The Synthesis of 2-Aminobenzoxazoles Using Reusable Ionic Liquid as a Green Catalyst under Mild Conditions

A facile, green, and efficient method for the direct oxidative amination of benzoxazoles using heterocyclic ionic liquid as catalyst has been developed. The reaction proceeded smoothly at room temperature and gave the desirable 2-aminobenzoxazoles with good to excellent yields (up to 97%). The catalyst 1-butylpyridinium iodide can be easily recycled and reused with similar efficacies for at least four cycles.

Recently, metal-free-catalyzed oxidative coupling reactions have undergone rapid advances in order to solve drawbacks of transition metal catalysis [21][22][23][24][25]. Thus, the discovery of green and sustainable oxidative C-H amination of benzoxazoles under metal-free conditions will be of great value. Hypervalent iodine compounds have gained much attention in organic synthesis as versatile and powerful oxidants [26][27][28][29]. For example, Chang and co-workers [30] employed stoichiometric amounts of PhI(OAc) 2 , and Bhanage et al. [31]. used 2-iodoxybenzoic acid (IBX) to get direct oxidative C-H bond amination of benzoxazoles. Moreover, much progress in the direct oxidative amination of benzoxazoles has been achieved through the use of a combination of an iodine source and oxidant [32][33][34][35][36][37][38]. For instance, a metal-free approach for the oxidative amination of benzoxazoles using molecular iodine as a catalyst and tert-butyl hydroperoxide (TBHP) as an oxidant was reported by Lamani and Prabhu [32]. At the same time, another report was presented by Nachtsheim's group on the oxidative C-H amination of benzoxazoles under metal-free conditions using tetrabutylammonium iodide (TBAI) as catalyst and aqueous solutions of H2O2 or TBHP as co-oxidant at 80 °C (Scheme 1b) [33]. These catalytic systems effectively overcome some drawbacks of using stoichiometric amounts of hypervalent iodine compounds. Nevertheless, these approaches still suffer from minor drawbacks, such as high temperature, long reaction time, and low yields. Therefore, designing a highly mild, efficient, green, and recyclable catalyst system for the oxidative C-H amination of benzoxazoles under metal-free conditions at room temperature is desperately needed.
Ionic liquids (ILs) have attracted continuing interest from the majority of chemists. ILs were usually used as green reaction media because of their unique chemical and physical properties, such as high thermal stabilities, negligible vapor pressures, and nonflammability [39][40][41][42][43][44]. Recently, ILs have been employed as solvents in transition-metal-catalyzed C-H activation reactions [45][46][47][48][49]. However, it is important to note that there are few examples of the C-H bond activation reaction using classical heterocyclic ionic liquids as promoters or catalysts. We recently developed the first oxidative cross-coupling reaction for C-C bond formation promoted by ionic liquid 1,3-dibutyl-1H-benzo[d] [1,2,3]triazol-3-ium bromide [50]. Soon after, the first study using IL-catalyzed C-H activation reaction for C-N bond formation has been disclosed [51]. Inspired by these works, we herein report a mild, efficient, and metal-free strategy for C-H oxidative amination of benzoxazoles by using heterocyclic ionic liquid 1-butylpyridinium iodide ([BPy]I) as catalyst, TBHP as oxidant, and acetic acid as an additive at room temperature (Scheme 1c). Scheme 1. Reported and designed routes for the oxidative amination of benzoxazoles. IL: ionic liquid; TBHP: tert-butyl hydroperoxide. Equiv: equivalent

Results and Discussion
The investigation started with the reaction of benzoxazole (1a) and morpholine (2a) as model substrates (Table 1). In the presence of 5 mol% [BPy]I, 1.5 equiv. of TBHP, and 3 equiv. of acetic acid, the reaction of 1a and 2a was proceeded at room temperature for 7 h to give 2-morpholinobenzo[d]oxazole (3a) in 94% yield (Table 1, entry 1). Encouraged by the result, further optimization of the reaction conditions was carried out. Unfortunately, when other ionic liquids (e.g., 1-butylpyridinium chloride ([BPy]Cl) and 1-butylpyridinium bromide ([BPy]Br)) were in this reaction system or the system was run in the absence of catalyst, the response almost did not give satisfactory results (

