Deep eutectic solvent-catalyzed arylation of benzoxazoles with aromatic aldehydes

A novel and efficient methodology for the arylation of benzoxazoles with aromatic aldehydes catalyzed by deep eutectic solvent has been developed. The reaction smoothly proceeded with a wide range of substrates to give the desired products in high yields within short reaction time. Deep eutectic solvents are easily recovered and reused without significant loss of catalytic activity.


Introduction
2][3][4] Therefore, the development of efficient synthetic methods for C2-arylation of benzoxazoles has received much attention. 5,68][9] However, this protocol still suffered from inherent drawbacks associated with the use of uncommon, toxic, and expensive agents such as aryltrimethylammonium triates, 7 aryl halides or triates, [10][11][12][13][14][15][16][17] aryl boronic acids, 18 sodium arylsulnates, 19 arylsulfonyl hydrazides, 20 and 3-phenylpropionic acid. 21Additionally, the requirement of high-cost palladium catalysts and other expensive additives also prevents the palladium-catalyzed cross-coupling procedure from being employed in large-scale synthesis. 22Recently, the replacement of palladium by other transition metals, such as bis(diisopropylphosphinomethyl) amine nickel(II) and nickel(0) complexes, 23 metal-organic frameworks, 24,25 Cu/Fe system, 26 CeO 2 /Fe 3 O 4 , 27 CuCN(PPh 3 ) 2 , 28 and Ni(COD) 2 , 29 has been investigated.These direct arylation methods have received much attention due to their advantage of avoiding the use of stoichiometric amounts of expensive organometallic reagents or additives.However, these protocols still encounter several problems including low yields, long reaction times, poor substrate scope, and high toxicity.Therefore, the development of an effective alternative method for the arylation of benzoxazoles remains highly desirable.Aromatic aldehydes are considered as preferable reagents in the arylation of benzoxazoles owing to their widespread availability, non-toxicity, and low-cost production.The reaction between benzoxazoles and aromatic aldehydes can be conducted in the presence of a suitable catalyst, e.g., molecular I 2 or FeSO 4 . 30,31Until now, there has been no further report on the arylation of benzoxazoles using aldehydes as reagents.
In an attempt to develop a cost-effective and environmentally benign protocol, we focus on exploring a new and affordable catalyst for direct arylation of benzoxazoles under "greener" conditions.3][34] DESs have found many applications as green solvents in diverse elds including nanotechnology, 35 separation processes, 36 transition metal catalyzed reactions, 37 material chemistry, 38 stabilization of DNA, 39 and organic synthesis. 402][43][44][45][46][47][48][49] Recently, we have reported DESs-catalyzed organic transformations such as Friedel-Cras acylation and esterication of sterically hindered alcohols. 50,51As our ongoing efforts to develop environmentally benign syntheses, it is the aim of this communication to describe our preliminary results in the arylation of benzoxazoles with aromatic aldehyde using DES as a green catalyst.Notable features of our report include: (i) straightforward and affordable preparation of catalyst, (ii) simple work-up, (iii) removable additive agents, (iv) recyclable, biodegradable, and low-toxic catalyst.

Preparation and characterization of [ZnCl 2 ][ethylene glycol] 4
DESs were synthesized by mixing zinc chloride and ethylene glycol (HBDs) at a dened molar ratio (1 : 4) and heating at 120 C for 1 h at atmospheric pressure under constant magnetic stirring until a homogeneous liquid was formed.The charge delocalization which occurs through hydrogen bonding between the halide anion and ethylene glycol is responsible for the decrease in the T m of the mixture. 52,53he NMR characterization are in good agreement with the structure of [ZnCl 2 ][ethylene glycol] 4 and the NMR spectra show that the catalyst is free of impurities.DESs with high viscosity and the inter-as well as intra-dipolar interactions can cause the broadening effect on the resonance signals of NMR spectrum. 54 The Raman spectra of ethylene glycol, zinc chloride, and [ZnCl 2 ][ethylene glycol] 4 are presented in Fig. 2 for a comparative analysis in the region from 50 to 1500 cm À1 .In pure ZnCl 2 , we have observed a strong signal at 225 cm À1 and another weak signal at 290 cm À1 ; however, at low ZnCl 2 molar fraction (in deep eutectic solvent) the feature at 290 cm À1 becomes strong and the signal at 225 cm À1 disappears.Rubim et al. have also observed the same feature for ZnCl 2 in eutectic mixture with 1-butyl-3-methylimidazolium chloride. 56Thus, the Raman spectrum of [ZnCl 2 ][ethylene glycol] 4 does not change as compared with the signal of ethylene glycol but additional peaks from ZnCl 2 appear at 80 and 290 cm À1 .
Thermal gravimetric analysis (TGA) of [ZnCl 2 ][ethylene glycol] 4 was performed in Fig. 3.The major weight loss occurs in the temperature range from 200 C to 475 C, which make the [ZnCl 2 ][ethylene glycol] 4 suitable for high-temperature reaction conditions.

