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. 2020 Apr 24;8:239. doi: 10.3389/fchem.2020.00239

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

Jie Mou 1,2,*, Ninghai Chen 2,†, Yu Zhao 1,†, Hao Qi 2, Sihan Meng 2, Rui Xiang 1, Dongsheng Pei 3,*
PMCID: PMC7193868  PMID: 32391312

Abstract

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.

Keywords: green chemistry technology; synthetic method; 2,3-dihydroquinazolin-4(1H)-one; aqueous media; reverse zinc oxide micelle; nanoreactor

Introduction

N-heterocycles are important integral pharmacophoric units ubiquitously used in a variety of biologically active natural products, agrochemicals, pharmaceutical and synthetic drugs (Khan et al., 2016). 2,3-Dihydroquinazolin-4(1H)-one plays an important role in the aromatic nitrogen-containing heterocycles because of their abundant pharmacological and biological activities (Kshirsagar, 2015; Zawawi et al., 2015; Dohle et al., 2018). Compounds containing this motif have shown significant biological activities which include anticancer, anticonvulsant, antidefibrillatory, analgesic, diuretic, antihistamine, antihypertensive, and many other activities (Patil et al., 2015; Zawawi et al., 2015). These heterocycles participate in physiological processes as markers or messenger molecules and a large number of pharmaceuticals based on these heterocycles have been reported in the past few decades (Saeedi et al., 2018). For example, N1-substituted-2,3-dihydroquinazolin-4(1H)-one (I) is a cholinesterase inhibitor (Sultana et al., 2017), 1,7-disubstituted-2,3-dihydroquinazolin-4(1H)-one (II) is a selective PKC inhibitor (Katoh et al., 2016), bis(2,3-dihydroquinazolin-4(1H)-one (III) showed potent radical scavenging activities (Sivaguru et al., 2017), 2,7-disubstituted-2,3-dihydroquinazolin-4(1H)-one (IV) is a TRPM2 inhibitor (Zhang et al., 2018), 2-disubstituted-2,3-dihydroquinazolin-4(1H)-one (V) showed antitubulin activity (Singh and Raghav, 2015), and 2,2-disubstituted-2,3-dihydroquinazolin-4(1H)-one (VI) is considered as a potential lead compound as dual AChE/BChE inhibitor (Sarfraz et al., 2017) Figure 1.

Figure 1.

Figure 1

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Important lead compounds with 2,3-dihydroquinazolin-4(1H)-one skeleton.

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 ZnCl2 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). Catalyst-containing 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).

Scheme 1.

Scheme 1

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Synthesis of 2,3-dihydroquinazolin−4(1H)-one derivatives.

Materials and Methods

All solvents and reagents were commercial and used without further purification. All terminal products were confirmed by mp, FT-IR spectroscopy, 1H 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. 1H NMR spectra were recorded on a JNM-ECZ400s/L spectrometer (400 MHz, Joel, Japan) using CDCl3 or DMSO-d6 as the deuterated solvent. The chemical shifts have been reported in (ppm) downfield relative to (Me)4Si. 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°.

Scheme 2.

Scheme 2

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Preparation of reverse ZnO nanomicelles.

General Procedure for Preparation of 2,3-dihydroquinazolin-4(1H)-ones 3a−3l

To a solution of the catalyst in H2O (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.

Results

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.

Figure 2.

Figure 2

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(A) Particle size and distribution of reverse ZnO nanomicelles by PSS. (B) TEM image of reverse ZnO nanomicelles. (C) XRD spectrum of ZnO nanoparticles.