Results and Discussion
The investigation started with the reaction of benzoxazole (1a) and morpholine (2a) as model substrates (Table 1). In the presence of 5 mol% [BPy]I, 1.5 equiv. of TBHP, and 3 equiv. of acetic acid, the reaction of 1a and 2a was proceeded at room temperature for 7 h to give 2-morpholinobenzo[d]oxazole (3a) in 94% yield ( Table 1, entry 1). Encouraged by the result, further optimization of the reaction conditions was carried out. Unfortunately, when other ionic liquids (e.g., 1-butylpyridinium chloride ([BPy]Cl) and 1-butylpyridinium bromide ([BPy]Br)) were in this reaction system or the system was run in the absence of catalyst, the response almost did not give satisfactory results (  6,[8][9][10]. In water and under solvent-free condition, product 3a was obtained in lower yields of 57% and 51%, respectively (Table 1, entries [11][12]. Other oxidants, such as benzoyl peroxide (BPO), m-chloroperoxybenzoic acid (m-CPBA), di-tert-butyl peroxide (DTBP), and H 2 O 2 were used instead of TBHP (Table 1, entries [13][14][15][16], the effect of reactions decreased dramatically and TBHP was proven to be the best oxidant. optimal solvent (Table 1, entries 6, 8-10). In water and under solvent-free condition, product 3a was obtained in lower yields of 57% and 51%, respectively (Table 1, entries [11][12]. Other oxidants, such as benzoyl peroxide (BPO), m-chloroperoxybenzoic acid (m-CPBA), di-tert-butyl peroxide (DTBP), and H2O2 were used instead of TBHP (Table 1, entries [13][14][15][16], the effect of reactions decreased dramatically and TBHP was proven to be the best oxidant. Under optimized reaction conditions, benzoxazole (1a) and various cyclic or acyclic secondary amines (2) were investigated to examine the scope of the process. The results are listed in Scheme 2. Piperidine, thiomorpholine, 3-methylpiperidine, and 1-methylpiperazine reacted smoothly with benzoxazole to form the corresponding amination products 3b, 3c, 3d, and 3e in good to excellent yields (Scheme 2). The introduction of heteroatom and substituent on piperidine had no impact on the reaction system. Subsequently, it was found that both electron-donating and electron-withdrawing groups on the piperazine-such as methyl, phenyl, acetyl, ethoxycarbonyl, and tert-butoxycarbonyl-reacted effectively with benzoxazole (1a) to provide the respective aminobenzoxazoles (Scheme 2, 3e: 90%, 3f: 97%, 3g: 91%, 3h: 82%, 3i: 95%). As is well known, 2-(N-alkylpiperazyl)benzoxazoles of this type were already described as potent 5-HT3-receptor antagonists [2]. The coupling of benzoxazole proceeded successfully with 1,2,3,4-tetrahydroisoquinoline to give the desired aminated product 3j in 93% yield (Scheme 2). In addition to cyclic amines, acyclic secondary amines such as diethylamine, dibenzylamine, and diallylamine reacted well with benzoxazole to produce the desired products 3k-3m in good to excellent yields (Scheme 2). To our delight, oxidations or halogenations of the methylene units, the aromatic ring, or the double bonds did not occur. It should be mentioned that N,N-diallylbenzoxazol-2-amine (3m) was regarded as one of the useful organic synthetic intermediates. Under optimized reaction conditions, benzoxazole (1a) and various cyclic or acyclic secondary amines (2) were investigated to examine the scope of the process. The results are listed in Scheme 2. Piperidine, thiomorpholine, 3-methylpiperidine, and 1-methylpiperazine reacted smoothly with benzoxazole to form the corresponding amination products 3b, 3c, 3d, and 3e in good to excellent yields (Scheme 2). The introduction of heteroatom and substituent on piperidine had no impact on the