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Article

General Synthesis of 2-Substituted Benzoxazoles Based on Tf2O-Promoted Electrophilic Activation of Tertiary Amides

by
Hongchen Li
1,2,*,
Xingyong Wang
1,
Fujun Zhao
1,
Lu Wang
1 and
Songbao Fu
1,*
1
CNOOC Institute of Chemicals & Advanced Materials, Beijing 102209, China
2
Department of Chemistry, Tsinghua University, Beijing 100084, China
*
Authors to whom correspondence should be addressed.
Molecules 2025, 30(7), 1510; https://doi.org/10.3390/molecules30071510
Submission received: 2 March 2025 / Revised: 24 March 2025 / Accepted: 27 March 2025 / Published: 28 March 2025
(This article belongs to the Special Issue 30th Anniversary of Molecules—Recent Advances in Organic Chemistry)
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Abstract

:
We report a method for the synthesis of 2-substituted benzoxazoles from tertiary amides and 2-aminophenols in the presence of triflic anhydride (Tf2O) and 2-Fluoropyridine (2-F-Pyr). The cascade reaction involves the activation of the amide carbonyl group by Tf2O, nucleophilic addition, intramolecular cyclization, and elimination. Furthermore, we explore the scope of this method by varying both the amide and 2-aminophenol substrates, highlighting its versatility in the synthesis of a wide range of functionalized benzoxazole derivatives.

1. Introduction

The 2-substituted benzoxazoles are an important class of heterocyclic compounds [1,2,3,4]. These compounds have attracted significant attention for their promising applications in medicinal chemistry [5,6,7,8,9,10,11,12,13,14,15,16,17], materials science [18], and organic electronics [19]. In particular, 2-substituted benzoxazoles exhibit a range of pharmacological activities, including anti-microbial [6], anti-cancer [8], anti-inflammatory [16], and anticonvulsant effects [17], which makes them valuable scaffolds for the development of new therapeutic agents (Figure 1).
Given the importance of 2-substituted benzoxazoles, numerous synthetic strategies have been developed to construct these valuable heterocyclic frameworks. Currently, the synthesis of 2-substituted benzoxazoles can be broadly categorized into two main approaches (Scheme 1a) [20,21,22]. The first approach involves the direct functionalization of the C-H bond at the C2 position, which allows the direct functionalization of the benzoxazole core (Scheme 1a, Path A) [23,24,25,26]. This strategy has attracted considerable attention due to its high atom economy and the ability to introduce a wide variety of functional groups without the need for pre-functionalized substrates. However, many of these transformations still require strong oxidants, high temperatures or very low temperatures, and special catalysts, which can limit their practical application. In addition, the use of transition metal catalysts poses challenges in pharmaceutical and industrial applications due to the presence of metal residues that require additional purification steps.
In view of the challenges associated with direct C-H functionalization at the C2 position of benzoxazoles, an alternative and widely used strategy for the synthesis of 2-substituted benzoxazoles is the cyclization of suitably functionalized precursors [27,28,29,30,31,32,33]. This method makes it possible to construct the benzoxazole core straightforwardly and to introduce the desired substituent at the C2 position at the same time (Scheme 1a, Path B). One of the most common methods is the cyclization of 2-aminophenols with aryl or alkyl precursors, such as benzoic acids [27], aryl methyl ketones [28,29], alkynes [30], and styrene derivatives [31,32,33]. These cyclization strategies provide a more general and versatile route to 2-substituted benzoxazoles. They often show high selectivity and better substrate tolerance compared to C-H activation methods.
In recent years, amide transformation has gained significant attention as a starting material for the synthesis of heterocyclic compounds [34,35,36,37,38]. This is due to the availability and versatility of amide substrates. However, efficient activation of the amide functional group is the key challenge in using amides for heterocycle synthesis. Amides are generally considered to be relatively inert compared to other carbonyl-containing compounds, such as esters or acids. This is mainly because the amide is affected by the increased stability of the electrophilic carbonyl carbon, resulting in much lower reactivity with nucleophilic reagents [34]. Under mild conditions, this makes direct reactions difficult. Recent advances in electrophilic activation strategies, including using strong acids like Tf2O, have proven to be very effective [39,40,41,42,43,44]. Herein, we report a method that explores the use of Tf2O-promoted electrophilic activation to synthesize 2-substituted benzoxazoles, highlighting its potential as a more selective and efficient activation strategy compared to traditional methods (Scheme 1b).
The ability of Tf2O to activate amides through the formation of highly reactive intermediates opens up new ways of functionalizing both amides and 2-aminophenols. This provides access to a wide range of substituted benzoxazoles.