Synthesis of 2,3-dihydroquinazolin-4(1H)-one Derivatives

2-(4-nitrophenyl)-2,3-dihydroquinazolin-4(1H)-one (3a)

Yellow solid; mp: 158–161°C, Lit 165–168°C (Ramesh et al., 2017); IR(KBr, ν, cm−1): 3340, 1670, 1586, 1520, 1445, 1344, 1296, 1186; 1H NMR (400 MHz, CDCl3) δ 8.55 (s, 2H), 8.40–8.35 (m, 2H), 8.32 (dd, J = 7.9, 2.0 Hz, 1H), 8.05 (dd, J = 9.2, 2.5 Hz, 2H), 7.58–7.53 (m, 1H), 7.46–7.41 (m, 1H), 7.08 (dd, J = 7.9, 2.0 Hz, 1H), 5.97 (s, 1H). HRMS (ESI) calcd for [C14H11N3O3-H+]: 268.0717, found: 268.0725.

2-(3-nitrophenyl)-2,3-dihydroquinazolin-4(1H)-one (3b)

Yellow solid; mp: 166–169°C, Lit 163–165°C (Shaabani et al., 2008); IR(KBr, ν, cm−1): 3337, 1674, 1588, 1526, 1447, 1353, 1271, 1188; 1H NMR (400 MHz, CDCl3) δ 8.70 (t, J = 2.0 Hz, 1H), 8.54 (s, 1H), 8.45–8.39 (m, 2H), 8.32 (dd, J = 8.0, 1.6 Hz, 1H), 8.21 (d, J = 7.8 Hz, 1H), 7.73 (t, J = 8.0 Hz, 1H), 7.58–7.53 (m, 1H), 7.45–7.41 (m, 1H), 7.07 (dd, J = 8.0, 1.6 Hz, 1H), 5.92 (s, 1H). HRMS (ESI) calcd for [C14H11N3O3-H+]: 268.0717, found: 268.0718.

2-(2-chlorophenyl)-2,3-dihydroquinazolin-4(1H)-one (3c)

White solid; mp: 208–210°C, Lit 207–209°C (Ghafuri et al., 2019); IR(KBr, ν, cm−1): 3362, 1647, 1614, 1503, 1330, 1253, 1055; 1H NMR (400 MHz, CDCl3) δ 7.91 (dd, J = 7.8, 1.6 Hz, 1H), 7.79–7.67 (m, 1H), 7.42–7.38 (m, 1H), 7.36–7.26 (m, 3H), 6.89–6.85 (m, 1H), 6.66 (dd, J = 7.8, 1.6 Hz, 1H), 6.34 (t, J = 1.8 Hz, 1H), 6.05 (s, 1H), 4.63 (s, 1H). HRMS (ESI) calcd for [C14H11ClN2O-H+]: 257.0476, found: 257.0457.

2-(3-bromophenyl)-2,3-dihydroquinazolin-4(1H)-one (3d)

White solid; mp: 183–185°C, Lit 184–185°C (Khoshnavazi et al., 2016); IR(KBr, ν, cm−1): 3288, 1647, 1614, 1514, 1299, 1195, 1070; 1H NMR (400 MHz, CDCl3) δ7.93 (dd, J = 8.0, 1.5 Hz, 1H), 7.77 (s, 1H), 7.59–7.56 (m, 1H), 7.51 (d, J = 7.8 Hz, 1H), 7.37–7.28 (m, 2H), 6.91 (t, J = 7.5 Hz, 1H), 6.67 (d, J = 8.0 Hz, 1H), 5.87 (s, 1H), 5.80 (s, 1H), 4.38 (s, 1H). HRMS (ESI) calcd for [C14H11BrN2O-H+]: 300.9971, found: 300.9987.

2-(4-hydroxyphenyl)-2,3-dihydroquinazolin-4(1H)-one (3e)

White solid; mp: 182.6–184.9°C, Lit 192–194°C (Dindulkar et al., 2014); IR(KBr, ν, cm−1): 3288, 1647, 1614, 1514, 1299, 1195, 1070; 1H NMR (400 MHz, DMSO-d6) δ 9.45 (s, 1H), 8.04 (s, 1H), 7.58–7.55 (m, 1H), 7.29–7.16 (m, 3H), 6.89 (s, 1H), 6.76–6.60 (m, 4H), 5.61 (s, 1H). HRMS (ESI) calcd for [M-H+]: 239.0815, found: 239.0796. HRMS (ESI) calcd for [C14H12N2O2-H+]: 240.3562, found: 240.0795.

