Phuong Hoang Tran* and
Anh-Hung Thi Hang
Department of Organic Chemistry, Faculty of Chemistry, University of Science, Viet Nam National University, Ho Chi Minh City 721337, Viet Nam. E-mail: thphuong@hcmus.edu.vn
First published on 20th March 2018
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.
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. Deep eutectic solvents (DESs) which were discovered for the first time by Abbott in 2001 have been known as a new class of ionic liquids possessing many outstanding characteristics.32–34 DESs have found many applications as green solvents in diverse fields including nanotechnology,35 separation processes,36 transition metal catalyzed reactions,37 material chemistry,38 stabilization of DNA,39 and organic synthesis.40 Besides, DESs have been known as preferable alternative solvents/catalysts for organic synthesis due to their non-hazardous, non-toxic, stable, non-flammable, and inexpensive nature.41–49 Recently, we have reported DESs-catalyzed organic transformations such as Friedel–Crafts acylation and esterification of sterically hindered alcohols.50,51 As 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.
The NMR characterization are in good agreement with the structure of [ZnCl2][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 high viscosity of DES used in the current work involves the formation of massive hydrogen bond network between each component.55 Fig. 1 displays the FT-IR spectra of ethylene glycol and [ZnCl2][ethylene glycol]4. The spectrum of the [ZnCl2][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 [ZnCl2][ethylene glycol]4. Particularly, the absorption bands of ethylene glycol at 3390 cm−1 could be ascribed to stretch vibration of O–H functional group. As observed in Fig. 1, the O–H stretching vibration of [ZnCl2][ethylene glycol]4 shifts 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.47,53,55
The Raman spectra of ethylene glycol, zinc chloride, and [ZnCl2][ethylene glycol]4 are presented in Fig. 2 for a comparative analysis in the region from 50 to 1500 cm−1. In pure ZnCl2, we have observed a strong signal at 225 cm−1 and another weak signal at 290 cm−1; however, at low ZnCl2 molar fraction (in deep eutectic solvent) the feature at 290 cm−1 becomes strong and the signal at 225 cm−1 disappears. Rubim et al. have also observed the same feature for ZnCl2 in eutectic mixture with 1-butyl-3-methylimidazolium chloride.56 Thus, the Raman spectrum of [ZnCl2][ethylene glycol]4 does not change as compared with the signal of ethylene glycol but additional peaks from ZnCl2 appear at 80 and 290 cm−1.
Thermal gravimetric analysis (TGA) of [ZnCl2][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 [ZnCl2][ethylene glycol]4 suitable for high-temperature reaction conditions.
Entry | Catalytic amount (mol%) | Time (h) | Temperature (°C) | Yieldb (%) |
---|---|---|---|---|
a Reaction conditions: benzoxazole (1 mmol), benzaldehyde (0.5 mmol), solvent-free.b Isolated yield. | ||||
1 | 1 | 6.0 | 120 | 60 |
2 | 2 | 6.0 | 120 | 75 |
3 | 3 | 6.0 | 120 | 80 |
4 | 5 | 6.0 | 120 | 95 |
5 | 10 | 6.0 | 120 | 95 |
6 | 5 | 1.0 | 120 | 0 |
7 | 5 | 1.5 | 120 | 0 |
8 | 5 | 2.5 | 120 | 0 |
9 | 5 | 4.0 | 120 | 30 |
10 | 5 | 4.5 | 120 | 75 |
11 | 5 | 6.0 | 120 | 95 |
12 | 5 | 6.5 | 120 | 97 |
13 | 5 | 6.0 | 90 | 40 |
14 | 5 | 6.0 | 100 | 45 |
15 | 5 | 6.0 | 110 | 80 |
16 | 5 | 6.0 | 120 | 95 |
17 | 5 | 6.0 | 130 | 95 |
18 | 5 | 6.0 | 140 | 95 |
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 fluoro 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-fluorobenzaldehyde and 4-hydroxybenzaldehyde whose resulting arylated products were only obtained in significantly 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).
