Fe-Catalyzed Synthesis of 2-Benzoxazolone—An Important Fragment of Biologically Active Compounds ^†

Abstract

2-Benzoxazolone, as well as its derivatives, are valuable structural fragments of a number of important biologically active substances. 2-Benzoxazolone derivatives are promising as antitumor, antimicrobial, antiretroviral, anticonvulsant, tranquilizing, and insecticidal agents. 2-Benzoxazolone is usually produced by the condensation of o-aminophenol with urea, phosgene, and other carbonic acid derivatives. There are also methods for the synthesis of 2-benzoxazolone from salicylamide with trichloroisocyanuric acid as a chlorinating agent, from hydroxybenzoic acid using ammonium azide and the Vilsmeier complex. The disadvantages of these methods are the high cost of the initial reagents, the need to use aggressive and toxic reagents (phosgene, ammonium azide), and the complexity of the hardware design for the reactors. We have developed the highly efficient oxidative cyclocarbonylation of 2-aminophenol to oxazolidin-2-one using FeCl₃*6H₂O and Fe(acac)₃ as catalysts under relatively mild conditions (100–120 °C) in the presence of CCl₄ and water. We assume that in situ-formed carbon dioxide is involved in a cyclization reaction with o-aminophenol to form the target 2-benzoxazole. The reaction takes 2–10 h to give 2-benzoxazolone a high yield.

1. Introduction

2-Benzoxazolone, as well as its derivatives, are valuable structural fragments of a number of important biologically active substances. 2-Benzoxazolone derivatives are promising as antitumor [1], antimicrobial [2], antiretroviral [3], anticonvulsant [4], tranquilizing [5], and insecticidal [6] agents. 2-Benzoxazolone is usually produced by the condensation of o-aminophenol with urea [7], phosgene [8], and other carbonic acid derivatives. There are also methods for the synthesis of 2-benzoxazolone from salicylamide with trichloroisocyanuric acid as a chlorinating agent [9], from hydroxybenzoic acid using ammonium azide, and the Vilsmeier complex [10]. The disadvantages of these methods are the high cost of the initial reagents, the need to use aggressive and toxic reagents (phosgene, ammonium azide), and the complexity of the hardware design for the reactors.

2. Results and Discussion

We have developed the highly efficient oxidative cyclocarbonylation of 2-aminophenol to 2-benzoxazolone 1 using FeCl₃*6H₂O and Fe(acac)₃ as catalysts under relatively mild conditions (100–120 °C) in the presence of CCl₄ and water. The reaction was studied under various conditions, including the molar ratio of catalyst and reagents: [o-aminophenol]:[CCl₄l:[H₂O]:[FeCl₃*6H₂O] = [50–200]:[400–7800]:[0–800]:[1–10], 100–120 °C, 0.25–10 h. A number of solvents were also tested: propanol, ethanol, 1-butanol, benzyl alcohol, ethyl acetate, toluene, and acetonitrile. The yield of 2-benzoxazolone was 75% in acetonitrile using the following conditions: [o-aminophenol]:[CCl₄l:[H₂O]:[FeCl₃*6H₂O] = 50:400:800:1, 120 °C, 2 h (Scheme 1). The reaction was carried out in a micro-autoclave (ampoule with stirring). Carrying out the reaction in an open system using microwave irradiation made it possible to reduce the reaction time to 30 min; however, the yield of 2-benzoxazolone did not exceed 40%. The structure of 2-benzoxazolone was established by ¹H, ¹³C NMR spectroscopy, infrared spectroscopy, and GC-MS, as well as a comparison with the literature data [11]:

We assume that carbon dioxide and hydrogen chloride are formed in situ under the reaction conditions, similarly to [12]. Then, CO₂ reacts to o-aminophenol to give the target benzoxazolone (Scheme 2).

The formation of carbon dioxide was confirmed by GC-MS. According to the weather observatory on Mauna Loa in May 2022, the maximum concentration of CO₂ in the atmosphere was 0.042% (420.99 ppm) [13]. In the sample we analyzed, there was 12.5 times more carbon dioxide than in the atmosphere (Figure 1).

It should be noted that the introduction of Et₃N into the reaction reduces the yield of 2-benzoxazole by 25%. Et₃N “binds” to the HCl formed during the reaction, so we do not exclude the role of acid catalysis.

3. Conclusions

Thus, we developed a method to produce 2-benzoxazolone from o-aminophenol and carbon tetrachloride in the presence of iron-containing catalysts.

4. Experimental Part

o-Aminophenol, carbon tetrachloride (Aldrich), FeCl₃*6H₂O, and Fe(acac)₃ (Acros) were commercial reagents. ¹H and ¹³C NMR spectra were recorded on a Bruker Avance-II 400 Ascend instrument (400 MHz for ¹H and 100 MHz for¹³C in CDCl₃). Mass spectra were run on a Shimadzu GCMS-QP2010Plus mass spectrometer (SPB-5 capillary column, 30 m × 0.25 mm, helium as the carrier gas, temperature programming from 40 to 300 °C at 8 °C/min, the evaporation temperature of 280 °C, ion source temperature of 200 °C, and ionization energy of 70 eV). The course of the reaction and the purity of the products were monitored by gas-liquid chromatography on a Shimadzu GC-9A, GC-2014 instrument [2 m × 3 mm column, SE-30 silicone (5%) on Chromaton N-AW-HMDS as the stationary phase, with temperature programming from 50 to 270 °C at 8 °C/min, helium as the carrier gas (47 mL/min)].

4.1. Method A

The reaction was carried out in a glass ampoule (V = 10 mL) placed in a stainless-steel micro-autoclave (V = 17 mL) under controlled heating with stirring. FeCl₃*6H₂O, o-aminophenol, CCl_4, and H₂O at a molar ratio [o-aminophenol]:[CCl₄l:[H₂O]:[FeCl₃*6H₂O] = 50:400:800:1 were loaded into the ampoule. The sealed ampoule was placed in an autoclave, which was hermetically sealed. The reaction was carried out at 100–120 °C for 2–10 h. After the completion of the reaction, the ampoule was opened, the reaction mixture was neutralized with dry NaHCO₃, impurities were purified by chromatography (SiO₂, eluent—ethyl acetate), and the solvents were distilled off on a rotary evaporator.

4.2. Method B

The synthesis of benzoxazolone was carried out in a round bottom flask equipped with a reflux condenser in a microwave oven with a power of 600 watts at 120 °C for 30 min. The reaction proceeded under constant stirring (built-in magnetic stirrer). After the completion of the synthesis, the reaction mixture was treated similarly to Method A.