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       This study reports a highly efficient method for the synthesis of benzoxazoles using catechol, aldehyde and ammonium acetate as feedstock via coupling reaction in ethanol with ZrCl4 as catalyst. A series of benzoxazoles (59 types) were successfully synthesized by this method in yields up to 97%. Other advantages of this approach include large-scale synthesis and the use of oxygen as an oxidizing agent. The mild reaction conditions allow subsequent functionalization, which facilitates the synthesis of various derivatives with biologically relevant structures such as β-lactams and quinoline heterocycles.
       The development of new methods of organic synthesis that can overcome the limitations in obtaining high-value compounds and increase their diversity (to open up new potential areas of application) has attracted much attention in both academia and industry1,2. In addition to the high efficiency of these methods, the environmental friendliness of the approaches being developed will also be a significant advantage3,4.
       Benzoxazoles are a class of heterocyclic compounds that have attracted much attention due to their rich biological activities. Such compounds have been reported to possess antimicrobial, neuroprotective, anticancer, antiviral, antibacterial, antifungal, and anti-inflammatory activities5,6,7,8,9,10,11. They are also widely used in various industrial fields including pharmaceuticals, sensorics, agrochemistry, ligands (for transition metal catalysis), and materials science12,13,14,15,16,17. Due to their unique chemical properties and versatility, benzoxazoles have become important building blocks for the synthesis of many complex organic molecules18,19,20. Interestingly, some benzoxazoles are important natural products and pharmacologically relevant molecules, such as nakijinol21, boxazomycin A22, calcimycin23, tafamidis24, cabotamycin25 and neosalvianene (Figure 1A)26.
       (A) Examples of benzoxazole-based natural products and bioactive compounds. (B) Some natural sources of catechols.
       Catechols are widely used in many fields such as pharmaceuticals, cosmetics and materials science27,28,29,30,31. Catechols have also been shown to possess antioxidant and anti-inflammatory properties, making them potential candidates as therapeutic agents32,33. This property has led to its use in the development of anti-aging cosmetics and skin care products34,35,36. Furthermore, catechols have been shown to be effective precursors for organic synthesis (Figure 1B)37,38. Some of these catechols are widely abundant in nature. Therefore, its use as a raw material or starting material for organic synthesis can embody the green chemistry principle of “utilizing renewable resources”. Several different routes have been developed to prepare functionalized benzoxazole compounds7,39. Oxidative functionalization of the C(aryl)-OH bond of catechols is one of the most interesting and novel approaches to the synthesis of benzoxazoles. Examples of this approach in the synthesis of benzoxazoles are reactions of catechols with amines40,41,42,43,44, with aldehydes45,46,47, with alcohols (or ethers)48, as well as with ketones, alkenes and alkynes (Figure 2A)49. In this study, a multicomponent reaction (MCR) between catechol, aldehyde and ammonium acetate was used for the synthesis of benzoxazoles (Figure 2B). The reaction was carried out using a catalytic amount of ZrCl4 in ethanol solvent. Note that ZrCl4 can be considered as a green Lewis acid catalyst, it is a less toxic compound [LD50 (ZrCl4, oral for rats) = 1688 mg kg−1] and is not considered to be highly toxic50. Zirconium catalysts have also been successfully used as catalysts for the synthesis of various organic compounds. Their low cost and high stability to water and oxygen make them promising catalysts in organic synthesis51.
       To find suitable reaction conditions, we selected 3,5-di-tert-butylbenzene-1,2-diol 1a, 4-methoxybenzaldehyde 2a and ammonium salt 3 as model reactions and carried out the reactions in the presence of different Lewis acids (LA), different solvents and temperatures to synthesize benzoxazole 4a (Table 1). No product was observed in the absence of catalyst (Table 1, entry 1). Subsequently, 5 mol % of different Lewis acids such as ZrOCl2.8H2O, Zr(NO3)4, Zr(SO4)2, ZrCl4, ZnCl2, TiO2 and MoO3 were tested as catalysts in EtOH solvent and ZrCl4 was found to be the best (Table 1, entries 2–8). To improve the efficiency, various solvents were tested including dioxane, acetonitrile, ethyl acetate, dichloroethane (DCE), tetrahydrofuran (THF), dimethylformamide (DMF) and dimethyl sulfoxide (DMSO). The yields of all the tested solvents were lower than that of ethanol (Table 1, entries 9–15). Using other nitrogen sources (such as NH4Cl, NH4CN and (NH4)2SO4) instead of ammonium acetate did not improve the reaction yield (Table 1, entries 16–18). Further studies showed that temperatures below and above 60 °C did not enhance the reaction yield (Table 1, entries 19 and 20). When the catalyst loading was changed to 2 and 10 mol %, the yields were 78% and 92%, respectively (Table 1, entries 21 and 22). The yield decreased when the reaction was carried out under nitrogen atmosphere, indicating that atmospheric oxygen may play a key role in the reaction (Table 1, entry 23). Increasing the amount of ammonium acetate did not improve the reaction results and even decreased the yield (Table 1, entries 24 and 25). In addition, no improvement in the reaction yield was observed with increasing the amount of catechol (Table 1, entry 26).