2. Results and Discussion

2.1. Synthesis

2.1.1. Optimization of Reaction Conditions

As part of our continuing research into amide activation to construct heterocyclic compounds, we hypothesized that amides could be directly cyclized as starting materials to synthesize 2-substituted benzoxazoles. As expected, we successfully obtained the target product 2-benzylbenzo[d]oxazole (3aa) by the reaction of 1-morpholino-2-phenylethan-1-one (1a) and 2-aminophenol (2a) in the presence of Tf2O (Table 1, entry 1). Based on these preliminary results, we investigated different reaction conditions to optimize the process. First, the effect of different bases on the reaction was tested. The results are summarized in Table 1. The yield of the product was significantly increased by adding pyridine-based organic bases to the reaction (Table 1, entries 2-9). However, if the pyridine ring contains strong electron-absorbing functional groups (such as –SO3H and –NO2), the effect of the pyridine base is less obvious and the yield is reduced (Table 1, entries 8-9). When inorganic bases, such as CsF and K2CO3, were used, the reaction showed little improvement (Table 1, entries 10-11). The reaction yield was significantly increased by increasing the amount of 2-Fluoropyridine (Table 1, entries 12–14).
We then further optimized the reaction by exploring the impact of different conditions. A variety of solvents were tested, and DCM gave the best results (Table 2, entries 1–4). Reducing the reaction temperature had little effect on the yield, with the highest yield being obtained at room temperature (Table 2, entries 5–6). There is no significant increase in yield by further extension of the reaction time above one hour (Table 2, entries 7–8). By adjusting the ratio of the two starting materials, the highest yield, which was 95%, was obtained when the ratio of 1a/2a was 1.1/1 (Table 2, entries 9–11).

2.1.2. The Effect of Different Amide N-Leaving Groups on the Reaction

After establishing the optimal reaction conditions, we tested the effect of different amide N-leaving groups on the reaction, focusing primarily on the influence of various alkyl and aryl groups (R1 and R2) on the nitrogen atom in amides (Scheme 2). At first, we examined the impact of different functional groups (R1 and R2) on the nitrogen atom of benzylamides. Unfortunately, the reaction only worked best when the nitrogen atom contained the morpholine functional group (Scheme 2, 1a). In cases where other functional groups (R1 and R2) were present on the nitrogen, the yields ranged from 22% to 67% (Scheme 2, 1m–1q). In order to verify these findings, we obtained similar results by substituting the benzamides for benzylamides (Scheme 2, 1r–1t). This variation in yield is probably due to the polar oxygen atom in morpholine.

2.1.3. Substrates’ Scope Under Optimized Conditions

Under the optimal reaction conditions, we explored the scope of amide compounds in the reaction. As shown in Scheme 3, amides (1) with different alkyl groups (R3) have been reacted with 2-aminophenol (2a) to give the corresponding products (3). The yields ranged from moderate to excellent. When the benzyl group contains various functional groups, such as methyl, methoxy, or halogen groups, the reaction generally proceeds with excellent results (3aa–3ah). No significant steric or electronic effects were observed over the above substrates. It is noteworthy that other alkyl amides, such as isopropyl and cycloalkyl amides, also reacted efficiently (3ai–3aj). Excitingly, the alkylamides containing halogens and alkenes also led to the desired products (3ak–3al). This significantly extends the scope of 2-alkylbenzoxazole synthesis. The same method can also be used to prepare 2-arylbenzooxazole with a yield of 87% (3ar). This can be achieved by using benzamide as the starting material. To demonstrate the potential usefulness of the method, we carried out the reaction on a gram scale and obtained the product 3aa in a yield comparable to that of the small-scale reaction.
We also explored the effects of different substituents on the nucleophiles in the reaction (Scheme 4). Alkyl-substituted 2-aminophenols, such as methyl and tert-butyl 2-aminophenols, can be used to give good yields of 2-benzylbenzoxazoles (3ba–3da). If the 2-aminophenols contains halogen substituents, such as chlorine or bromine, the target product is also obtained in excellent yields (3ea–3fa). The nitro-substituted aminophenol compound shows an impressive tolerance in this reaction and the desired products are produced with an ideal yield of 65% (3ga). Despite a moderate yield, an aromatic pyridine substrate also gives the target product (3ha). In particular, replacing the aminophenol group with o-thiosamine leads to the formation of 2-alkylbenzothiazole (3ia). This greatly expands the synthetic scope of benzoheterocyclic compounds. We also tested several special substituents of 2-aminophenol, such as amino groups, sulfonamide groups, or ester groups. The experimental results found that under the action of Tf2O, the amino and amide groups form amidine, and the esters can consume anhydrides, which makes it difficult to continue the reaction. (3ja–3la).