reaction system. Subsequently, it was found that both electron-donating and electron-withdrawing groups on the piperazine-such as methyl, phenyl, acetyl, ethoxycarbonyl, and tert-butoxycarbonyl-reacted effectively with benzoxazole (1a) to provide the respective aminobenzoxazoles (Scheme 2, 3e: 90%, 3f: 97%, 3g: 91%, 3h: 82%, 3i: 95%). As is well known, 2-(N-alkylpiperazyl)benzoxazoles of this type were already described as potent 5-HT 3 -receptor antagonists [2]. The coupling of benzoxazole proceeded successfully with 1,2,3,4-tetrahydroisoquinoline to give the desired aminated product 3j in 93% yield (Scheme 2). In addition to cyclic amines, acyclic secondary amines such as diethylamine, dibenzylamine, and diallylamine reacted well with benzoxazole to produce the desired products 3k-3m in good to excellent yields (Scheme 2). To our delight, oxidations or halogenations of the methylene units, the aromatic ring, or the double bonds did not occur. It should be mentioned that N,N-diallylbenzoxazol-2-amine (3m) was regarded as one of the useful organic synthetic intermediates. To further study the potential of our method, we turned our attention to the amination reaction between various benzoxazoles and morpholine. The results are summarized in Scheme 3. Methyl-and halogen-substituted benzoxazoles could be easily aminated to generate the desired products 4a-4d in up to 97% yield with perfect regioselectivity. To expand the potential of the present synthetic methodology, a diversity of benzoxazoles including 5-methylbenzoxazole, 6-methylbenzoxazole, and 5-chlorobenzoxazole reacted satisfactorily with various linear and cyclic secondary amines such as diallylamine, dibenzylamine, and tert-butyl piperazine-1-carboxylate to furnish the corresponding 2-aminobenzothiazole derivatives 4e-4i in good to excellent yields (84-94%). To further study the potential of our method, we turned our attention to the amination reaction between various benzoxazoles and morpholine. The results are summarized in Scheme 3. Methyland halogen-substituted benzoxazoles could be easily aminated to generate the desired products 4a-4d in up to 97% yield with perfect regioselectivity. To expand the potential of the present synthetic methodology, a diversity of benzoxazoles including 5-methylbenzoxazole, 6-methylbenzoxazole, and 5-chlorobenzoxazole reacted satisfactorily with various linear and cyclic secondary amines such as diallylamine, dibenzylamine, and tert-butyl piperazine-1-carboxylate to furnish the corresponding 2-aminobenzothiazole derivatives 4e-4i in good to excellent yields (84%-94%). To further study the potential of our method, we turned our attention to the amination reaction between various benzoxazoles and morpholine. The results are summarized in Scheme 3. Methyl-and halogen-substituted benzoxazoles could be easily aminated to generate the desired products 4a-4d in up to 97% yield with perfect regioselectivity. To expand the potential of the present synthetic methodology, a diversity of benzoxazoles including 5-methylbenzoxazole, 6-methylbenzoxazole, and 5-chlorobenzoxazole reacted satisfactorily with various linear and cyclic secondary amines such as diallylamine, dibenzylamine, and tert-butyl piperazine-1-carboxylate to furnish the corresponding 2-aminobenzothiazole derivatives 4e-4i in good to excellent yields (84-94%). To demonstrate the potential industrial utility of our protocol, the [BPy]I-catalyzed scale-up reaction was performed. The direct oxidative amination of benzoxazole (1a) with morpholine was easily carried out under the standard reaction conditions to generate the desired product 3a in 93% isolated yield (Scheme 4). To demonstrate the potential industrial utility of our protocol, the [BPy]I-catalyzed scale-up reaction was performed. The direct oxidative amination of benzoxazole (1a) with morpholine was easily carried out under the standard reaction conditions to generate the desired product 3a in 93% isolated yield (Scheme 4).
