An Aqueous Facile Synthesis of 2,3-Dihydroquinazolin-4(1H)-One Derivatives by Reverse Zinc Oxide Micelles as Nanoreactor

A green synthetic protocol has been developed for the efficient preparation of 2,3-dihydroquinazolin−4(1H)-one derivatives with excellent yield in aqueous media. Reverse zinc oxide micelles catalyzed the reactions efficiently and selectively as the hallow nanoreactor. Moreover, the catalyst was reusable without significant loss of catalytic efficiency. The notable advantages of the procedure are high yields and mild reaction conditions, simple operation, nonchromatographic purification, environmentally friendly and good versatile substrates.

Owing to wide range of applications, several approaches for the preparation of 2,3-dihydroquinazolin-4(1H)-one have been reported (Pospisilova et al., 2018;Pathare et al., 2019). The preferable route is to directly catalyze the condensation of anthranilamide with aldehydes for target products (Xing et al., 2017). However, most of these approaches are associated with numerous limitations including complicated reactions, vast excess of oxidant, non-renewable solvents, harsh reaction conditions (such as temperatures of up to 100 • C), long reaction time and low reaction yields (Bie et al., 2016;Parua et al., 2017;Sun et al., 2018;Wang et al., 2018). In recent years, the focus has been on the development of economical and convenient methods for the synthesis of dihydroquinazolin-4(1H)-one derivatives via a tolerable approach (Tamaddon and Kazemivarnamkhasti, 2016;Liu et al., 2018). Additionally, an efficient and highly selective catalyst is definitely indispensable. Wu et al. (2013) developed an efficient method for the preparation of dihydroquinazolinones analogs by employing ZnCl 2 as a catalyst in EtOH. However, the percentage of product yielded is lower than 50%. To our delight, the group IIB transition metal Lewis acids are promising catalyzers for this transformation. Nano-sized metal oxides usually undergo agglomeration when they are dispersed in solutions due to their large specific surface area and high surface activity (Punnoose et al., 2014;Curran et al., 2017;Liu et al., 2018), which has a major impact on their reactivity. And the porous nanomaterial was found to be an efficient, selective and waste-free green approach (Rostamnia and Xin, 2014). Catalystcontaining hollow nanocapsules have attracted particular interest because they provide the storage spaces or reaction chambers for a diffusional product/substrate exchange between the inner cavity and the bulk solution to take place efficiently (Sanles-Sobrido et al., 2012). Consequently, we designed the reverse zinc oxide nanomicelles as functional catalyst nanoreactors to achieve the dual purpose of both stabilizing the dispersal and providing nano-size control.
Our previous studies have shown that the Betti reaction could be promoted by reverse zinc oxide micelles in aqueous efficiently and selectively (Mou et al., 2017). As interest continues in the potential use of such a catalyst, we report herein a simple, one-pot synthesis of 2-substituted 2,3-dihydroquinazolin-4(1H)-one from substituted aldehydes and anthranilamide in the presence of reverse zinc oxide micelles as a catalytic system (Scheme 1).

MATERIALS AND METHODS
All solvents and reagents were commercial and used without further purification. All terminal products were confirmed by mp, FT-IR spectroscopy, 1 H NMR and HRMS. Melting points were measured in open capillary tubes and were uncorrected. FT-IR spectra were obtained on an infrared spectrophotometer (Jasco FT-IR 4100 Series, Perkin-Elmer, USA) using KBr disks. 1 H NMR spectra were recorded on a JNM-ECZ400s/L spectrometer (400 MHz, Joel, Japan) using CDCl 3 or DMSO-d 6 as the deuterated solvent. The chemical shifts have been reported in (ppm) downfield relative to (Me) 4 Si. High-resolution-mass spectra (HRMS) analyses were recorded at room temperature on a micrOTOF-Q instrument (Bruker, USA).