2.2. Proposed Mechanism

Based on the experimental results and previous studies [26,45], we proposed a possible reaction mechanism for the synthesis of 2-substituted benzoxazole (Scheme 5). First of all, the amide (1) reacts with Tf2O and 2-Fluoropyridine to form an intermediate amidinium salt A. Then, the amino nitrogen of the 2-aminophenol compound (2a) acts as a nucleophile and attacks the carbon of the amidinium to form the intermediate C. In this step, one molecule of B is released by the addition/elimination reaction. Next, an intramolecular cyclization reaction is carried out to produce the intermediate D. Finally, the target product 3 is obtained by elimination reaction.

3. Materials and Methods

3.1. Materials and General Methods

The reaction vessel uses a thick-walled pressure bottle (upper pressure limit: 6 bar; reactor volume: 15 mL or 350 mL). All reagents used in experiment were obtained from commercial sources and used without further purification. Chromatographic purification of products was accomplished using silica gel (200–300 mesh). All melting points were determined on a Yanaco MP-500 micro melting point apparatus (Yanaco, Kyoto, Japan) and were uncorrected. All spectra of 1H NMR (400 MHz) and 13C NMR (100 MHz) were recorded on a JEOL JNM-ECA 400 spectrometer (JEOL, Tokyo, Japan) in CDCl3. NMR spectrum data processing using Delta NMR processing and control software (5.3.1 Windows). TMS was used as an internal reference and J values are given in Hz. PE is petroleum ether (60–90 °C).

3.2. General Procedure for the Preparation of 2-Substituted Benzoxazoles 3

2-Fluoropyridine (1 mmol, 97 mg) was added to a solution of amide 1a (0.55 mmol, 113 mg) in 1 mL DCM. The mixture was cooled to 0 °C and Tf2O (0.6 mmol, 170 mg) was added dropwise and stirred for 15 minutes. Then, 2-aminophenol 2a (0.5 mmol, 54.5 mg) was added and the reaction was stirred for 1 hour at room temperature. The reaction was quenched with 0.5 mL Et3N. The solvent was evaporated and the residue was purified by chromatography (silica gel, PE: EtOAc = 20:1) to give the desired product 2-benzylbenzo[d]oxazole (3aa, 99 mg, 95%) as a yellowish oil.
The products 3ab–3ar and 3ba–ia were prepared by similar procedure.