N-(4-(4-oxo-1,2,3,4-tetrahydroquinazolin-2-yl)phenyl)acetamide(3f)

White solid; mp: >220°C, Lit 241–242°C (Rostamizadeh et al., 2010); IR(KBr, ν, cm−1): 3330, 1680, 1649, 1610, 1509, 1312; 1H NMR (400 MHz, DMSO-d6) δ 9.94 (s, 1H), 8.20 (s, 1H), 7.61–7.50 (m, 3H), 7.37 (d, J = 8.5 Hz, 2H), 7.25–7.16 (m, 1H), 6.97 (s, 1H), 6.69 (t, J = 7.1 Hz, 1H), 6.64 (t, J = 7.4 Hz, 1H), 5.66 (s, 1H), 2.00 (s, 3H). HRMS (ESI) calcd for [C16H15N3O2-H+]: 280.1081, found: 280.1089.

4-(4-oxo-1,2,3,4-tetrahydroquinazolin-2-yl)phenyl acetate(3g)

White solid; mp: 193–194°C; IR(KBr, ν, cm−1): 3300, 1768, 1654, 1613, 1507, 1390, 1217; 1H NMR (400 MHz, CDCl3) δ 7.92 (dd, J1 = 7.8, 1.5 Hz, 1H), 7.64–7.52 (m, 2H), 7.35–7.30 (m, 1H), 7.20–7.10 (m, 2H), 6.91–6.87 (m, 1H), 6.65 (dd, J1 = 7.8 Hz, J2 = 1.5 Hz, 1H), 5.89 (s, 1H), 5.80 (s, 1H), 4.4(s, 1H), 2.31 (s, 3H). HRMS (ESI) calcd for [C16H14N2O3-H+]: 281.0921, found: 281.2468.

2-(2-(trifluoromethyl)phenyl)-2,3-dihydroquinazolin-4(1H)-one(3h)

White solid; mp: 188–190°C, Lit 187–188°C (Dutta et al., 2019); IR(KBr, ν, cm−1): 3356, 1671, 1610, 1507, 1484, 1230, 1210; 1H NMR (400 MHz, CDCl3) δ 7.93 (dd, J = 7.8, 1.5 Hz, 1H), 7.54–7.45 (m, 2H), 7.34–7.30 (m, 1H), 6.99–6.82 (m, 3H), 6.65 (d, J = 7.9 Hz, 1H), 5.84 (s, 1H), 5.71 (s, 1H), 4.35 (s, 1H). HRMS (ESI) calcd for [C13H11N3O-H+]: 224.0818, found: 224.0831.

2-(pyridin-2-yl)-2,3-dihydroquinazolin-4(1H)-one(3i)

White solid; mp: 172–175°C; IR(KBr, ν, cm−1): 3319, 3076, 1656, 1613, 1510, 1312, 1279, 1132, 1122, 1161, 772; 1H NMR (400 MHz, CDCl3) δ 8.15 (d, J = 7.8 Hz, 1H), 7.89 (dd, J = 7.8, 1.3 Hz, 1H), 7.73–7.59 (m, 2H), 7.52 (t, J = 7.7 Hz, 1H), 7.36–7.28 (m, 1H), 6.90–6.86 (m, 1H), 6.65 (dd, J = 7.8, 1.3 Hz, 1H), 6.35 (s, 1H), 5.92 (s, 1H), 4.44(s, 1H). HRMS (ESI), calcd for [C15H11F3N2O-H+]: 291.0740, found: 291.0747.