Preparation and Characterization of Catalyst
The reverse zinc oxide nanomicelles was synthesized following the reported procedure (Mou et al., 2017) (Scheme 2). Reverse micelles were formed by the self-assembly of the surfactant in cyclohexane. The particle size and distribution of reverse ZnO nanomicelles were recorded on NICOMP 380ZLS particle size analyzer (PSS, USA). The morphology was illustrated using transmission electron microscopy (TEM, Joel, Japan). The micelles were dispersed via ultrasonication in water for 1 min before deposition on the TEM grid. X-ray diffractometers (XRD) were conducted on a Rigaku D/max-III type instrument (Denki, Japan) using Cu Kα (1.54 Å) radiation with a scanning speed of 4 • /min from 5 • to 90 • .
General Procedure for Preparation of 2,3-dihydroquinazolin-4(1H)-ones 3a−3l To a solution of the catalyst in H 2 O (10 mol%, 5 mL), anthranilamide (0.1 mmol) and substituted aromatic aldehydes (0.1 mmol) were added. The resulting mixture was stirred under 70 • C for a period of time. The reaction was monitored by thin layer chromatography (TLC). After completion of the reaction, the precipitate was filtered and recrystallized from ethanol (95%) to obtain the pure target product. The catalyst remaining in the water filter liquor could be used directly as a catalyst media for subsequent runs.

Characterization of Reverse ZnO Nanomicelles
The distribution of sphere diameters and TEM image are shown in Figures 2A,B, respectively. The image revealed that the average diameter was 280 nm and the size distribution was about 60%. The XRD pattern of ZnO nanoparticles calcined at 400 • C is shown in Figure 2C. The diffraction peaks appeared at 2θ value similarly to the hexagonal structure of zincite phase reported in JCPDS File Card No. 05-0664.

Optimization Studies
The catalytic activity of reverse ZnO nanomicelles in the preparation of 2,3-dihydroquinazolin-4(1H)-ones was investigated after the catalyst characterization. In this respect, the cyclocondensation of anthranilamide and 4-nitrobenzaldehyde was selected as a model reaction to optimize the reaction condition by varying solvent, catalyst amount and reaction temperature. The results were exhibited in Table 1. It was found that the catalyst amount plays a vital role in the product yield and conversion time ( Table 1, entries 1-5). The reaction was initially employed in water at room temperature for 1 h with 3% catalyst dosage, the target product 3a was obtained with 71% yield (entry 1). The yield was increased from 70 to 99% with the increasing amount of catalyst, the highest yield reach 99% when 10% reverse ZnO nanomicelles were applied. The reaction time was greatly shortened by increasing the amount of catalyst, but the yield did not increase significantly more than 10 mol% ZnO nanomicelles added. It is indicated that the desired product 3a was obtained by catalytic amounts of reverse ZnO nanomicelles. Notably, the  terminal product was isolated by filtration and recrystallazation with excellent yield without any column purification. Subsequently, the feasibility of the strategy to various solvents was investigated. The organic solvents such as dichloromethane (CH 2 Cl 2 ), tetrahydrofuran (THF), dimethyl formamide (DMF), ethanol (EtOH) were examined. Surprisingly, although raw materials dissolved perfectly in these organic solvents, none of them affords higher yield of the target product than water (entries 9-12). An almost quantitative yield was achieved within 2 h when the reaction was conducted in organic solvents. Even the best of them, dichloromethane, only afforded 28% yield (Table 1, entry 9), which is about one third of the yield under the same condition in water (Table 1, Entry 1). From these results, it was evident that water is most suitable for the synthesis of 3a in the presence of reverse zinc oxide micelle. This phenomenon may be a result of the unusual feature of the reverse zinc oxide micelle and the reaction mechanism which will be further discussed.

Stability of the Catalytic System
We then investigated the relationship between temperature and the product yield ( Figure 3A). Notably, this system had extraordinary reaction activity and an ability to give a good yield at room temperature or low temperature (4 • C). The highest yield was obtained at 80 • C. However, taking energy consumption into consideration, we thought 70 • C was the most suitable temperature for the reaction, as it cost less, despite producing slightly less yield than 80 • C did. When the temperature elevated to 90 • C, the yield declined possibly due to the micelles' loss of surface area caused by dissociation. Additionally, we explored the best reaction time ( Figure 3B). As is shown in Figure 3B, the FIGURE 4 | Reusability of reverse ZnO micelles in the preparation of 3e. Reaction conditions: 1 (1 mmol), 2e (1 mmol), catalyst (reverse ZnO nanomicelles, 10 mol%), solvent (water, 5 mL), 70 • C, 12 min. Isolated yield. reaction proceeded quickly in 8 min, reaching a fairly high yield. No obvious increase of the yield was detected after the reaction was conducted for 8 min.
Additionally, we examined the reusability and recyclability of the catalyst (Figure 4). The aqueous layer containing the catalyst was decanted and reused for the next run under the same condition. As is shown in Figure 4, the yields of the product remained essentially constant for the 5 successive cycles higher than 95% yield, indicating superb stability and reusability of the catalyst.

