Eco-Friendly Syntheses of 2-Substituted Benzoxazoles and 2-Substituted Benzothiazoles from 2-Aminophenols, 2-Aminothiophenols and DMF Derivatives in the Presence of Imidazolium Chloride

A simple, economical and metal-free approach to the synthesis of 2-substituted benzoxazoles and 2-substituted benzothiazoles from 2-aminophenols, 2-aminothiophenols and DMF derivatives, only using imidazolium chloride (50% mmol) as promoter without any other additive, was reported. Various 2-substituted benzoxazoles and 2-substituted benzothiazoles were thus prepared in moderate to excellent yields.

Since these reports, many improvements to these reactions have been made by the use of alternative catalysts. In 2013, Yoon et al. [21] reported an improved method to form benzimidazoles using 2-acyl-4,5-dichloropyridazin-3(2H)-one as acyl transfer agent under transition-metal-free Since these reports, many improvements to these reactions have been made by the use of alternative catalysts. In 2013, Yoon et al. [21] reported an improved method to form benzimidazoles using 2-acyl-4,5-dichloropyridazin-3(2H)-one as acyl transfer agent under transition-metal-free conditions, (Scheme 1(a)), but, this reagent is expensive and additional POCl3 is needed. Liu and Chung have reported [22][23][24] the synthesis of benzothiazoles from 2-aminobenzenethiol using silane as a CO2 fixing agent. However, the practicality of these methods is offset by the need for a special reactor, the stoichiometric amount of catalyst and limited substrate scope which diminish their synthetic utility in practical application (Scheme 1(b-d)). Bhanage et al. [25] have reported an improved method to form benzimidazoles from O-phenylenediamines and DMF. In their reports, a metal catalyst (Zn(OAc)2) was employed (Scheme 1(e)). Recently, Das et al. [26] reported oxalic/malonic acids as carbon building blocks for benzoxazole, quinazoline and quinazolinone synthesis. In their reports, a large amount (4-8 equiv.) of corrosive oxalic/malonic acids were employed (Scheme 1(f)). However, most of these methods suffer from one or more disvantages, including the use of some environmental unfriendly catalysts, the use of expensive reagents, long reaction times, toxic or nonreusable catalysts, metal catalysts and additional reagents. Therefore, efficient and environmentally friendly syntheses of 2-substituted benzoxazoles and 2-substituted benzothiazoles heterocycles are of great importance. We have recently reported [27,28] the use of imidazolium chloride as catalyst and DMF derivatives as eco-friendly carbon sources in the formation of amido bonds and benzimidazole derivatives (Scheme 2). We envisioned that this process might be extended to 2aminophenols and 2-aminothiophenols, which would provide access to benzoxazole and benzothiazole derivatives using inexpensive, stable, and easy to synthesize DMF derivatives as carbon sources and imidazolium chloride as the promoter [29][30][31]. However, most of these methods suffer from one or more disvantages, including the use of some environmental unfriendly catalysts, the use of expensive reagents, long reaction times, toxic or non-reusable catalysts, metal catalysts and additional reagents. Therefore, efficient and environmentally friendly syntheses of 2-substituted benzoxazoles and 2-substituted benzothiazoles heterocycles are of great importance. We have recently reported [27,28] the use of imidazolium chloride as catalyst and DMF derivatives as eco-friendly carbon sources in the formation of amido bonds and benzimidazole derivatives (Scheme 2). We envisioned that this process might be extended to 2-aminophenols and 2-aminothiophenols, which would provide access to benzoxazole and benzothiazole derivatives using inexpensive, stable, and easy to synthesize DMF derivatives as carbon sources and imidazolium chloride as the promoter [29][30][31].

Results and Discussion
Considering the imidazolium chloride catalyst system has been successfully applied in the formation of amido bonds and benzimidazole derivatives, next, we attempted to synthesize 2substituted benzoxazole derivatives by reacting O-aminophenol with DMF derivatives under the

Results and Discussion
Considering the imidazolium chloride catalyst system has been successfully applied in the formation of amido bonds and benzimidazole derivatives, next, we attempted to synthesize 2-substituted benzoxazole derivatives by reacting O-aminophenol with DMF derivatives under the same conditions, however, the results showed that the main products were acetamide intermediates due to the less reactivity of the hydroxyl group compared to the amino group under these conditions ( Table 1, entries 1-4).