2-(4-methoxyphenyl)-2,3-dihydroquinazolin-4(1H)-one (3j)

Brown solid; mp: 184–185°C, Lit 182–184°C (Katla et al., 2017); IR(KBr, ν, cm−1): 3292, 2851, 1665, 1613, 1514, 1256, 1066; 1H NMR (400 MHz, CDCl3) δ 8.61–8.59 (m, 1H), 7.91 (dd, J = 7.8, 1.6 Hz, 1H), 7.78–7.73 (m, 1H), 7.59 (d, J = 7.9 Hz, 1H), 7.32–7.29 (m, 2H), 6.89–6.85 (m, 1H), 6.71 (d, J = 7.2 Hz, 1H), 6.52 (s, 1H), 5.91 (t, J = 2.3 Hz, 1H), 5.00 (s, 1H), 3.71 (s, 3H). HRMS (ESI) calcd for [C15H14N2O2-H+]: 253.0972, found: 253.0973.

2-(2,4-dimethoxyphenyl)-2,3-dihydroquinazolin-4(1H)-one(3k)

White solid; mp: 178–181°C, Lit 182–183°C (Hour et al., 2000); IR(KBr, ν, cm−1): 3425, 3298, 2837, 1653, 1613, 1509, 1256, 1033; 1H NMR (400 MHz, CDCl3) δ 7.90 (dd, J = 7.8, 1.5 Hz, 1H), 7.47 (d, J = 8.1 Hz, 1H), 7.32–7.25 (m, 1H), 6.89–6.77 (m, 1H), 6.65–6.57 (m, 1H), 6.51–6.40 (m, 2H), 6.17 (t, J = 1.6 Hz, 1H), 5.87 (s, 1H), 4.54 (s, 1H), 3.84 (s, 3H), 3.80 (s, 3H). HRMS (ESI), calcd for [C16H16N2O3-H+]: 283.1077, found: 283.2685.

2-(4-hydroxy-3,5-dimethoxyphenyl)-2,3-dihydroquinazolin-4(1H)-one(3l)

White solid; mp: >220°C; IR(KBr, ν, cm−1): 3365, 3334, 2835, 1663, 1612, 1511, 1243, 1204; 1H NMR (400 MHz, CDCl3) δ (ppm): δ 7.93 (d, J = 7.7 Hz, 1H), 7.35–7.32 (m, 1H), 6.90 (t, J = 7.5 Hz, 1H), 6.82 (s, 2H), 6.68 (d, J = 8.0 Hz), 5.80 (s, 1H), 5.76 (s, 1H), 5.67 (s, 1H), 4.38 (s, 1H), 3.91 (s, 6H). HRMS (ESI) calcd for [C13H18N2O3-H+]: 299.1026, found: 299.1018.

Discussion

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.

Table 1.

Optimization of reaction condition.

graphic file with name fchem-08-00239-i0001.jpg
Entry Catalyst (mol%) Solventa Temp. (°C) Time (min) Yield (%)b
1 3 Water 25 60 71
2 5 Water 25 45 82
3 10 Water 25 30 71
4 15 Water 25 10 95
5 20 Water 25 8 95
6 10 Water 60 5 90
7 10 Water 70 5 89
8 10 Water 90 5 95
9 10 CH2Cl2 25 120 28
10 10 THF 60 120 21
11 10 DMF 80 120 14
12 10 EtOH 60 120 16
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a

Reactions were conducted in solvent 5.0 mL on a 1 mmol scale at the special temperature using 10 mol% reverse ZnO nanomicelles as catalyst, 12 h.

b

Isolated yields.

Subsequently, the feasibility of the strategy to various solvents was investigated. The organic solvents such as dichloromethane (CH2Cl2), 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 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.

Figure 3.

Figure 3

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(A) Effects of the reaction temperature on the preparation of 3a. Reactions were employed on a 1 mmol scale; reverse ZnO nanomicelles 10 mol%; (B) Influence of the reaction time on the yield of 3a. Reactions were conducted on a 1 mmol scale; reverse ZnO nanomicelles 10 mol%, 70°C.

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.

Figure 4.

Figure 4

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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.

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 (–NO2) 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-3,5-dimethoxybenzaldehyde were explored in this reaction under the optimized reaction conditions and found the formation of target products in good yield.

Table 2.

Substrate scope of the reactiona.