Versatility of the Substrates
Using the optimized reaction conditions (water, 70 • C, 10 mol% catalyst), the generality and diversity of our methodology was evaluated by anthranilamide with a wide range of substituted aromatic aldehydes and the results are shown in Table 2. The reaction preceded smoothly using aldehydes bearing either electron-donating or electron-withdrawing groups to give the corresponding products. Aromatic aldehydes bearing strong electron-withdrawing groups (-NO 2 ) could promote the reaction and offered better yields than those of aldehydes with electron-donating groups (OH, OMe) or halogen-substituted (-Br, -Cl). For aldehydes containing the electron-withdrawing group (acetylamino-and acetoxy-), the reaction rate was relatively fast and the yield of the product was also higher due to the electron deficiency. Heterocyclic aldehydes (pyridine) offered the corresponding products in good yields.  Nevertheless, o-trifluoromethyl substituted benzaldehyde only afforded 65% target product after 1 h, which may attribute to the disadvantage of steric hindrance. To further expand the scope of the green method, a variety of multiple substituent aldehydes like 2,4-dimethoxybenzaldehyde and 4-hydroxy-3,5dimethoxybenzaldehyde were explored in this reaction under the optimized reaction conditions and found the formation of target products in good yield.

Advantages of Reverse Zinc Oxide Nanomicelles Catalyst System
Comparison of the reverse zinc oxide nanomicelles-catalyzed preparation of 2,3-dihydroquinazolin-4(1H)-ones in water with a range of other strategies demonstrated the high yields, low consumption of the catalyst, short reaction times, and the ecofriendly nature of the protocol (Table 3).

Plausible Mechanism
The plausible mechanism for the formation of reverse zinc oxide nanomicelles-catalyzed synthesis of 2,3-dihydroquinazolin-4(1H)-ones in water is shown in Scheme 3. In this case, benzaldehyde prefers for the interior of the reverse micelles to coordinate with ZnO oxide, whereas the more polar anthranilamide reside on average in the head group region of the reverse micelles. Firstly, the coordination compound of zinc oxide-aldehyde intermediate (i)  following condensation of the imine with the amino group of anthranilamide produced the target product (iii) and released zinc oxide. It is suspected that the inherent surface acidity of zinc oxide nanomicelles activates the benzaldehyde carbonyl carbon, making the carbon center highly electrophilic for the nucleophilic addition of anthranilamide. Hydrogen transfer resulted in protonated N, O-hemiketal followed by anchimeric assistance by the -NH 2 group to give an imine which further undergoes intramolecular cyclization and deprotonation to give the desired dihydroquinazolinone product.
Reverse nanomicelles played an important role in combining the substrates, stabilizing the intermediate and promoting the dehydration condensation under neutral conditions in water catalyzed by the cationic water pool encapsulated in reverse micelles. The enhanced surface area due to nano particle size is an added advantage for its reactivity. Water promotes the nucleophilic addition reaction between imine intermediate and anthranilamide for the high polarity. All of these important factors are responsible for the high accessibility of the substrate molecules on the catalyst surface. Thus, the reaction occurred more easily in a micelles special with respect to its functioning as a nanoreactor.

CONCLUSIONS
In conclusion, an efficient and convenient procedure for 2,3dihydroquinazolin-4(1H)-ones has been developed via one-pot synthesis from anthranilamide and benzaldehyde. Reverse ZnO nano micelles were employed as catalyst and water was used as a SCHEME 3 | Plausible mechanism for ZnO nanomicelles catalyzed cyclocondensation reaction of 3a.
green solvent for this transformation, producing excellent yields without the formation of by-products. The advantages of this method include atom economy, as well as being environmentally benign. The results prove the crucial role of reverse ZnO micelles as nanoreactors and will find more extensive applications in the field of green chemistry.

DATA AVAILABILITY STATEMENT
All datasets generated for this study are included in the article/supplementary material.