Results and Discussion
Considering the imidazolium chloride catalyst system has been successfully applied in the formation of amido bonds and benzimidazole derivatives, next, we attempted to synthesize 2substituted benzoxazole derivatives by reacting O-aminophenol with DMF derivatives under the same conditions, however, the results showed that the main products were acetamide intermediates due to the less reactivity of the hydroxyl group compared to the amino group under these conditions ( Table 1, entries 1-4). The results of our experiments to optimize the reaction conditions for the synthesis of 2substituted benzoxazoles, using 2-aminophenol (1a) as a model substrate, are listed in Table 2.

Results and Discussion
Considering the imidazolium chloride catalyst system has been successfully applied in the formation of amido bonds and benzimidazole derivatives, next, we attempted to synthesize 2substituted benzoxazole derivatives by reacting O-aminophenol with DMF derivatives under the same conditions, however, the results showed that the main products were acetamide intermediates due to the less reactivity of the hydroxyl group compared to the amino group under these conditions ( Table 1, entries 1-4).

Results and Discussion
Considering the imidazolium chloride catalyst system has been successfully applied in the formation of amido bonds and benzimidazole derivatives, next, we attempted to synthesize 2substituted benzoxazole derivatives by reacting O-aminophenol with DMF derivatives under the same conditions, however, the results showed that the main products were acetamide intermediates due to the less reactivity of the hydroxyl group compared to the amino group under these conditions ( Table 1, entries 1-4).

Results and Discussion
Considering the imidazolium chloride catalyst system has been successfully applied in the formation of amido bonds and benzimidazole derivatives, next, we attempted to synthesize 2substituted benzoxazole derivatives by reacting O-aminophenol with DMF derivatives under the same conditions, however, the results showed that the main products were acetamide intermediates due to the less reactivity of the hydroxyl group compared to the amino group under these conditions ( Table 1, entries 1-4).

Results and Discussion
Considering the imidazolium chloride catalyst system has been successfully applied in the formation of amido bonds and benzimidazole derivatives, next, we attempted to synthesize 2substituted benzoxazole derivatives by reacting O-aminophenol with DMF derivatives under the same conditions, however, the results showed that the main products were acetamide intermediates due to the less reactivity of the hydroxyl group compared to the amino group under these conditions ( Table 1, entries 1-4).

Results and Discussion
Considering the imidazolium chloride catalyst system has been successfully applied in the formation of amido bonds and benzimidazole derivatives, next, we attempted to synthesize 2substituted benzoxazole derivatives by reacting O-aminophenol with DMF derivatives under the same conditions, however, the results showed that the main products were acetamide intermediates due to the less reactivity of the hydroxyl group compared to the amino group under these conditions ( Table 1, entries 1-4). Considering the imidazolium chloride catalyst system has been successfully applied in the formation of amido bonds and benzimidazole derivatives, next, we attempted to synthesize 2substituted benzoxazole derivatives by reacting O-aminophenol with DMF derivatives under the same conditions, however, the results showed that the main products were acetamide intermediates due to the less reactivity of the hydroxyl group compared to the amino group under these conditions ( Table 1, entries 1-4).

