1. Introduction

Heterocyclic compounds widely exist in the nature with widespread biological activities and they also have been assigned as privileged structures in drug development. For example, 2,3- dihydroquinazolin-4(1H)-ones are an important class of heterocycles with a broad spectrum of biological and pharmaceutical activities, such as anticancer, analgesic, antitumor and diuretic. Some 2,3-dihydro-4(1H)-quinazolinones are herbicides and plant growth regulators ^{[1, 2]}. Furthermore, they could be oxidized to 2- substituted-4(1H)-quinazolinones ^[3], which exhibit many central nervous system effects, cardiovascular and anti-inflammatory activity, and act as psychotropic, hypnotic, cardiotonic and antihistamine agents. Quinazolinones are potent antibacterial, antifungal, antiviral, antimycobacterial and antimalarial substances. They are also used as inhibitors of various enzymes including monoamine oxidase, aldose reductase, tumor necrosis factor R and thymidylate synthase ^[4].

As a result, anumber of synthetic strategies have been developed for the preparation of 2,3-dihydroquinazolin-4(1H)-ones or quinazolin- 4(3H)-ones. The most common approach involves condensation of 2-anthranilamide with structurally diverse aldehydes or ketones in the presence of various catalysts, such as 2-morpholinoethanesulfonic acid ^[5], p-TSA/NaHSO₃^[6], TiCl₄/Zn ^[7], CuCl₂^[8], ionic liquid water ^[9], TFA ^[10], ammonium chloride ^[11], chiral phosphoric acids ^[12], HCl ^[13] and SmI₂ ^[14]. Many of the reported synthetic protocols suffered from unsatisfactory product yields, critical product isolation procedures, volatile organic solvents and harsh reaction conditions such as high reaction temperatures, strong acidic media and prolonged reaction time.

In addition, there is a paucity of synthetic route to implement the selectivity of two such compounds ^[15]. Many of the reported methods are associated with the use of extra-oxidant to complete the fusion of the quinazolin-4(3H)-ones. Traditionally, at least a stoichiometricamountof toxic oxidants, such asDDQ^[16], CuCl₂ ^[17], MnO₂ ^[18], KMnO₄ ^[19], K₂(S₂O₈) ^[20] and PhI(OAc)₂^[21]were used with possible uncontrollable explosive danger yielding almost the same amount of oxidant-derived waste. On the other hand, aerobic oxidationis interesting in keepingwiththe notion of green chemistry, sincemolecular oxygen is a cleaner and larger atom-efficient oxidant than other oxidants. Furthermore, molecular oxygen theoretically produces only water as the by-product after oxidation.

Herein, we report a versatile procedure for the fabrication of quinazolin-4(3H)-ones and 2,3-dihydroquinazolin-4(1H)-ones selectively catalyzed by Y(OTf)₃ (Scheme 1). This methodology utilizes oxygen in air as oxidant in terms of green chemistry and atom economy and two target compounds were obtained by employing different solvent. We also demonstrate that yttrium is mild catalyst to efficiently activate the oxygen.

2. Experimental

¹H NMR and ¹³C NMR spectra were made on Bruker ARX 400 for proton and carbon using DMSO-d₆ or CDCl₃ as the solvent with tetramethylsilane as an internal standard at room temperature. All reagents were obtained from commercial sources and used as received.

A general procedure for preparation of dihydroquinazolinones 3: Y(OTf)₃ (0.0268 g, 0.05 mmol) were dissolved in 10 mL EtOH and stirred until the solid dissolved completely, then anthranilamide 1a (0.1498 g, 1.1 mmol) and benzaldehyde 2a (0.101 mL, 1.0 mmol) was added into the reaction mixture. After 1.5 h, the reaction was completed which was determined by TLC analysis. Water (15 mL) was added to the reaction mixture, and the crystalline products were collected by filtration to give the crude product. The crude products thus obtained were crystallized from EtOH to give pure products 3a.

A general procedure for preparation of quinazolinones 4: Y(OTf)₃ (0.0268 g, 0.05 mmol) were dissolved in 10 mL DMSO and stirred until the solid dissolved completely, then anthranilamide 1a (0.1498 g, 1.1 mmol) and benzaldehyde 2a (0.101 mL, 1.0 mmol) was added into the reaction mixture. Then the mixture was heated to 110 ^°C under air atmosphere. After completion of the reaction monitored by TLC, the reaction mixture was cooled to room temperature. Water (15 mL) was added to the reaction mixture, and the crystalline products were collected by filtration to give the crude product. The crude products thus obtained were crystallized from EtOH to give pure products 4a. All ¹H NMR and ¹³C NMR results were summarized in Supporting information.