3.3. Analytical Data of Compound 3aa–3ar and 3ba–ia

2-Benzylbenzo[d]oxazole (3aa) [46]. The solvent was evaporated and the residue was purified by chromatography (silica gel, PE: EtOAc = 20:1) to give the desired product 3aa (99 mg, 95%) as a yellowish oil. 1H NMR (400 MHz, CDCl3) δ 7.72–7.64 (m, 1H), 7.45–7.40 (m, 1H), 7.39–7.28 (m, 4H), 7.28–7.21 (m, 3H), 4.24 (s, 2H). 13C NMR (100 MHz, CDCl3) δ 165.1, 150.9, 141.3, 134.7, 128.9 (2C), 128.7 (2C), 127.2, 124.6, 124.1, 119.7, 110.3, 35.2.
2-(4-Methylbenzyl)benzo[d]oxazole (3ab) [46]. The solvent was evaporated and the residue was purified by chromatography (silica gel, PE:EtOAc = 20:1) to give the desired product 3ab (100 mg, 90%) as a yellowish oil. 1H NMR (400 MHz, CDCl3) δ 7.70–7.65 (m, 1H), 7.47–7.41 (m, 1H), 7.31–7.23 (m, 4H), 7.17–7.11 (m, 2H), 4.22 (s, 2H), 2.32 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 165.4, 151.0, 141.3, 136.9, 131.7, 129.5 (2C), 128.8 (2C), 124.6, 124.1, 119.8, 110.4, 34.8, 21.0.
2-(3-Methylbenzyl)benzo[d]oxazole (3ac) [46]. The solvent was evaporated and the residue was purified by chromatography (silica gel, PE:EtOAc = 20:1) to give the desired product 3ac (89 mg, 80%) as a yellowish oil. 1H NMR (400 MHz, CDCl3) δ 7.72–7.65 (m, 1H), 7.47–7.42 (m, 1H), 7.31–7.14 (m, 5H), 7.10–7.05 (m, 1H), 4.22 (s, 2H), 2.33 (s, 3H).13C NMR (100 MHz, CDCl3) δ 165.3, 151.0, 141.3, 138.5, 134.6, 129.7, 128.7, 128.0, 126.0, 124.6, 124.1, 119.8, 110.4, 35.2, 21.3.
2-(2-Methylbenzyl)benzo[d]oxazole (3ad) [46]. The solvent was evaporated and the residue was purified by chromatography (silica gel, PE:EtOAc = 20:1) to give the desired product 3ad (106 mg, 95%) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.70–7.64 (m, 1H), 7.45–7.39 (m, 1H), 7.31–7.22 (m, 3H), 7.22–7.14 (m, 3H), 4.24 (s, 2H), 2.38 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 165.0, 150.9, 141.3, 136.7, 133.2, 130.5, 129.9, 127.5, 126.3, 124.5, 124.0, 119.7, 110.3, 33.0, 19.6.
2-(4-Methoxybenzyl)benzo[d]oxazole (3ae) [46]. The solvent was evaporated and the residue was purified by chromatography (silica gel, PE:EtOAc = 20:1) to give the desired product 3ae (111 mg, 93%) as a yellowish oil. 1H NMR (400 MHz, CDCl3) δ 7.70–7.65 (m, 1H), 7.47–7.42 (m, 1H), 7.32–7.23 (m, 4H), 6.91–6.84 (m, 2H), 4.20 (s, 2H), 3.77 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 165.5, 158.8, 151.0, 141.3, 130.0 (2C), 126.7, 124.6, 124.1, 119.7, 114.2 (2C), 110.4, 55.2, 34.4.
2-(4-Fluorobenzyl)benzo[d]oxazole (3af) [47]. The solvent was evaporated and the residue was purified by chromatography (silica gel, PE:EtOAc = 20:1) to give the desired product 3af (99 mg, 87%) as a yellowish oil. 1H NMR (400 MHz, CDCl3) δ 7.71–7.65 (m, 1H), 7.48–7.42 (m, 1H), 7.37–7.24 (m, 4H), 7.06–6.98 (m, 2H), 4.23 (s, 2H). 13C NMR (100 MHz, CDCl3) δ 164.9, 162.1 (d, J = 244.1 Hz), 151.0, 141.3, 130.5 (2C, d, J = 7.6 Hz), 130.4 (d, J = 3.8 Hz), 124.8, 124.2, 119.8, 115.7 (2C, d, J = 21.9 Hz), 110.4, 34.4.
2-(4-Chlorobenzyl)benzo[d]oxazole (3ag) [25]. The solvent was evaporated and the residue was purified by chromatography (silica gel, PE:EtOAc = 20:1) to give the desired product 3ag (114 mg, 94%) as a white oil. 1H NMR (400 MHz, CDCl3) δ 7.71–7.65 (m, 1H), 7.48–7.42 (m, 1H), 7.33–7.24 (m, 6H), 4.22 (s, 2H). 13C NMR (100 MHz, CDCl3) δ 164.6, 151.0, 141.2, 133.3, 133.1, 130.3 (2C), 128.9 (2C), 124.8, 124.2, 119.8, 110.4, 34.5.