DMA
Considering the imidazolium chloride catalyst system has been successfully applied in the formation of amido bonds and benzimidazole derivatives, next, we attempted to synthesize 2substituted benzoxazole derivatives by reacting O-aminophenol with DMF derivatives under the same conditions, however, the results showed that the main products were acetamide intermediates due to the less reactivity of the hydroxyl group compared to the amino group under these conditions ( Table 1, entries 1-4).  The results of our experiments to optimize the reaction conditions for the synthesis of 2substituted benzoxazoles, using 2-aminophenol (1a) as a model substrate, are listed in Table 2.  The results of our experiments to optimize the reaction conditions for the synthesis of 2substituted benzoxazoles, using 2-aminophenol (1a) as a model substrate, are listed in Table 2.  The results of our experiments to optimize the reaction conditions for the synthesis of 2substituted benzoxazoles, using 2-aminophenol (1a) as a model substrate, are listed in Table 2.  The results of our experiments to optimize the reaction conditions for the synthesis of 2-substituted benzoxazoles, using 2-aminophenol (1a) as a model substrate, are listed in Table 2.
Initially, the reaction did not occur in DMA without imdazolium chloride ( Table 2, entry 1) and 0.5 equiv. of HCl was found to give only traces of product 2a ( Table 2, entry 2). The reaction was performed in DMA at 140 • C and we obtained a 18% yield of the product ( Table 2, entry 3). Furthermore, on increasing the temperature to 150 and 160 • C for 8 h the product was obtained in 43% and 60% yield, respectively (Table 2, entries 4, 5), indicating that the reaction was highly sensitive to temperature. Encouraged by this promising result, next, with the aim to decrease the imidazolium chloride loading, we then carried out the reaction at 160 • C. It was observed that under these conditions 0.5 equiv. of imidazolium chloride were sufficient to obtain a good yield, and no further improvements in the yield of the target product were observed with higher mole equivalents of imidazolium chloride ( Table 2, entries 8, 9 and 10). In addition, we tried various solvents like xylenes, water and benzene, but unsatisfactory yields of the product was obtained (Table 2, entries 11, 12 and 13).
The results of our experiments to optimize the reaction conditions for the synthesis of 2substituted benzoxazoles, using 2-aminophenol (1a) as a model substrate, are listed in Table 2. Initially, the reaction did not occur in DMA without imdazolium chloride ( Table 2, entry 1) and 0.5 equiv. of HCl was found to give only traces of product 2a ( Table 2, entry 2). The reaction was performed in DMA at 140 °C and we obtained a 18% yield of the product ( Table 2, entry 3). Furthermore, on increasing the temperature to 150 and 160 °C for 8 h the product was obtained in 43% and 60% yield, respectively (Table 2, entries 4, 5), indicating that the reaction was highly sensitive to temperature. Encouraged by this promising result, next, with the aim to decrease the imidazolium chloride loading, we then carried out the reaction at 160 °C. It was observed that under these conditions 0.5 equiv. of imidazolium chloride were sufficient to obtain a good yield, and no further improvements in the yield of the target product were observed with higher mole equivalents of  Under the optimized conditions, we next set out to examine the scope and limitations of this reaction and the results are shown in Table 3. All the substrates listed afforded the corresponding target product, under the standard conditions, in moderate to good yield (52-87%). Both electron-donating and electron-withdrawing groups were tolerated under the reaction conditions. Mono-substituents on the benzene moiety showed no obvious influence on the reaction outcome and produced desired products in good yields (Table 3, 2a, 2c, 2g and 2h). It is noteworthy to mention that a functional group like bromo (Table 3, 2h) is tolerable under this condition. With aromatic-substituted substrates, the reaction affords the corresponding benzoxazole derivatives 2b-f, 2d and 2g in 52-86% yields, respectively (Table 2, entries 2, 3, 4, 7 and 9), although a longer reaction time is required. However, when the phenyl ring bore electron-withdrawing substituents, such as a nitro group (Table 3, 2f), the yield was decreased. These results suggest that the electron-withdrawing groups disfavor the formation of the activated reaction intermediate.