3. Results and discussion

Initially, we examined the model cyclocondensation reaction between anthanilamide (1) and benzaldehyde (2a) at 80^°C in alcohol with altered catalysts, and the results are summarized in Table 1. It turned out that in the absence of the catalyst only trace product was obtained for even longer time (Table 1, entry 1). In the presence of Lewis catalysts, such as ZnCl₂, CuCl₂, FeCl₃, the yields were dramatically improved (Table 1, entries 2–4). Interestingly, the reaction appears to work more efficiently using rare earth chlorides (Table 1, entries 5–9). Among the eight selected catalysts, Y(OTf)₃ has proved to be the most effective (Table 1, entry 8).

To determine the effect of solvents, next we examined our reaction in different solvents as depicted in Table 2. Among all the solvents screened, it was found that alcohol was the most suitable solvent for this reaction (Table 2, entry 3). Interestingly, the reaction also proceeds in good yield at room temperature (Table 2, entry 4), which was chosen as the optimal condition for further work.

Encouraged by the above experiments, we further explored the synthetic protocol and the scope by employing different kinds of aldehydes functionalized with electron-rich and electron-deficient groups to form a series of dihydroquinazolinones. The results were summarized in Table 3. Clearly, all reactions worked well irrespective of substiuents on the aldehydes substrates (Table 3, entries 1–14). Heteroaromatic aldehyde was also readily introduced into the quinazolinone skeleton at 2-position, and desired product was formed in excellent yield (Table 3, entry 15).

During the above reaction, trace of dihydroquinazolinones could be transformed to quinazolinones. The unexpected results prompted us to focus on the synthesis of quinazolin-4(3H)-one 4 using different oxidant such as H₂O₂, AATEMPOBF₄^-, NHPI, PhI(OAc)₂, but with relatively unsatisfactory yield. To further improve the yield, this reaction proceeded in DMSO with the presence of Y(OTf)₃. As expected, 4a was obtained in good yield while a trace amount of 3a was generated.

Then various aldehydes with either electron-donating or electron-withdrawing groups on aromatic ring were investigated in DMSO, and the results were listed in Table 4. It is noteworthy that various aldehydes were observed to be well tolerated under optimized conditions furnishing the product in good yields. Moreover, the reaction with nonaromatic aldehyde (Table 4, entry 18) also afforded the product in excellent yield.

Then the roles of air and catalyst in the reaction were explored. Under nitrogen atmosphere, in the presence of Y(OTf)₃, only a trace amount of quinazolinones 4a was detected whereas the dihydroquinalzolinone 3a was obtained in good yield (Table 5, entry 1). When the same reaction was carried out in air, the yield of 4a reached nearly 100% (Table 5, entry 2). It can therefore be deduced that oxygen in air as an oxidant promotes the transformation of 3a to product 4a. In the absence of catalyst, compound 3a was produced only in 9% yield while 4a in trace yield in air, indicating that the catalyst plays an important role not only in the condensation process but also the oxidation.

According to the aforementioned observations, a tentative reaction mechanism is outlined in Scheme 2. The present reaction consists of Schiff base formation, intramolecular cyclization, dioxygen activation and heterocyclic compounds oxidation. Condensation of 1a and 2a generates the corresponding Schiff base A with Y(OTf)₃ as an accelerant. The oxidative cyclization of Schiff base A could be envisioned to form heterocycle 3a which then undergoes Y(OTf)₃-catalyzed aerobic oxidation to yield the desired product 4a. 4. Conclusion

In conclusion, we have developed a green and efficient method to selectively synthesize dihydroquinazolinones and quinazolinones catalyzed by Y(OTf)₃ via regulating solvents. This method provides a simple, compatible and potentially powerful synthetic protocol for the modular construction of quinazolinones and dihydroquinazolinones, which are important units of biologically active molecules. The usage of molecular oxygen in air renders this protocol very attractive and practical. Furthermore, our results demonstrated that the rare earth catalysts play a decisive role in aerobic oxidation. A detailed study on the scope of our synthetic methodology is ongoing in our laboratory.

Acknowledgment

We gratefully acknowledge the National Natural Science Foundation of China (No. 20802052) for financial support.

Appendix A. Supplementary data

Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.cclet.2015.07. 026.