2-(4-Bromobenzyl)benzo[d]oxazole (3ah) [29]. The solvent was evaporated and the residue was purified by chromatography (silica gel, PE:EtOAc = 20:1) to give the desired product 3ah (133 mg, 93%) as a white solid, mp 95−98 °C. 1H NMR (400 MHz, CDCl3) δ 7.71–7.65 (m, 1H), 7.48–7.42 (m, 3H), 7.32–7.21 (m, 4H), 4.20 (s, 2H). 13C NMR (100 MHz, CDCl3) δ 164.4, 151.0, 141.2, 133.6, 131.9 (2C), 130.7 (2C), 124.8, 124.2, 121.3, 119.8, 110.4, 34.6.
2-Isopropylbenzo[d]oxazole (3ai) [48]. The solvent was evaporated and the residue was purified by chromatography (silica gel, PE:EtOAc = 30:1) to give the desired product 3ai (55 mg, 68%, stirred in DCE at 90 °C for 1 h) as a brown oil. 1H NMR (400 MHz, CDCl3) δ 7.71–7.66 (m, 1H), 7.51 7.45 (m, 1H), 7.32–7.25 (m, 2H), 3.25 (heptuple, J = 6.9 Hz, 1H), 1.46 (d, J = 6.9 Hz, 6H). 13C NMR (100 MHz, CDCl3) δ 171.3, 150.7, 141.2, 124.4, 124.0, 120.0, 110.2, 28.9, 20.3 (2C).
2-(2-Cyclohexylethyl)benzo[d]oxazole (3aj) [26]. The solvent was evaporated and the residue was purified by chromatography (silica gel, PE:EtOAc = 30:1) to give the desired product 3aj (93 mg, 81%, stirred in DCE at 90 °C for 1 h) as a brown oil. 1H NMR (400 MHz, CDCl3) δ 7.69–7.63 (m, 1H), 7.50–7.44 (m, 1H), 7.32–7.24 (m, 2H), 2.98–2.89 (m, 2H), 1.82–1.61 (m, 7H), 1.39–1.10 (m, 4H), 1.05–0.88 (m, 2H). 13C NMR (100 MHz, CDCl3) δ 167.6, 150.7, 141.4, 124.3, 123.9, 119.4, 110.2, 37.1, 34.1, 32.9 (2C), 26.5, 26.1(3C).
2-(5-Bromopentyl)benzo[d]oxazole (3ak) [49]. The solvent was evaporated and the residue was purified by chromatography (silica gel, PE:EtOAc = 30:1) to give the desired product 3ak (63 mg, 47%, stirred in DCE at 90 °C for 1 h) as a white solid, mp 81−83 °C. 1H NMR (400 MHz, CDCl3) δ 7.70–7.64 (m, 1H), 7.51–7.45 (m, 1H), 7.33–7.26 (m, 2H), 3.42 (t, J = 6.6 Hz, 2H), 2.95 (t, J = 7.6 Hz, 2H), 1.98–1.88 (m, 4H), 1.64–1.54 (m, 2H). 13C NMR (100 MHz, CDCl3) δ 166.7, 150.7, 141.3, 124. 5, 124.1, 119.5, 110.2, 33.3, 32.3, 28.4, 27.6, 25.8.
2-(But-3-en-1-yl)benzo[d]oxazole (3al) [50]. The solvent was evaporated and the residue was purified by chromatography (silica gel, PE:EtOAc = 30:1) to give the desired product 3al (36 mg, 42%, stirred in DCE at 90 °C for 1 h) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.70–7.64 (m, 1H), 7.51–7. 45 (m, 1H), 7.32–7.25 (m, 2H), 6.00–5.82 (m, 1H), 5.17–5.08 (m, 1H), 5.08–5.00 (m, 1H), 3.03 (t, J = 7.6 Hz, 2H), 2.71–2.59 (m, 2H). 13C NMR (100 MHz, CDCl3) δ 166.4, 150.8, 141.3, 136.2, 124.4, 124.0, 119.5, 116.0, 110.2, 30.5, 28.1.
2-Phenylbenzo[d]oxazole (3ar) [26]. The solvent was evaporated and the residue was purified by chromatography (silica gel, PE:EtOAc = 15:1) to give the desired product 3ar (85 mg, 87%) as a white solid, mp 95−97 °C (lit. 97–98 °C). 1H NMR (400 MHz, CDCl3) δ 8.27–8.24 (m, 2H), 7.79–7.76 (m, 1H), 7.59–7.49 (m, 4H), 7.37–7.31 (m, 2H). 13C NMR (100 MHz, CDCl3) δ 162.9, 150.7, 142.1, 131.5, 128.9 (2C), 127.6 (2C), 127.1, 125.1, 124.5, 119.9, 110.5.
2-Benzyl-4-methylbenzo[d]oxazole (3ba) [33]. The solvent was evaporated and the residue was purified by chromatography (silica gel, PE:EtOAc = 20:1) to give the desired product 3ba (104 mg, 93%) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.41–7.29 (m, 4H), 7.29–7.22 (m, 2H), 7.20–7.12 (m, 1H), 7.11–7.05 (m, 1H), 4.27 (s, 2H), 2.61 (s, 3H).13C NMR (100 MHz, CDCl3) δ 164.2, 150.8, 140.5, 135.0, 130.1, 128.9 (2C), 128.7 (2C), 127.2, 124.7, 124.3, 107.7, 35.3, 16.5.