Next, to evaluate further the scope of this methodology, the reaction was carried out with a series of O-aminothiophenol and DMF derivatives, affording the corresponding target products in moderate to good yields (Table 4), under the same optimized conditions. Different para substituents on the O-aminothiophenols 3a-d also gave good yields (75-85%, Table 4, 4a-4k). Similarly, the cyclization reactions of O-aminophenol with aromatic-substituted DMF derivatives also gave the target products 4e-4k in excellent yields. 2-amino-5-nitrobenzenethiol and N,N-Dimethyl-4-nitrobenzamide acid dimethylamide substrate were also found to be stabilized under the conditions and gave the desired products 4d and 4g in moderate yields (75%, 60% and 75%). In addition, a heteroaromatic substrate was well tolerated and gave the desired target product 4j in 75% yield. To explore the reaction mechanism, control experiments were conducted under the standard reaction conditions. By stirring N-(2-hydroxyphenyl)-acetamide with DMA at 140 • C for 8 h in the presence of 0.1 eq imidazolium chloride only 12% yield of target product was obtained (Scheme 3), while a satisfactory yield (85%) was observed at 160 • C, indicating that the reaction was highly sensitive to temperature. substituted substrates, the reaction affords the corresponding benzoxazole derivatives 2b-f, 2d and 2g in 52-86% yields, respectively (Table 2, entries 2, 3, 4, 7 and 9), although a longer reaction time is required. However, when the phenyl ring bore electron-withdrawing substituents, such as a nitro group (Table 3, 2f), the yield was decreased. These results suggest that the electron-withdrawing groups disfavor the formation of the activated reaction intermediate. required. However, when the phenyl ring bore electron-withdrawing substituents, such as a nitro group (Table 3, 2f), the yield was decreased. These results suggest that the electron-withdrawing groups disfavor the formation of the activated reaction intermediate. required. However, when the phenyl ring bore electron-withdrawing substituents, such as a nitro group (Table 3, 2f), the yield was decreased. These results suggest that the electron-withdrawing groups disfavor the formation of the activated reaction intermediate.     Next, to evaluate further the scope of this methodology, the reaction was carried out with a series of O-aminothiophenol and DMF derivatives, affording the corresponding target products in moderate to good yields (Table 4), under the same optimized conditions.  Next, to evaluate further the scope of this methodology, the reaction was carried out with a series of O-aminothiophenol and DMF derivatives, affording the corresponding target products in moderate to good yields (Table 4), under the same optimized conditions.  Next, to evaluate further the scope of this methodology, the reaction was carried out with a series of O-aminothiophenol and DMF derivatives, affording the corresponding target products in moderate to good yields (Table 4), under the same optimized conditions.  Next, to evaluate further the scope of this methodology, the reaction was carried out with a series of O-aminothiophenol and DMF derivatives, affording the corresponding target products in moderate to good yields (Table 4), under the same optimized conditions.  Next, to evaluate further the scope of this methodology, the reaction was carried out with a series of O-aminothiophenol and DMF derivatives, affording the corresponding target products in moderate to good yields (Table 4), under the same optimized conditions.  a Experiments were performed with substance 1 (5 mmol) and DMA (5 mL) at 160 °C for 8 h. b Yields after column purification. C Experiments were performed with substance 1 (5 mmol) and DMA derivatives (10 mmol) at 160 °C for 10 h. Next, to evaluate further the scope of this methodology, the reaction was carried out with a series of O-aminothiophenol and DMF derivatives, affording the corresponding target products in moderate to good yields (Table 4), under the same optimized conditions. a Experiments were performed with substance 1 (5 mmol) and DMA (5 mL) at 160 °C for 8 h. b Yields after column purification. C Experiments were performed with substance 1 (5 mmol) and DMA derivatives (10 mmol) at 160 °C for 10 h.
Next, to evaluate further the scope of this methodology, the reaction was carried out with a series of O-aminothiophenol and DMF derivatives, affording the corresponding target products in moderate to good yields (Table 4), under the same optimized conditions. a Experiments were performed with substance 1 (5 mmol) and DMA (5 mL) at 160 °C for 8 h. b Yields after column purification. C Experiments were performed with substance 1 (5 mmol) and DMA derivatives (10 mmol) at 160 °C for 10 h.
Next, to evaluate further the scope of this methodology, the reaction was carried out with a series of O-aminothiophenol and DMF derivatives, affording the corresponding target products in moderate to good yields (Table 4), under the same optimized conditions. 10 a Experiments were performed with substance 1 (5 mmol) and DMA (5 mL) at 160 °C for 8 h. b Yields after column purification. C Experiments were performed with substance 1 (5 mmol) and DMA derivatives (10 mmol) at 160 °C for 10 h.