Ionic liquids have several advantages compared with other catalysts; for example, they are recyclable and environmentally friendly. The coupling reaction of 5-methylbenzoxazole and morpholine was chosen as a model system to study the reusability of the [BPy]I as catalyst under the standard reaction conditions. After the reaction was finished, ethyl acetate and water were added, and then the [BPy]I was recovered from the water layer and reused after drying in vacuo. The [BPy]I was utilized repeatedly at least four times without any significant loss of activity ( Figure  1). In order to elucidate the reaction mechanism, control experiments were carried out. When the radical scavenger BHT (2,6-di-tert-butyl-4-methylphenol, 3 equiv.), ethene-1,1-diyldibenzene (3 equiv.), or TEMPO (2,2,6,6-tetramethylpiperidine-N-oxyl, 3 equiv.) were added to the reaction mixture under the optimal conditions, the yield of 3a was not decreased. Thus, the reaction may not be a radical reaction. Subsequently, N-iodomorpholine hydroiodide was prepared. Then, the reaction of benzoxazole (0.672 mmol, 1 equiv.) and N-iodomorpholine hydroiodide (0.672 mmol, 1 equiv.) with acetic acid (2.016 mmol, 3 equiv.) as an additive in 2 mL CH3CN at room temperature for 3.5 h afforded the desired product 3a in 25% yield ( Table 2, entry 1). When the dosage of N-iodomorpholine hydroiodide was increased from 1 equiv. to 2 equiv., the desired amination product was obtained in 53% yield ( Table 2, entry 2). It is worth noting that the reaction of 1a and 2a underwent smoothly in the presence of 15 mol% N-iodomorpholine hydroiodide, 1.5 equiv. TBHP, and 3 equiv. acetic acid to give 2-morpholinobenzo[d]oxazole (3a) in 95% yield ( Table 2, entry 3). All of the above results indicate that the activation of the morpholine (2a) via in situ preparation of a highly reactive N-I bond from [BPy]I and TBHP seems plausible.  Ionic liquids have several advantages compared with other catalysts; for example, they are recyclable and environmentally friendly. The coupling reaction of 5-methylbenzoxazole and morpholine was chosen as a model system to study the reusability of the [BPy]I as catalyst under the standard reaction conditions. After the reaction was finished, ethyl acetate and water were added, and then the [BPy]I was recovered from the water layer and reused after drying in vacuo. The [BPy]I was utilized repeatedly at least four times without any significant loss of activity ( Figure 1). To demonstrate the potential industrial utility of our protocol, the [BPy]I-catalyzed scale-up reaction was performed. The direct oxidative amination of benzoxazole (1a) with morpholine was easily carried out under the standard reaction conditions to generate the desired product 3a in 93% isolated yield (Scheme 4).
Ionic liquids have several advantages compared with other catalysts; for example, they are recyclable and environmentally friendly. The coupling reaction of 5-methylbenzoxazole and morpholine was chosen as a model system to study the reusability of the [BPy]I as catalyst under the standard reaction conditions. After the reaction was finished, ethyl acetate and water were added, and then the [BPy]I was recovered from the water layer and reused after drying in vacuo. The [BPy]I was utilized repeatedly at least four times without any significant loss of activity ( Figure  1). In order to elucidate the reaction mechanism, control experiments were carried out. When the radical scavenger BHT (2,6-di-tert-butyl-4-methylphenol, 3 equiv.), ethene-1,1-diyldibenzene (3 equiv.), or TEMPO (2,2,6,6-tetramethylpiperidine-N-oxyl, 3 equiv.) were added to the reaction mixture under the optimal conditions, the yield of 3a was not decreased. Thus, the reaction may not be a radical reaction. Subsequently, N-iodomorpholine hydroiodide was prepared. Then, the reaction of benzoxazole (0.672 mmol, 1 equiv.) and N-iodomorpholine hydroiodide (0.672 mmol, 1 equiv.) with acetic acid (2.016 mmol, 3 equiv.) as an additive in 2 mL CH3CN at room temperature for 3.5 h afforded the desired product 3a in 25% yield ( Table 2, entry 1). When the dosage of N-iodomorpholine hydroiodide was increased from 1 equiv. to 2 equiv., the desired amination product was obtained in 53% yield (Table 2, entry 2). It is worth noting that the reaction of 1a and 2a underwent smoothly in the presence of 15 mol% N-iodomorpholine hydroiodide, 1.5 equiv. TBHP, and 3 equiv. acetic acid to give 2-morpholinobenzo[d]oxazole (3a) in 95% yield ( Table 2, entry 3). All of the above results indicate that the activation of the morpholine (2a) via in situ preparation of a highly reactive N-I bond from [BPy]I and TBHP seems plausible.  