1, 4-Dihydro-2H-3, 1-benzoxazin-2-one is an important structural motif that can be found in a wide range of biologically active compounds. For example, efavirenz, which is a non-nucleoside reverse transcriptase inhibitor for the treatment of HIV infections, consists of a substituted 1, 4-dihydro-2H-3, 1-benzoxazin-2-one core ^[1-3]. Several other compounds containing this structural motif have been reported to be orally active nonsteroidal progesterone receptor antagonists, which could be used for the treatment of hormone-dependent cancers ^[4-6]. 1, 4-Dihydro-2H-3, 1-benzoxazin-2-one also represents a useful tool compound in organic synthesis for the preparation of aza-ortho-xylylene via a thermal decarboxylation reaction ^[7-9]. In light of the many uses of this compound, considerable research efforts have been directed towards the development of efficient methods for its synthesis. Traditionally, 1, 4-dihydro-2H-3, 1-benzoxazin-2-one has been readily prepared by the reaction of 2-aminobenzyl alcohol with phosgene ^[10] or a suitable alternative such as chloroformate ^[11], triphosgene ^[12], urea ^[13] or N, N'-carbonyldiimidazole (CDI) ^[5]. However, there are several drawbacks associated with these methods, including high toxicity, low atom economy and the emission of the corrosive waste products. Selenium- ^{[14, 15]} and palladium-catalyzed ^[16] reactions have been developed for the preparation of 1, 4-dihydro-2H-3, 1-benzoxazin-2-one by the carbonylation of 2-nitrobenzyl alcohol with carbon monoxide. Unfortunately, only one third of the CO consumed during these reactions is transferred to the product, with the other two thirds being converted to the greenhouse gas CO₂ as a byproduct. Furthermore, the expensive palladium catalyst used in this carbonylation reaction increased the overall cost of the transformation. Palladium-catalyzed ^[17] and sulfur-assisted ^[18] reactions have also been developed as alternative processes for the carbonylation of 2-aminobenzyl alcohol to give 1, 4-dihydro-2H-3, 1-benzoxazin-2-one. However, the application of these methods had been limited by the high cost of the palladium catalyst, the requirement for a two-step procedure or low product yield. 1, 4-Dihydro-2H-3, 1-benzoxazin-2-one has also been prepared by a variety of different methods, including the direct carbonylation or tandem aza-Wittig/heterocumulene-mediated annulation of 2-azidobenzyl alcohol ^{[19, 20]}, aminolysis-Hofmann rearrangement of phthalides ^[21], lithium borohydride reduction of 1, 2-dihydro-3, 1-benzoxazine-2, 4-dione ^[22] and intramolecular nucleophilic substitution of 2-(hydroxymethyl)phenyl-carbamate ^[23]. However, these processes generally require the use of complex and expensive starting materials or multi-step procedures, thereby limiting their practical utility. Despite the many achievements listed above, the development of a green, efficient and cost-effective approach for the synthesis of 1, 4-dihydro-2H-3, 1-benzoxazin-2-one is still highly desired. Herein, we report a facile one-pot procedure for the synthesis of 1, 4-dihydro-2H-3, 1-benzoxazin-2-one by the selenium-catalyzed oxidative carbonylation of 2-aminobenzyl alcohol with carbon monoxide (Scheme 1).

CO (99.9%), O₂ (99.9%) and selenium (99.95%) were purchased from commercial corporations and used as provided without further purification. All of the other chemicals were purchased as the AR grade and were used without further purification. ¹H NMR spectroscopy was conducted on a Bruker DPX-400 spectrometer (Bruker) using CDCl₃ as a solvent with Me₄Si as an internal reference standard. Coupling constants (J) were reported in Hz. Column chromatography was performed on silica gel (200-300 mesh). The melting point of the product was determined using a Keyi XT4 apparatus (Beijing, China) and was uncorrected.

2-Aminobenzyl alcohol (2 mmol), Se (0.2 mmol), Et₃N (5 mmol) and THF (5 mL) were added to a 100-mL autoclave equipped with a magnetic stirrer. The reactor was then sealed and flushed three times with a gaseous mixture of CO and O₂ (CO:O₂ = 4:1). The autoclave was then pressurized with a gaseous mixture of CO and O₂ (CO:O₂ = 4:1) to 2.5 MPa and heated in an oil bath at 150 ℃ with vigorous stirring for 5 h. Upon completion of the reaction, as determined by thin layer chromatography analysis, the autoclave was cooled to room temperature and depressurized, followed by stirring for 30 min in air to allow for the precipitation of the Se. The mixture was then filtered and the filtrate was concentrated to give a residue, which was purified by column chromatography (petroleum ether/ethyl acetate, 3:1) to give 1, 4-dihydro-2H-3, 1-benzoxazin-2-one in 87% yield.

Colorless needles; mp 123-124 ℃ (lit. ^[14] 118-119 ℃); ¹H NMR (400 MHz, CDCl₃) δ = 8.36 (s, 1H), 7.28 (d, J = 12.0 Hz, 1H), 7.12 (d, J = 8.0 Hz, 1H), 7.07 (d, J = 8.0 Hz, 1H), 6.85 (d, J = 8.0 Hz, 1H), 5.34 (s, 2H).