Next, to evaluate further the scope of this methodology, the reaction was carried out with a series of O-aminothiophenol and DMF derivatives, affording the corresponding target products in moderate to good yields (Table 4), under the same optimized conditions. Next, to evaluate further the scope of this methodology, the reaction was carried out with a series of O-aminothiophenol and DMF derivatives, affording the corresponding target products in moderate to good yields (Table 4), under the same optimized conditions. Next, to evaluate further the scope of this methodology, the reaction was carried out with a series of O-aminothiophenol and DMF derivatives, affording the corresponding target products in moderate to good yields (Table 4), under the same optimized conditions. Next, to evaluate further the scope of this methodology, the reaction was carried out with a series of O-aminothiophenol and DMF derivatives, affording the corresponding target products in moderate to good yields (Table 4), under the same optimized conditions. of O-aminothiophenol and DMF derivatives, affording the corresponding target products in moderate to good yields (Table 4), under the same optimized conditions. of O-aminothiophenol and DMF derivatives, affording the corresponding target products in moderate to good yields (Table 4), under the same optimized conditions. of O-aminothiophenol and DMF derivatives, affording the corresponding target products in moderate to good yields (Table 4), under the same optimized conditions. Different para substituents on the O-aminothiophenols 3a-d also gave good yields (75-85%, Table 4, 4a-4k). Similarly, the cyclization reactions of O-aminophenol with aromatic-substituted DMF derivatives also gave the target products 4e-4k in excellent yields. 2-amino-5-nitrobenzenethiol and N,N-Dimethyl-4-nitrobenzamide acid dimethylamide substrate were also found to be stabilized under the conditions and gave the desired products 4d and 4g in moderate yields (75%, 60% and 75%). In addition, a heteroaromatic substrate was well tolerated and gave the desired target product Different para substituents on the O-aminothiophenols 3a-d also gave good yields (75-85%, Table 4, 4a-4k). Similarly, the cyclization reactions of O-aminophenol with aromatic-substituted DMF derivatives also gave the target products 4e-4k in excellent yields. 2-amino-5-nitrobenzenethiol and N,N-Dimethyl-4-nitrobenzamide acid dimethylamide substrate were also found to be stabilized under the conditions and gave the desired products 4d and 4g in moderate yields (75%, 60% and 75%). In addition, a heteroaromatic substrate was well tolerated and gave the desired target product  Different para substituents on the O-aminothiophenols 3a-d also gave good yields (75-85%, Table 4, 4a-4k). Similarly, the cyclization reactions of O-aminophenol with aromatic-substituted DMF derivatives also gave the target products 4e-4k in excellent yields. 2-amino-5-nitrobenzenethiol and N,N-Dimethyl-4-nitrobenzamide acid dimethylamide substrate were also found to be stabilized under the conditions and gave the desired products 4d and 4g in moderate yields (75%, 60% and 75%). In addition, a heteroaromatic substrate was well tolerated and gave the desired target product  Different para substituents on the O-aminothiophenols 3a-d also gave good yields (75-85%, Table 4, 4a-4k). Similarly, the cyclization reactions of O-aminophenol with aromatic-substituted DMF derivatives also gave the target products 4e-4k in excellent yields. 2-amino-5-nitrobenzenethiol and N,N-Dimethyl-4-nitrobenzamide acid dimethylamide substrate were also found to be stabilized under the conditions and gave the desired products 4d and 4g in moderate yields (75%, 60% and 75%). In addition, a heteroaromatic substrate was well tolerated and gave the desired target product 4j in 75% yield. To explore the reaction mechanism, control experiments were conducted under the standard reaction conditions. By stirring N- ( Different para substituents on the O-aminothiophenols 3a-d also gave good yields (75-85%, Table 4, 4a-4k). Similarly, the cyclization reactions of O-aminophenol with aromatic-substituted DMF derivatives also gave the target products 4e-4k in excellent yields. 2-amino-5-nitrobenzenethiol and N,N-Dimethyl-4-nitrobenzamide acid dimethylamide substrate were also found to be stabilized under the conditions and gave the desired products 4d and 4g in moderate yields (75%, 60% and 75%). In addition, a heteroaromatic substrate was well tolerated and gave the desired target product 4j in 75% yield. To explore the reaction mechanism, control experiments were conducted under the standard reaction conditions. By stirring N- ( Different para substituents on the O-aminothiophenols 3a-d also gave good yields (75-85%, Table 4, 4a-4k). Similarly, the cyclization reactions of O-aminophenol with aromatic-substituted DMF derivatives also gave the target products 4e-4k in excellent yields. 2-amino-5-nitrobenzenethiol and N,N-Dimethyl-4-nitrobenzamide acid dimethylamide substrate were also found to be stabilized under the conditions and gave the desired products 4d and 4g in moderate yields (75%, 60% and 75%). In addition, a heteroaromatic substrate was well tolerated and gave the desired target product 4j in 75% yield. To explore the reaction mechanism, control experiments were conducted under the standard reaction conditions. By stirring N-(2-hydroxyphenyl)-acetamide with DMA at 140 °C for 8 h in the presence of 0.1 eq imidazolium chloride only 12% yield of target product was obtained