Entry | Product | Condition | Yielda (%) |
---|---|---|---|
a Isolated yield.b On 10 mmol or 20 mmol scale. | |||
1 | 120 °C, 6 h | 95 (94)b | |
2 | 120 °C, 5 h | 93 | |
3 | 120 °C, 5 h | 94 | |
4 | 120 °C, 4 h | 95 | |
5 | 140 °C, 6 h | 75 | |
6 | 120 °C, 4 h | 80 | |
7 | 120 °C, 4 h | 92 | |
8 | 120 °C, 5 h | 70 | |
9 | 120 °C, 5 h | 90 | |
10 | 120 °C, 5 h | 72 | |
11 | 120 °C, 4 h | 90 | |
12 | 120 °C, 6 h | 93 | |
13 | 120 °C, 6 h | 80 | |
14 | 120 °C, 5 h | 94 | |
15 | 120 °C, 4 h | 90 | |
16 | 120 °C, 4 h | 90 | |
17 | 120 °C, 4 h | 95 | |
18 | 120 °C, 4.5 h | 75 | |
19 | 120 °C, 4.5 h | 85 | |
20 | 120 °C, 6.5 h | 70 | |
21 | 120 °C, 6 h | 82 | |
22 | 120 °C, 5 h | 95 | |
23 | 120 °C, 4 h | 95 | |
24 | 120 °C, 4 h | 90 | |
25 | 120 °C, 4 h | 95 | |
26 | 120 °C, 4 h | 75 | |
27 | 120 °C, 4 h | 95 | |
28 | 120 °C, 6 h | 85 | |
29 | 120 °C, 6.5 h | 75 | |
30 | 120 °C, 6 h | 85 | |
31 | 140 °C, 6 h | 70 | |
32 | 140 °C, 5 h | 75 | |
33 | 140 °C, 5 h | 75 | |
34 | 140 °C, 5 h | 80 | |
35 | 140 °C, 6 h | 72 | |
36 | 140 °C, 6 h | 80 | |
37 | 140 °C, 6 h | 85 |
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 solvent-catalyzed 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.
Entry | Catalyst | Reagent | Condition | Yield (%) |
---|---|---|---|---|
1 | FeSO4 (0.2 equiv.), H2O/diglyme/O2 | 150 °C, 20 h | 70 (ref. 31) | |
2 | I2 (2 equiv.), PhCl, DMF | 130 °C, 30 h | 75 (ref. 30) | |
3 | [Pd(π-allyl)Cl]2 (0.1 equiv.), PCy3, NaOtBu (2 equiv.), DMF | 120 °C, 12 h | 43 (ref. 7) | |
4 | CuCN(PPh3)2 (10 mol%), PPh3, Cs2CO3, pivalonitrile | Reflux, 24 h | 85 (ref. 28) | |
5 | Ni(COD)2 (0.1 equiv.), dcype (0.2 equiv.), Cs2CO3 (1.5 equiv.), p-xylene | 140 °C, 22 h | 91 (ref. 29) | |
6 | Current work: [ZnCl2][ethylene glycol]4 (5 mol%), solvent-free | 120 °C, 6 h | 95 |
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 I2 or FeSO4 to afford the key intermediate 2-aminophenol. Its nucleophilic addition to aldehydes followed by oxidative ring closure provided arylated benzoxazoles as final products.30,31 As an extra part in our research to check the conformability of the proposed mechanism for the same reaction catalyzed by [ZnCl2][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 [ZnCl2][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 ring-opening step prior to the condensation step with aldehydes. Although the mechanism is not clear now, the method possesses attractive merits including cheap and 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. After completion of the reaction, the product was extracted with diethyl ether (10 × 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 after five consecutive recycles. IR spectroscopy of fresh and recovered deep eutectic solvent indicated that no detectable structural degradation can be seen (Fig. 5). After each recycling test, 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.
Fig. 4 Reuse of [ZnCl2][ethylene glycol]4 catalyst in the arylation of benzoxazole with benzaldehyde. |
Fig. 5 FT-IR of fresh [ZnCl2][ethylene glycol]4 (a) and [ZnCl2][ethylene glycol]4 after the fifth recovery (b). |
Footnote |
† Electronic supplementary information (ESI) available. See DOI: 10.1039/c8ra01094c |
This journal is © The Royal Society of Chemistry 2018 |