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graphic file with name fchem-08-00239-i0003.jpg graphic file with name fchem-08-00239-i0004.jpg graphic file with name fchem-08-00239-i0005.jpg graphic file with name fchem-08-00239-i0006.jpg
3a (10 min, 99%) 3b (8 min, 99%) 3c (20 min, 99%) 3d (22 min, 96%)
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3e (50 min, 92%) 3f (40 min, 99%) 3g (50 min, 94%) 3h (30 min, 88%)
graphic file with name fchem-08-00239-i0011.jpg graphic file with name fchem-08-00239-i0012.jpg graphic file with name fchem-08-00239-i0013.jpg graphic file with name fchem-08-00239-i0014.jpg
3i (30 min, 92%) 3j (52 min, 85%) 3k (60 min, 99%) 3i (50 min, 97%)
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a

Reactions were carried out with benzaldehyde (1.2 mmol), anthranilamide (1 mmol) and reverse ZnO nanomicelles (10 mol%) in water (5 mL) at 70°C.

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 eco-friendly nature of the protocol (Table 3).

Table 3.

Comparison of nanomillce catalyst with reported procedure.

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Entry R Catalyst (mol%) Solvent Temp. (°C) Time (min) Yield (%) References
1 4-NO2 Cu(I)-SBA-15 CH2Cl2 25 50 80 Hajjami et al., 2017
2 3-NO2 Pd(0)-SMT-MCM-41 EtOH 80 150 94 Noori et al., 2017
3 2-Cl Br-TBA-Fe3O4 Water 70 60 91 Shiri et al., 2017
4 3-Br Carbon dots CH3CN 40 75 74 Majumdar et al., 2017
5 4-OH Phosphatidylcholine nanoliposomes Water 80 60 91 Tamaddon and Kazemivarnamkhasti, 2016
6 4-NHCOCH3 Indion Ina 225H Water 20 180 90 Satish Reddy et al., 2015
7 4-OCOCH3 Basic ion liquid Choline chloride 20 240 80 Obaiah et al., 2014
8 2-pyridin-2-yl thiamine hydrochloride Water Reflux 25 80 Devi et al., 2017
9 2-CF3 / CH2Cl2 Reflux 3 day 98 Zheng et al., 2013
10 4-OCH3 g-C3N4 EtOH Reflux 15 91 Ghafuri et al., 2019
11 4-NO2 ChSO3HC Water r.t. 62 80 Azizi and Shirdel, 2017
12 3,5-OCH3-4-OH p-sulfonic acid calix[4]arene Water 20 24 84 Rahman et al., 2015
13 4-NO2 ZnO nanomicelles Water 70 10 99 This work
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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) is formed. Subsequently, the condensation of the zinc oxide-aldehyde intermediate (i) with the anthranilamide produces imine intermediate (ii) after the dehydration and removal of zinc oxide. Finally, intermediate (i) was activated after ZnO connected to it and the following condensation of the imine with the amino group of anthranilamide produced the target product (iii) and released zinc oxide.

Scheme 3.

Scheme 3

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Plausible mechanism for ZnO nanomicelles catalyzed cyclocondensation reaction of 3a.

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 –NH2 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 2,3-dihydroquinazolin-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 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.

Author Contributions

JM: conceptualization. JM and NC: methodology. YZ, HQ, and SM: formal analysis. NC and RX: data curation. JM and NC: writing-original draft preparation. JM: writing-review and editing. DP: supervision. DP and JM: funding acquisition.

Conflict of Interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Acknowledgments

NC, HQ, and SM thank College students Innovation Project of Jiangsu Province (201910313073Y, 201910313098H) for the financial support.

Footnotes

Funding. This work was supported by the National Natural Science Foundation of China (No. 81872080, 81572349), Jiangsu Provincial Medical Talent (ZDRCA2016055), the Science and Technology Department of Jiangsu Province (BK20181148), College students Innovation Project of Jiangsu Province (201910313073Y, 201910313098H), the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD) and Top-notch Academic Programs Project of Jiangsu Higher Education Institutions.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Data Availability Statement

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

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