In order to elucidate the reaction mechanism, control experiments were carried out. When the radical scavenger BHT (2,6-di-tert-butyl-4-methylphenol, 3 equiv.), ethene-1,1-diyldibenzene (3 equiv.), or TEMPO (2,2,6,6-tetramethylpiperidine-N-oxyl, 3 equiv.) were added to the reaction mixture under the optimal conditions, the yield of 3a was not decreased. Thus, the reaction may not be a radical reaction. Subsequently, N-iodomorpholine hydroiodide was prepared. Then, the reaction of benzoxazole (0.672 mmol, 1 equiv.) and N-iodomorpholine hydroiodide (0.672 mmol, 1 equiv.) with acetic acid (2.016 mmol, 3 equiv.) as an additive in 2 mL CH 3 CN at room temperature for 3.5 h afforded the desired product 3a in 25% yield ( Table 2, entry 1). When the dosage of N-iodomorpholine hydroiodide was increased from 1 equiv. to 2 equiv., the desired amination product was obtained in 53% yield ( Table 2, entry 2). It is worth noting that the reaction of 1a and 2a underwent smoothly in the presence of 15 mol% N-iodomorpholine hydroiodide, 1.5 equiv. TBHP, and 3 equiv. acetic acid to give 2-morpholinobenzo[d]oxazole (3a) in 95% yield (Table 2, entry 3). All of the above results indicate that the activation of the morpholine (2a) via in situ preparation of a highly reactive N-I bond from [BPy]I and TBHP seems plausible. for 3.5 h afforded the desired product 3a in 25% yield ( Table 2, entry 1). When the dosage of N-iodomorpholine hydroiodide was increased from 1 equiv. to 2 equiv., the desired amination product was obtained in 53% yield (Table 2, entry 2). It is worth noting that the reaction of 1a and 2a underwent smoothly in the presence of 15 mol% N-iodomorpholine hydroiodide, 1.5 equiv. TBHP, and 3 equiv. acetic acid to give 2-morpholinobenzo[d]oxazole (3a) in 95% yield ( Table 2, entry 3). All of the above results indicate that the activation of the morpholine (2a) via in situ preparation of a highly reactive N-I bond from [BPy]I and TBHP seems plausible. Based on the above results and existing literature [33], a plausible mechanism is proposed as shown in Scheme 5. Initially, [BPy]I is oxidized by TBHP to form [BPy] + [I(OAc) 2 ] − (A) in the presence of acetic acid, and then releases acetylhypoiodite B. Subsequently, C is generated by combining morpholine with highly potent I + source B. Immediately following, the reaction of C and benzoxazole affords D. Finally, the desired amination reaction product 3a can be obtained after the elimination of hydrogen iodide. Based on the above results and existing literature [33], a plausible mechanism is proposed as shown in Scheme 5. Initially, [BPy]I is oxidized by TBHP to form [BPy] + [I(OAc)2] − (A) in the presence of acetic acid, and then releases acetylhypoiodite B. Subsequently, C is generated by combining morpholine with highly potent I + source B. Immediately following, the reaction of C and benzoxazole affords D. Finally, the desired amination reaction product 3a can be obtained after the elimination of hydrogen iodide. Scheme 5. The proposed mechanism. HOAc: acetic acid.

Experimental Section
A reaction vessel was charged with acetic acid (2.016 mmol) and TBHP (70% in water, 1.008 mmol) in acetonitrile (2 mL). After the addition of [BPy]I (0.1008 mmol), benzoxazole (0.672 mmol) and secondary amines (1.344 mmol) were added. Then, the reaction mixture was stirred at room temperature for 3.5 h. After the reaction finished, the mixture was extracted with dichloromethane (5 × 10 mL), and the combined organic phases were dried over anhydrous Na2SO4. The solvent was evaporated under vacuum, and the crude residue was purified by column chromatography on silica gel. Aqueous phase was dried in a vacuum evaporator to recover the ionic liquid and directly reused in subsequent runs.

Conclusions
In summary, we have found an IL-catalyzed direct oxidative amination of benzoxazoles under metal-free conditions at room temperature. This mild catalytic system is suitable for the oxidative amination reactions between a wide range of secondary amines and benzoxazoles. In addition, the inexpensive and environmentally friendly ionic liquid [BPy]I can be easily recycled and reused for four runs without any obvious loss of catalytic activity. ILs-catalyzed C-H bond activation is ongoing in our group.