2-Benzyl-5-methylbenzo[d]oxazole (3ca) [33]. The solvent was evaporated and the residue was purified by chromatography (silica gel, PE:EtOAc = 20:1) to give the desired product 3ca (99 mg, 89%) as a yellowish oil. 1H NMR (400 MHz, CDCl3) δ 7.46 (s, 1H), 7.39–7.29 (m, 5H), 7.29–7.23 (m, 1H), 7.10–7.05 (m, 1H), 4.24 (s, 2H), 2.43 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 165.2, 149.3, 141.5, 134.9, 133.9, 128.9 (2C), 128.7 (2C), 127.2, 125.7, 119.7, 109.8, 35.3, 21.4.
2-Benzyl-5-(tert-butyl)benzo[d]oxazole (3da) [46]. The solvent was evaporated and the residue was purified by chromatography (silica gel, PE:EtOAc = 20:1) to give the desired product 3da (115 mg, 87%) as a yellowish oil. 1H NMR (400 MHz, CDCl3) δ 7.72–7.69 (m, 1H), 7.40–7.29 (m, 6H), 7.29–7.22 (m, 1H), 4.24 (s, 2H), 1.36 (s, 9H). 13C NMR (100 MHz, CDCl3) δ 165.3, 149.0, 147.7, 141.2, 134.9, 128.9 (2C), 128.8 (2C), 127.2, 122.3, 116.3, 109.5, 35.3, 34.8, 31.7 (3C).
2-Benzyl-5-chlorobenzo[d]oxazole (3ea) [25]. The solvent was evaporated and the residue was purified by chromatography (silica gel, PE:EtOAc = 20:1) to give the desired product 3ea (116 mg, 95%) as a yellowish oil. 1H NMR (400 MHz, CDCl3) δ 7.66–7.65 (m, 1H), 7.39–7.31 (m, 5H), 7.31–7.23 (m, 2H), 4.25 (s, 2H). 13C NMR (100 MHz, CDCl3) δ 166.6, 149.6, 142.4, 134.3, 129.6, 129.0 (2C), 128.9 (2C), 127.4, 125.0, 119.8, 111.1, 35.2.
2-Benzyl-5-bromobenzo[d]oxazole (3fa) [33]. The solvent was evaporated and the residue was purified by chromatography (silica gel, PE:EtOAc = 20:1) to give the desired product 3fa (137 mg, 95%) as a yellowish oil. 1H NMR (400 MHz, CDCl3) δ 7.82–7.80 (m, 1H), 7.42–7.23 (m, 7H), 4.25 (s, 2H). 13C NMR (100 MHz, CDCl3) δ 166.4, 150.0, 142.9, 134.3, 128.9 (2C), 128.8 (2C), 127.7, 127.4, 122.8, 116.9, 111.7, 35.2.
2-Benzyl-5-nitrobenzo[d]oxazole (3ga) [51]. The solvent was evaporated and the residue was purified by chromatography (silica gel, PE:EtOAc = 15:1) to give the desired product 3ga (83 mg, 65%) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 8.58–8.56 (m, 1H), 8.29–8.25 (m, 1H), 7.57–7.55 (m, 1H), 7.42–7.27 (m, 5H), 4.32 (s, 2H). 13C NMR (100 MHz, CDCl3) δ 168.4, 154.5, 145.1, 141.7, 133.7, 129.0 (2C), 129.0 (2C), 127.7, 120.9, 116.2, 110.6, 35.2.
2-Benzyloxazolo[4,5-b]pyridine (3ha) [52]. The solvent was evaporated and the residue was purified by chromatography (silica gel, PE:EtOAc = 8:1) to give the desired product 3ha (73 mg, 69%) as a colorless solid, mp 93−95 °C (lit. 95–97 °C). 1H NMR (400 MHz, CDCl3) δ 8.55–8.50 (m, 1H), 7.77–7.69 (m, 1H), 7.43–7.38 (m, 2H), 7.38–7.32 (m, 2H), 7.31–7.26 (m, 1H), 7.26–7.20 (m, 1H), 4.33 (s, 2H). 13C NMR (100 MHz, CDCl3) δ 168.2, 155.7, 146.2, 143.1, 134.0, 129.0 (2C), 128.8 (2C), 127.4, 119.8, 118.0, 35.5.
2-Benzylbenzo[d]thiazole (3ia) [53]. The solvent was evaporated and the residue was purified by chromatography (silica gel, PE:EtOAc = 30:1) to give the desired product 3ia (72 mg, 64%) as a yellowish oil. 1H NMR (400 MHz, CDCl3) δ 7.99 (d, J = 8.0 Hz, 1H), 7.77 (d, J = 8.4 Hz, 1H), 7.47–7.40 (m, 1H), 7.38–7.25 (m, 6H), 4.43 (s, 2H). 13C NMR (100 MHz, CDCl3) δ 171.1, 153.2, 137.1, 135.6, 129.1 (2C), 128.8 (2C), 127.3, 125.9, 124.8, 122.7, 121.5, 40.6.