       After determining the optimal reaction conditions, the versatility and applicability of the reaction were studied (Figure 3). Since alkynes and alkenes have important functional groups in organic synthesis and are easily amenable to further derivatization, several benzoxazole derivatives were synthesized with alkenes and alkynes (4b–4d, 4f–4g). Using 1-(prop-2-yn-1-yl)-1H-indole-3-carbaldehyde as the aldehyde substrate (4e), the yield reached 90%. In addition, alkyl halo-substituted benzoxazoles were synthesized in high yields, which can be used for ligation with other molecules and further derivatization (4h–4i) 52. 4-((4-fluorobenzyl)oxy)benzaldehyde and 4-(benzyloxy)benzaldehyde afforded the corresponding benzoxazoles 4j and 4k in high yields, respectively. Using this method, we successfully synthesized benzoxazole derivatives (4l and 4m) containing quinolone moieties53,54,55. Benzoxazole 4n containing two alkyne groups was synthesized in 84% yield from 2,4-substituted benzaldehydes. Bicyclic compound 4o containing an indole heterocycle was successfully synthesized under optimized conditions. Compound 4p was synthesized using an aldehyde substrate attached to a benzonitrile group, which is a useful substrate for the preparation of (4q-4r) supramolecules56. To highlight the applicability of this method, the preparation of benzoxazole molecules containing β-lactam moieties (4q–4r) was demonstrated under optimized conditions via the reaction of aldehyde-functionalized β-lactams, catechol, and ammonium acetate. These experiments demonstrate that the newly developed synthetic approach can be used for late-stage functionalization of complex molecules.
       To further demonstrate the versatility and tolerance of this method to functional groups, we studied various aromatic aldehydes including electron-donating groups, electron-withdrawing groups, heterocyclic compounds, and polycyclic aromatic hydrocarbons (Figure 4, 4s–4aag). For example, benzaldehyde was converted to the desired product (4s) in 92% isolated yield. Aromatic aldehydes with electron-donating groups (including -Me, isopropyl, tert-butyl, hydroxyl, and para-SMe) were successfully converted to the corresponding products in excellent yields (4t–4x). Sterically hindered aldehyde substrates could generate benzoxazole products (4y–4aa, 4al) in good to excellent yields. The use of meta-substituted benzaldehydes (4ab, 4ai, 4am) allowed the preparation of benzoxazole products in high yields. Halogenated aldehydes such as (-F, -CF3, -Cl and Br) gave the corresponding benzoxazoles (4af, 4ag and 4ai-4an) in satisfactory yields. Aldehydes with electron withdrawing groups (e.g. -CN and NO2) also reacted well and gave the desired products (4ah and 4ao) in high yields.
       Reaction series used for the synthesis of aldehydes a and b. a Reaction conditions: 1 (1.0 mmol), 2 (1.0 mmol), 3 (1.0 mmol) and ZrCl4 (5 mol%) were reacted in EtOH (3 mL) at 60 °C for 6 h. b The yield corresponds to the isolated product.
       Polycyclic aromatic aldehydes such as 1-naphthaldehyde, anthracene-9-carboxaldehyde and phenanthrene-9-carboxaldehyde could generate the desired products 4ap-4ar in high yields. Various heterocyclic aromatic aldehydes including pyrrole, indole, pyridine, furan and thiophene tolerated the reaction conditions well and could generate the corresponding products (4as-4az) in high yields. Benzoxazole 4aag was obtained in 52% yield using the corresponding aliphatic aldehyde.