It was envisaged that the selenium-catalyzed oxidative carbonylation of 2-aminobenzyl alcohol could be conducted in a one-pot manner with carbon monoxide and oxygen. In practice, this reaction proceeded smoothly to give the desired product 1, 4-dihydro-2H-3, 1-benzoxazin-2-one and water, together with a small amount of 1, 3-bis(2-(hydroxymethyl)phenyl)urea, suggesting the competitive intermolecular N-carbonylation of 2-aminobenzyl alcohol. 2-Aminobenzyl alcohol reached complete conversion after 5 h when the reaction was conducted at 150 ℃, affording 1, 4-dihydro-2H-3, 1-benzoxazin-2-one in 87% yield (Table 1, entry 2). The outcome of the reaction appeared to be sensitive to the temperature. For example, the reaction failed to reach the complete conversion of 2-aminobenzyl alcohol when it was conducted at 140 ℃ for 5 h (Table 1, entry 3). Increasing the reaction temperature led to an increase in the conversion of 2-aminobenzyl alcohol, which reached 100% at 150 ℃ (Table 1, entry 2). Further increasing the temperature did not led to any further improvements in the efficiency of the reaction (Table 1, entry 4). Experimental results indicated that the selenium catalyst was critical to the success of the current catalytic system. Notably, the carbonylation reaction did not proceed in the absence of selenium (Table 1, entry 5). However, the reaction proceeded smoothly with as little as 0.1 equivalent of selenium (Table 1, entry 2). Further increasing the selenium loading failed to lead to further increases in the product yield (Table 1, entry 7). Strongly alkaline conditions are generally required for selenium-catalyzed carbonylation reactions to promote the formation of the active carbonyl selenide species (COSe). With this in mind, we proceeded to examine the effects of several bases on the carbonylation reaction. Although 2-aminobenzyl alcohol can act as a base, the reaction proceeded poorly in the absence of a n additional base (Table 1, entry 8). Several common bases, including NaOH, K₂CO₃, NaOAc, pyridine (C₅H₅N) and Et₃N were tested in the current reaction, and the results revealed that Et₃N gave the best results (Table 1, entries 2 and 9-12). We subsequently screened several doses of this base and found that 2.5 equivalents gave the optimum results (Table 1, entries 2, 13 and 14). We also investigate the ratio of CO to O₂ used in this reaction and found 2 MPa CO together with 0.5 MPa O₂ gave the best results (Table 1, entries 2 and 15-17). The carbonylation reaction proceed poorly in the absence of a solvent (Table 1, entry 18), which promoted us to seek a proper solvent for this reaction. Several common solvents we screened, including THF, acetone, EtOAc, DMF, CH₂Cl₂ and toluene, and the results revealed that the reaction performed most effectively with THF, followed by toluene (Table 1, entries 2 and 19-23).

One remarkable advantage of the current catalytic system is that the selenium catalyst has all of the functional characteristics of a phase-transfer catalyst, in that it cannot only efficiently catalyze the desired transformation, but can also be readily recovered from the reaction mixture. We noted that the selenium powder was generally insoluble in the media prior to the reaction, making the catalytic system heterogeneous at this stage in the process. However, during the reaction process, the selenium dissolved completely to form a homogeneous solution, allowing it to efficiently catalyze the carbonylation reaction. Upon completion of the reaction, the selenium powder precipitated from the reaction media via an oxidation reaction in air, allowing for the catalyst to be readily recovered by suction filtration. Notably, the recovered selenium could be recycled without any discernible decrease in its catalytic performance ^{[14, 24]}. For example, the selenium catalyst gave a product yield of 80% after five cycles.

A plausible mechanism for the formation of 1, 4-dihydro-2H-3, 1-benzoxazin-2-one is shown in Scheme 2. The reaction of selenium with carbon monoxide in the presence of Et₃N would give the active COSe species A ^{[25, 26]}. The nucleophilic attack of 2-aminobenzyl alcohol to A would generate intermediate B ^{[25, 27]}, which would undergo an intramolecular nucleophilic addition from the hydroxyl group on B to give the desired product 1, 4-dihydro-2H-3, 1-benzoxazin-2-one. This step would be accompanied by the release of H₂Se (C), which would be oxidized with oxygen to give selenium, thereby completing the catalytic cycle ^[27].

We have developed an efficient and economical approach for the synthesis of 1, 4-dihydro-2H-3, 1-benzoxazin-2-one from 2-aminobenzyl alcohol. The key features of this reaction include the use of the cheap and recyclable non-metal selenium as a catalyst instead of the noble metal palladium; carbon monoxide as a carbonylation agent instead of virulent phosgene or one of its derivatives; and oxygen as an oxidant. Under these conditions, the selenium-catalyzed carbonylation of 2-aminobenzyl alcohol proceeded efficiently in the presence of triethylamine to afford the desired product 1, 4-dihydro-2H-3, 1-benzoxazin-2-one in 87% yield. Overall, this process represents a low cost, atom economical, one-pot, phosgene-free process for the preparation of 1, 4-dihydro-2H-3, 1-benzoxazin-2-one without the formation of any corrosive waste or carbon dioxide, making this approach a particularly promising alternative to the existing procedures.