Optimization of reaction conditions
We initiated our studies by investigating various reaction conditions for the C2-arylation of benzoxazole by benzaldehyde (Tables 1 and 2).The optimized condition revealed that the airstable and environmentally benign [ZnCl 2 ][ethylene glycol] 4 proved to be an effective catalyst for the highly selective C2arylation of benzoxazole with benzaldehyde in 2 : 1 molar ratio.The method provided the desired product in high yield in the absence of other additives such as organic solvents or bases.It is also noteworthy that this arylation of benzoxazole proceeded smoothly without the need of inert atmosphere.
With the optimized catalyst in hand, the scope of the benzoxazoles and aromatic aldehydes in the arylation reaction was studied (Table 3).The results demonstrated that the developed pathway provided the C2-arylation products in high yields.Generally, the robust DES between ethylene glycol and zinc chloride allowed a variety of substituted benzoxazoles and aldehydes to transform into the desired products in good to   excellent yields with 100% selectivity in C2-arylation.First, a large number of aromatic aldehydes, regardless of containing electron-donating substituents (methyl, t-butyl, hydroxy, methoxy) or electron-withdrawing substituents (nitro, halide), can react with benzoxazoles to produce the expected products under the given reaction conditions (Table 3).However, low yields of the desired products were observed for benzaldehydes bearing severe electron-withdrawing groups such as nitro or uoro substituents (Table 3, entries 5, 6, 8, 10, 18, 26, 35).Next, the scope of various benzoxazoles was also evaluated.As our expectation both 5-methylbenzoxazole and 5-chlorobenzoxazole generally underwent the arylation to give the corresponding    products in very good yields ranging from 82 to 95% except the case of 4-uorobenzaldehyde and 4-hydroxybenzaldehyde whose resulting arylated products were only obtained in signicantly diminished yields of 70-75% (Table 3, entries 14-30).For the benzoxazole bearing a nitro substituent, the lower yields of arylation products with various aldehydes were recorded even though harsher conditions (higher temperature for prolonged reaction time) were employed (Table 3, entries 31-37).It is noteworthy that the condensation between benzoxazole and benzaldehyde was successfully performed on a 10 mmol or 20 mmol scale, and the yield is virtually the same as on 1 mmol scale (Table 3, entry 1).The versatility of benzothiazole and benzimidazole as substrates in the replacement of benzoxazole was also reported.The adducts resulted from the condensation of benzothiazole with various aromatic aldehydes were isolated in comparative yields with those derived from benzoxazole (Table 4, entries 1-6).Meanwhile, a failure in the formation of the desired product was noted for the case of benzimidazole (Table 4, entry 7), probably due to the existence of intermolecular hydrogen bonds between the NH of benzimidazole and DES.
A comparative study between the current method and previous ones was presented in Table 5. Deep eutectic solventcatalyzed arylation of benzoxazole afforded the arylated benzoxazole products in excellent yields under a mild and simple condition without the demand for any additives as in preceding reports (Table 5, entry 6).Remarkably, no loss of catalytic activity in the recycling test of DES is the most prominent artifact of this protocol.
As asserted in previous literature through isotope-labeling mechanistic studies, the arylation of benzoxazoles with aromatic aldehydes underwent the ring-opening step assisted by Lewis acids such as I 2 or FeSO 4 to afford the key intermediate 2-aminophenol.Its nucleophilic addition to aldehydes followed by oxidative ring closure provided arylated benzoxazoles as nal products. 30,31As an extra part in our research to check the conformability of the proposed mechanism for the same reaction catalyzed by [ZnCl 2 ][ethylene glycol] 4 , we also carried out   the acylation-cyclization of 2-aminophenol with benzaldehyde under the same optimized conditions which were previously applied for the arylation of benzoxazole by benzaldehyde.As the result, the same arylated benzoxazole product was obtained in a comparable yield of 85%.Additionally, in another control experiment whereby benzoxazole reacted with [ZnCl 2 ][ethylene glycol] 4 in the absence of benzaldehyde, 2-aminophenol was obtained in 62% yield.Thus, it is not doubtful that the arylation of benzoxazole studied herein must also undergo the ringopening step prior to the condensation step with aldehydes.Although the mechanism is not clear now, the method possesses attractive merits including cheap recyclable catalyst, non-toxicity, and wide scope of substrates.
The recyclability is an important feature for applying a catalyst in industrial processes.The recyclability of deep eutectic solvent of zinc chloride and ethylene glycol under study in this work was investigated in the model reaction.Aer completion of the reaction, the product was extracted with diethyl ether (10 Â 5 mL), the catalyst was separated from the ethereal solution and dried under vacuum.The recovered catalyst was   reused in the model reaction to the next run.As illustrated in Fig. 4, the efficiency of deep eutectic solvent was found to be constantly excellent even aer ve consecutive recycles.IR spectroscopy of fresh and recovered deep eutectic solvent indicated that no detectable structural degradation can be seen (Fig. 5).Aer each recycling a very small amount of DES leaching to diethyl ether phase during the work-up step was indirectly estimated by means of ICP-MS technique in which Zn content of about 0.08 ppm in the ethereal phase was determined.A slight decrease of catalytic activity was observed due to a little loss of deep eutectic solvent during the work-up process.