4. Conclusions

In conclusion, we have developed a new method for the synthesis of 2-substituted benzoxazoles from tertiary amides and 2-aminophenols in the presence of Tf2O and 2-Fluoropyridine. The 2-substituted benzoxazoles have been prepared by cascade reactions, including Tf2O-activated amides, nucleophilic addition, intramolecular cyclization, and elimination. The method was simple, mild, and effective for the synthesis of 2-substituted benzoxazoles and can be extended to the synthesis of 2-substituted benzothiazoles. Given its versatility and ease of use, we anticipate that this method will have broad applications in organic synthesis.

Supplementary Materials

The following supporting information can be downloaded at https://www.mdpi.com/article/10.3390/molecules30071510/s1: The structures of the substrates, 1H NMR and 13C NMR spectra of the products 3aa–3ar and 3ba–3ia.

Author Contributions

Conceptualization, H.L. and S.F.; methodology, H.L. and X.W.; investigation, F.Z.; data curation, L.W.; writing—original draft preparation, H.L. and X.W.; writing—review and editing, H.L. and S.F. All authors have read and agreed to the published version of the manuscript.

Funding

The authors thank the National Natural Science Foundation of China (Nos. U22B20137 and 21971138).

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

The data are contained within the article and Supplementary Materials.

Acknowledgments

We would like to thank Yunxiang Weng from the College of Chemistry and Materials Science, Fujian Normal University for his participation in the experimental discussion.

Conflicts of Interest

Authors Hongchen Li, Xingyong Wang, Fujun Zhao, Lu Wang and Songbao Fu were employed by the company CNOOC Institute of Chemicals & Advanced Materials. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

