irradiation with higher yields and purity, lower quantities of by-products, easier work-up, and purification compared to other more conventional techniques. [38,39] Moreover, some reactions that do not occur by conventional thermal heating techniques or produce products in poor yields can be accomplished in high yields under microwave irradiation. [40] By keeping this point in mind, herein we report the synthesis of two-substituted benzoxazoles by a nonconventional technique.

Chemicals and Instruments
All materials were of commercial reagent grade. The aromatic aldehydes and o-aminophenol were purified by standard procedures and purity was determined by thin layer chromatography (TLC). IR spectra were recorded as KBr pellets on a Perkin Elmer 781 spectrophotometer or an Impact 400 Nicolet Fourier transform infrared spectrophotometer (FTIR). 1 H NMR and 13 C NMR were recorded in CDCl 3 solvent on a Bruker DRX-400 spectrometer with tetramethylsilane as internal reference. Melting points obtained with a Yanagimoto micro melting point apparatus are uncorrected. The purity determination of the substrates and reaction monitoring were accomplished by TLC on silica-gel polygram SILG/UV 254 plates (from Merck Company).
Microwave irradiations were carried out in microwave oven specially designed for the organic synthesis (Milestone LAVIS 1000 Basic Microwave).

Typical Procedure for the Synthesis of Benzoxazoles from Arylaldehydes
A mixture of 2-aminophenol (0.13 g, 1.1 mmol), substituted benzaldehydes (2.2 mmol), and potassium cyanide (1.1 mmol) in 4 mL N,N-dimethylformamide was irradiated in a microwave oven at 450 W. The progress of the reaction was monitored using thin-layer chromatography (petroleum ether/ethyl acetate, 6/2). After the completion of the reaction, the mixture was cooled and extracted with ethyl acetate (3 £ 10 mL) and the organic layer was concentrated under reduced pressure. Then, recrystallization of the crude product was carried out in a boiling mixture of ethanol/water (1:1) to give the pure product.

Results and Discussion
In this research, an efficient, convenient microwave-assisted method was applied to the reaction of aromatic aldehydes and 2-aminophenol under mild conditions (Scheme 1). Fortunately, microwave irradiation as a facile and general method afforded the corresponding products within a few minutes in excellent yields. An important factor in performing reactions under microwave irradiation is choosing an appropriate solvent. Polar and ionic species interact with microwaves more efficiently. The different solvents, due to variation in polarities, have different behaviors under microwave irradiation. The ability of a specific substance (solvent or reagent) to convert electromagnetic radiation into heat is determined by the so-called loss factor (tan d). [46] A reaction medium with a high tan d absorbs most of the microwave energy and converts it into heat. So firstly, the solvent effect on the reaction of 2-aminophenol with benzaldehyde in the presence of KCN as a model reaction was investigated. The results are presented in Table 1.
As can be seen from Table 1, the solvents play an important role in the reaction. It was found that the best solvent for this reaction was N,N-dimethylformamide (DMF) and the reaction in this solvent afforded the desired product in 95% yield, while the performance of acetonitrile, and ethanol as solvents led to lower yields ( Table 1, entries 1-3). The reaction in dichloromethane did not produce benzoxazoles at all ( Table 1, entry 4).
Also, we carried out the reaction of 1.1 mmol 2-aminophenol with 2.2 mmol benzaldehyde in the presence of various amounts of KCN under 450 Watt microwave irradiation. The corresponding results can be seen in Table 2. As shown, the desired product was obtained with high yield in a short reaction time and in the presence of 1.1 mmol KCN (Table 2, entry 4).
In continuation of this work, in order to optimize the microwave power, the reaction of 2-aminophenol with benzaldehyde in the presence of KCN was carried out under different powers of microwave irradiation. It was observed that the reaction in the presence of microwave irradiation with the power of 450 W led to the best result, which was the obtained product with 95% isolated yield after 3 min (Table 3, entry 3).
To ascertain the scope and limitation of the present work, the microwave-assisted reaction of 2-aminophenol with several aromatic aldehydes was carried out according to the general experimental procedure. The corresponding results are shown in Table 4. As shown, the products were prepared in high yields and short reaction times, thereby confirming the generality and scope of this efficient method for one-pot synthesis of two-substituted benzoxazoles under microwave irradiation. The feature of this method was that, aromatic aldehydes with electron withdrawing groups (entries 4-6) as well as electron-donating groups (entries 2, 7, and 9) gave the excellent yields except a strong electron-withdrawing group at position 4 of benzaldehyde that did not yield the product (entry 15). Furthermore, heterocyclic aldehydes could also be used for the facile synthesis of several 2-heterocyclic substituted benzoxazoles (entries 12 and 13).
Comparing the results of microwave irradiation with conventional conditions [28,30,41,42,47] indicates that the synthesis of benzoxazoles from the reaction of 2-aminophenol with aromatic aldehydes can be accelerated by microwave irradiation. In this study, the products were obtained in the excellent yields after a short reaction time (about 1 min), while in the previously reported works the products were obtained in good to high yields after long reaction times (about 1 h). For example, in the previous report, [48] the reaction of 2-aminophenol with 4-methoxybenzaldehyde or 4-chlorobenzaldehyde catalyzed by FeCl 3 at 110 C after 24 h afforded 2-(4-methoxyphenyl) benzoxazole and 2-(4-chlorophenyl) benzoxazole in 76% and 66% yields respectively (Table 4, (Table 4, entry 5). Also, in this study, 2-aminophenol:KCN were used as 1:1 mol ratio and 2-phenyl benzoxazole as desired product was obtained in excellent yield (95 %) after short reaction time (3 min; Table 4, entry 1). While, in the previously reported work, 2-aminophenol:KCN has been used as 1:2 mol ratio and the corresponding product has been obtained in 85 % yield after 5 h [37] (Table 4, entry 18). This method offered several advantages including excellent yields, high purity, simple reaction conditions, high reaction rates and the easy work up procedures. These results demonstrated that the microwave irradiation is an efficient method for the one-pot synthesis of two-substituted benzoxazoles. The structures of products were completely characterized by spectroscopic and physical data and they were found to be in a good agreement with earlier reports. [19,[41][42][43][44][45]

Proposed Reaction Mechanism
The proposed mechanism for the formation of two-substituted benzoxazoles is presented in Scheme 2. As can be seen, the reaction likely proceeds according to the benzoin condensation, which involves formation of the benzoin (2). Intermediate (3) is formed by the reaction of 2-aminophenol with benzoin. Then, nucleophilic attack of hydroxyl group affords the corresponding product (4). To prove the correctness of this mechanism, the reaction of 2-aminophenol (1 mmol) with benzoin (1 mmol) in DMF as solvent was carried out in a microwave oven at power of 450 W and the desired product was obtained. This result was confirmed that the mechanism of reaction proceedes according the benzoin condensation (Scheme 3). As mentioned previously, by considering the proposed mechanism through the formation of benzoin, the 4-nitrobenzaldehyde could not be active in this reaction because of the very low nucleophilicity of cyanohydrin anion intermediate (1). This was due to the delocalization of minus charge via resonance of NO 2 group in para situation of the benzaldehyde. [49] Sch. 2. Proposed mechanism for the synthesis of benzoxazoles.

Conclusions
In summary, we have used microwave irradiation as a facile and efficient method for preparing of two-substituted benzoxazole derivatives. This method involved one-pot synthesis of two-substituted benzoxazoles by the reaction of 2-aminophenol with benzaldehydes, which was assisted by potassium cyanide under microwave irradiation. The reaction was performed to afford the desired products in good to excellent yields and short reaction times.