Experimental
General procedure for catalytic arylation of benzoxazole Benzoxazole (119 mg, 1.0 mmol) was treated with benzaldehyde (53 mg, 0.5 mmol) in the presence of [ZnCl 2 ][ethylene glycol] 4 (5 mg, 0.01 mmol) at 120 C for 6 h under solvent-free magnetic stirring.The completion of the reaction was checked by TLC and GC.The mixture was then diluted with diethyl ether (10 Â 5 mL).The solvent was removed on a rotary evaporator.
The crude product was puried by silica gel chromatography using acetone/petroleum ether (1/19) to afford the desired product (95% yield).The purity and identity of the product were conrmed by FT-IR, 1 H NMR, 13 C NMR, and MS.The recovered catalyst was activated by heating under reduced vacuum at 80 C for 30 min and reused for next cycles.

Conclusions
In conclusion, we have developed the rst DES-mediated arylation of benzoxazoles with aromatic aldehydes at the C2 position under solvent-free condition.The most important highlight of the current method is the use of inexpensive, air-and water-stable, and recyclable deep eutectic solvent in the replacement of highcost palladium catalysts.Interestingly, only a catalytic amount of deep eutectic solvent is requisite for the quantitative production of various 2-arylbenzoxazoles through a simplistic, environmentally benign, and low-cost synthetic procedure.

Fig. 1
displays the FT-IR spectra of ethylene glycol and [ZnCl 2 ][ethylene glycol] 4 .The spectrum of the [ZnCl 2 ][ethylene glycol] 4 is an overlap of those of ethylene glycol.The result showed that the structure of ethylene glycol was not destroyed in the [ZnCl 2 ][ethylene glycol] 4 .Particularly, the absorption bands of ethylene glycol at 3390 cm À1 could be ascribed to stretch vibration of O-H functional group.As observed in Fig. 1, the O-H stretching vibration of [ZnCl 2 ][ethylene glycol] 4 shis to lower wavenumber, indicating that O-H of ethylene glycol takes part in the formation of the hydrogen bond with the anion of zinc chloride.

a
Isolated yield.

Table 1
Optimization of catalyst for the arylation of benzoxazole a

Table 3
The scope of arylation of benzoxazoles with aromatic aldehydes

Table 4
The arylation of benzothiazole and benzimidazole with aromatic aldehydes under current method