Conclusions
In conclusion, in the present work, we have reported a new, efficient, metal free and economical method to synthesize 2-substituted benzoxazoles and 2-substituted benzothiazoles from 2-aminophenols or 2-aminothiophenols and DMF derivatives in the presence of imidazolium chloride without any other catalysts or additives. This method has wide substrate scope, providing moderate to excellent yields of the target products. Further applications of imidazolium chloride in the synthesis of other heterocycles or important medical intermediates are currently under investigation in our laboratory.

General Information
All reagents were purchased from Ltd. (Shenzhen, China), Meyer Reagent Co., Ltd. (Shanghai, China), Macklin Reagent Co., Ltd. (Shanghai, China), Chongqing Chuandong Chemical Co., Ltd. (Chongqing, China). etc., and used without further purification. 1 H-(600 MHz) and 13 C-NMR (151 MHz) spectra were recorded on an Avance III NMR spectrometer (Bruker, Bruker, Fällande, Switzerland) in CDCl3 using tetramethylsilane (TMS) or the residual CHCl3 signals as internally reference. Chemical shifts are reported in ppm and coupling constants (J) in Hz. Open-bed chromatography was carried out on silica gel (200-300 mesh, Qingdao, China) using gravity flow. All substrates are known compounds according to the literature.

Conclusions
In conclusion, in the present work, we have reported a new, efficient, metal free and economical method to synthesize 2-substituted benzoxazoles and 2-substituted benzothiazoles from 2-amino-phenols or 2-aminothiophenols and DMF derivatives in the presence of imidazolium chloride without any other catalysts or additives. This method has wide substrate scope, providing moderate to excellent yields of the target products. Further applications of imidazolium chloride in the synthesis of other heterocycles or important medical intermediates are currently under investigation in our laboratory.

General Information
All reagents were purchased from Ltd. (Shenzhen, China), Meyer Reagent Co., Ltd. (Shanghai, China), Macklin Reagent Co., Ltd. (Shanghai, China), Chongqing Chuandong Chemical Co., Ltd. (Chongqing, China). etc., and used without further purification. 1 H-(600 MHz) and 13 C-NMR (151 MHz) spectra were recorded on an Avance III NMR spectrometer (Bruker, Bruker, Fällande, Switzerland) in CDCl 3 using tetramethylsilane (TMS) or the residual CHCl 3 signals as internally reference. Chemical shifts are reported in ppm and coupling constants (J) in Hz. Open-bed chromatography was carried out on silica gel (200-300 mesh, Qingdao, China) using gravity flow. All substrates are known compounds according to the literature.

General Procedure for the Synthesis of Benzoxazole Derivatives 2a-2d
A mixture of 1a (0.6 g, 5.5 mmol, 1 equiv.), imidazolium chloride (0.17 g, 1.65 mmol, 0.3 equiv.) and DMA (5 mL) was stirred at 140 • C for 8 h. When the reaction was completed, water (15 mL) and ethyl acetate (20 mL) were added with stirring to the reaction mixture. The organic layer was extracted and dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel using PE/EA as eluent to give the target product 2a. Benzoxazole Derivatives 2a, 2c, 2g and 2h and Benzothiazole Derivatives 4a-4d

General Procedure for the Synthesis of
A tube-type Schlenk flask was charged with 1a (0.6 g, 5.5 mmol, 1 equiv.), imidazolium chloride (0.28 g, 2.75 mmol, 0.5 equiv.) and DMA (5 mL) and the mixture was stirred at 160 • C for 8 h. When the reaction was complete water (15 mL) and ethyl acetate (20 mL) were added with stirring to the reaction mixture. The organic layer was extracted and dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel using PE/EA as eluent to give the corresponding product 4a.