       Reaction region using commercial aldehydes a, b. a Reaction conditions: 1 (1.0 mmol), 2 (1.0 mmol), 3 (1.0 mmol) and ZrCl4 (5 mol %) were reacted in EtOH (5 mL) at 60 °C for 4 h. b The yield corresponds to the isolated product. c The reaction was carried out at 80 °C for 6 h; d The reaction was carried out at 100 °C for 24 h.
       To further illustrate the versatility and applicability of this method, we also tested various substituted catechols. Monosubstituted catechols such as 4-tert-butylbenzene-1,2-diol and 3-methoxybenzene-1,2-diol reacted well with this protocol, affording benzoxazoles 4aaa–4aac in 89%, 86%, and 57% yields, respectively. Some polysubstituted benzoxazoles were also successfully synthesized using the corresponding polysubstituted catechols (4aad–4aaf). No products were obtained when electron-deficient substituted catechols such as 4-nitrobenzene-1,2-diol and 3,4,5,6-tetrabromobenzene-1,2-diol were used (4aah–4aai).
       The synthesis of benzoxazole in gram quantities was successfully accomplished under optimized conditions, and compound 4f was synthesized in 85% isolated yield (Figure 5).
       Gram-scale synthesis of benzoxazole 4f. Reaction conditions: 1a (5.0 mmol), 2f (5.0 mmol), 3 (5.0 mmol) and ZrCl4 (5 mol%) were reacted in EtOH (25 mL) at 60 °C for 4 h.
       Based on literature data, a reasonable reaction mechanism has been proposed for the synthesis of benzoxazoles from catechol, aldehyde, and ammonium acetate in the presence of ZrCl4 catalyst (Figure 6). Catechol can chelate zirconium by coordinating two hydroxyl groups to form the first core of the catalytic cycle (I)51. In this case, the semiquinone moiety (II) can be formed via enol-keto tautomerization in complex I58. The carbonyl group formed in intermediate (II) apparently reacts with ammonium acetate to form the intermediate imine (III) 47. Another possibility is that the imine (III^), formed by the reaction of the aldehyde with ammonium acetate, reacts with the carbonyl group to form the intermediate imine-phenol (IV) 59,60. Subsequently, intermediate (V) can undergo intramolecular cyclization40. Finally, intermediate V is oxidized with atmospheric oxygen, yielding the desired product 4 and releasing the zirconium complex to begin the next cycle61,62.
       All reagents and solvents were purchased from commercial sources. All known products were identified by comparison with spectral data and melting points of tested samples. 1H NMR (400 MHz) and 13C NMR (100 MHz) spectra were recorded on a Brucker Avance DRX instrument. Melting points were determined on a Büchi B-545 apparatus in an open capillary. All reactions were monitored by thin-layer chromatography (TLC) using silica gel plates (Silica gel 60 F254, Merck Chemical Company). Elemental analysis was performed on a PerkinElmer 240-B Microanalyzer.
       A solution of catechol (1.0 mmol), aldehyde (1.0 mmol), ammonium acetate (1.0 mmol) and ZrCl4 (5 mol %) in ethanol (3.0 mL) was successively stirred in an open tube in an oil bath at 60 °C under air for the required time. The progress of the reaction was monitored by thin layer chromatography (TLC). After completion of the reaction, the resulting mixture was cooled to room temperature and ethanol was removed under reduced pressure. The reaction mixture was diluted with EtOAc (3 x 5 mL). Then, the combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo. Finally, the crude mixture was purified by column chromatography using petroleum ether/EtOAc as eluent to afford pure benzoxazole 4.
       In summary, we have developed a novel, mild and green protocol for the synthesis of benzoxazoles via sequential formation of CN and CO bonds in the presence of zirconium catalyst. Under the optimized reaction conditions, 59 different benzoxazoles were synthesized. The reaction conditions are compatible with various functional groups, and several bioactive cores were successfully synthesized, indicating their high potential for subsequent functionalization. Therefore, we have developed an efficient, simple and practical strategy for the large-scale production of various benzoxazole derivatives from natural catechols under green conditions using low-cost catalysts.
       All data obtained or analyzed during this study are included in this published article and its Supplementary Information files.
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