References

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Molecules 30 01510 g001
Figure 1. Representative 2-substituted benzoxazole derivatives and applications.
Figure 1. Representative 2-substituted benzoxazole derivatives and applications.
Molecules 30 01510 g001
Molecules 30 01510 sch001
Scheme 1. (a) C-H functionalization and oxidation condensation; (b) Tf2O-promoted electrophilic activation of tertiary amides.
Scheme 1. (a) C-H functionalization and oxidation condensation; (b) Tf2O-promoted electrophilic activation of tertiary amides.
Molecules 30 01510 sch001
Molecules 30 01510 sch002
Scheme 2. Scope of N-leaving groups a. Reactions were performed with 0.55 mmol of 1, 0.5 mmol of 2a, 1.0 mmol of 2-F-Pyr, and 0.6 mmol of Tf2O in DCM (1.0 mL) at room temperature for 1 h. In each case, the yield refers to the effective amount of isolated compound.
Scheme 2. Scope of N-leaving groups a. Reactions were performed with 0.55 mmol of 1, 0.5 mmol of 2a, 1.0 mmol of 2-F-Pyr, and 0.6 mmol of Tf2O in DCM (1.0 mL) at room temperature for 1 h. In each case, the yield refers to the effective amount of isolated compound.
Molecules 30 01510 sch002
Molecules 30 01510 sch003
Scheme 3. Substrate scopes of amide compounds a–c. a Reactions were performed with 0.55 mmol of 1, 0.5 mmol of 2a, 1.0 mmol of 2-F-Pyr, and 0.6 mmol of Tf2O in DCM (1.0 mL) at room temperature for 1 h. b stirred at 90 °C for 1 h. c gram scale: Reaction was performed with 22 mmol of 1a, 20 mmol of 2a, 40 mmol of 2-F-Pyr, and 24 mmol of Tf2O in DCM (50 mL) at room temperature for 1 h. In each case, the yield refers to the effective amount of isolated compound.
Scheme 3. Substrate scopes of amide compounds a–c. a Reactions were performed with 0.55 mmol of 1, 0.5 mmol of 2a, 1.0 mmol of 2-F-Pyr, and 0.6 mmol of Tf2O in DCM (1.0 mL) at room temperature for 1 h. b stirred at 90 °C for 1 h. c gram scale: Reaction was performed with 22 mmol of 1a, 20 mmol of 2a, 40 mmol of 2-F-Pyr, and 24 mmol of Tf2O in DCM (50 mL) at room temperature for 1 h. In each case, the yield refers to the effective amount of isolated compound.
Molecules 30 01510 sch003
Molecules 30 01510 sch004
Scheme 4. Substrate scopes of nucleophiles a. a Reactions were performed with 0.55 mmol of 1a, 0.5 mmol of 2, 1.0 mmol of 2-F-Pyr, and 0.6 mmol of Tf2O in DCM (1.0 mL) at room temperature for 1 h. In each case, the yield refers to the effective amount of isolated compound.
Scheme 4. Substrate scopes of nucleophiles a. a Reactions were performed with 0.55 mmol of 1a, 0.5 mmol of 2, 1.0 mmol of 2-F-Pyr, and 0.6 mmol of Tf2O in DCM (1.0 mL) at room temperature for 1 h. In each case, the yield refers to the effective amount of isolated compound.
Molecules 30 01510 sch004
Molecules 30 01510 sch005
Scheme 5. Proposed Mechanism.
Scheme 5. Proposed Mechanism.
Molecules 30 01510 sch005
Table 1. Testing the effect of different bases on the reaction a.
Table 1. Testing the effect of different bases on the reaction a.
Molecules 30 01510 i001
EntryBaseTf2O/Base (by Equiv)Yield of 3aa b (%)
1/1.2/041%
22-F-Pyr1.2/1.587%
32-Cl-Pyr1.2/1.585%
42,6-Lutidine1.2/1.568%
5DMAP1.2/1.546%
6Pyridine1.2/1.565%
73-F-Pyr1.2/1.580%
82-Pyridinesulfonic acid1.2/1.530%
92-Nitropyridine1.2/1.532%
10CsF1.2/1.531%
11K2CO31.2/1.520%
122-F-Pyr1.2/1.281%
132-F-Pyr1.2/2.089%
142-F-Pyr1.2/2.588%
a Reaction conditions: Tf2O was added to a stirred solution of 1a (0.6 mmol) and base in DCE (1 mL) at 0 °C. After 15 min, 2a (0.5 mmol) was added and stirred at 80 °C for 5 h. b Isolated yields.
Table 2. Optimization of reaction conditions a.
Table 2. Optimization of reaction conditions a.
Molecules 30 01510 i002
Entry1a/2a (by Equiv)T (°C)t (h)SolventYield of 3aa b (%)
11.2/1805DCM93
21.2/1805CHCl389
31.2/1805CH3CN63
41.2/1805Toluene56
51.2/1505DCM93
61.2/1255DCM94
71.2/1251DCM94
81.2/1250.5DCM86
91/1.2251DCM75
101/1251DCM87
111.1/1251DCM95
a Reaction conditions: Tf2O was added to a stirred solution of 1a (0.6 mmol) and base in DCE (1 mL) at 0 °C. After 15 min, 2a (0.5 mmol) was added and stirred at 80 °C for 5 h. b Isolated yields.
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Li, H.; Wang, X.; Zhao, F.; Wang, L.; Fu, S. General Synthesis of 2-Substituted Benzoxazoles Based on Tf2O-Promoted Electrophilic Activation of Tertiary Amides. Molecules 2025, 30, 1510. https://doi.org/10.3390/molecules30071510

AMA Style

Li H, Wang X, Zhao F, Wang L, Fu S. General Synthesis of 2-Substituted Benzoxazoles Based on Tf2O-Promoted Electrophilic Activation of Tertiary Amides. Molecules. 2025; 30(7):1510. https://doi.org/10.3390/molecules30071510

Chicago/Turabian Style

Li, Hongchen, Xingyong Wang, Fujun Zhao, Lu Wang, and Songbao Fu. 2025. "General Synthesis of 2-Substituted Benzoxazoles Based on Tf2O-Promoted Electrophilic Activation of Tertiary Amides" Molecules 30, no. 7: 1510. https://doi.org/10.3390/molecules30071510

APA Style

Li, H., Wang, X., Zhao, F., Wang, L., & Fu, S. (2025). General Synthesis of 2-Substituted Benzoxazoles Based on Tf2O-Promoted Electrophilic Activation of Tertiary Amides. Molecules, 30(7), 1510. https://doi.org/10.3390/molecules30071510

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