An Oxidant-Free and Mild Strategy for Quinazolin-4(3H)-One Synthesis via CuAAC/Ring Cleavage Reaction

An oxidant-free and highly efficient synthesis of phenolic quinazolin-4(3H)-ones was achieved by simply stirring a mixture of 2-aminobenzamides, sulfonyl azides, and terminal alkynes. The intermediate N-sulfonylketenimine underwent two nucleophilic additions and the sulfonyl group eliminated through the power of aromatization. The natural product 2-(4-hydroxybenzyl)quinazolin-4(3H)-one can be synthesized on a large scale under mild conditions with this method.


Introduction
Due to their great physiological importance and pharmaceutical usefulness for fighting tumors, quinazolin-4(3H)-ones are promising compounds for biological and medicinal applications [1][2][3][4]. Some natural and synthetic quinazolin-4(3H)-ones with therapeutic properties are already being tested in clinical trials as potential drugs. For instance, natural products like deoxyvasicinone (I) [5] and tryptanthrin (II) [6][7][8] (Figure 1) have demonstrated antibacterial, antidepressant, and anti-inflammatory properties. The compound 2-(4-hydroxybenzyl) quinazolin-4(3H)-one (HBQ, III) [9,10], which is obtained from a fungus found in marine sediment, has been shown to have significant cytotoxic activity against certain cancer cell lines as well as strong inhibitory effects on the replication of tobacco mosaic virus (TMV). Given their versatile pharmacological and biological characteristics, there is always an urgent need for the synthesis of quinazolin-4(3H)-one products.
Therefore, in this study, we present a highly efficient and oxidant-free approach to synthesize phenolic quinazolin-4(3H)-ones using the CuAAC/ring cleavage reaction (Scheme 1c). This method involves stirring a mixture of 2-aminobenzamides, sulfonyl azides, and terminal alkynes in the presence of a copper(I) catalyst under mild conditions. Since it was reported by Chang's group [40,41], the copper-catalyzed sulfonyl azide−alkyne cycloaddition/ring cleavage reaction (CuAAC/ring cleavage reaction) has been acknowledged as a gentle and effective method for synthesizing various nitrogenated compounds. It has also been used for modifying the structure of natural products, drugs, and biological macromolecules [42][43][44]. Our group has delved into this area and utilized the CuAAC/ring cleavage reaction to synthesize pyridine derivates, fused heterocycles, coumarins, indoles, and other nitrogenated compounds [45][46][47][48][49]. Therefore, in this study, we present a highly efficient and oxidant-free approach to synthesize phenolic quinazolin-4(3H)-ones using the CuAAC/ring cleavage reaction (Scheme 1c). This method involves stirring a mixture of 2-aminobenzamides, sulfonyl azides, and terminal alkynes in the presence of a copper(I) catalyst under mild conditions.

Results
Our investigations began with an examination of the synthesis of the parent and previously unreported system 3-benzyl-2-(3-hydroxybenzyl)quinazolin-4(3H)-one 4a via 2-amino-N-benzylbenzamide 1a, 3-ethynylphenol 2a, and tosyl azide 3a (Table 1). After an initial screening using CuI as a catalyst with the additive Et 3 N in a variety of solvents, we found that the desired conversion was affected by different solvents ( Table 1, entries 1−10). The results revealed that MeCN generated product 4a in the highest yield of 85%, the other solvents gave comparable yields, and EtOH generated product 4a with the lowest yield of 34%. Encouraged by these promising results, a variety of catalysts were then evaluated, as shown in

Results
Our investigations began with an examination of the synthesis of the parent and previously unreported system 3-benzyl-2-(3-hydroxybenzyl)quinazolin-4(3H)-one 4a via 2amino-N-benzylbenzamide 1a, 3-ethynylphenol 2a, and tosyl azide 3a (Table 1). After an initial screening using CuI as a catalyst with the additive Et3N in a variety of solvents, we found that the desired conversion was affected by different solvents ( Table 1, entries 1−10). The results revealed that MeCN generated product 4a in the highest yield of 85%, the other solvents gave comparable yields, and EtOH generated product 4a with the lowest yield of 34%. Encouraged by these promising results, a variety of catalysts were then evaluated, as shown in MeCN 89 c a Reaction conditions: 1a (0.10 mmol), 2a (0.11 mmol), and the catalyst (10 mol%) and base (0.11 mmol) in the solvent (2 mL) were added with 3a (0.11 mmol) and stirred at room temperature for 12 h. b Isolated yields. c MsN3 or PhSO2N3 was used instead of TsN3.  After the optimized reaction condition was established (Table 1, entry 5), the capacity of these reactions to affect the coupling of a range of different 2-aminobenzamides 1 was investigated. As shown in Scheme 2, the electronic effects of the substituents 2aminobenzamides 1 had an obvious influence. For example, the substrate bearing a -Me group was examined, and an 82% yield of 4b was isolated, which is the same efficiency as 4a. When 2-aminobenzamides 1 carried halogen substituents including Cl or Br, the anticipated products (4c-4f) were also obtained in good yields ranging from 80% to 92%. However, the strong electron-donating substituent gave the corresponding product 4g with a moderate yield of 76%, while the strongly electron-withdrawing substituent did not obtain the target product 4h due to the weak nucleophilic activity of the amino group. Finally, when the -NH 2 group was replaced by -NHMe, the target product 4i was not obtained.
PEER REVIEW 4 of 13 investigated. As shown in Scheme 2, the electronic effects of the substituents 2-aminobenzamides 1 had an obvious influence. For example, the substrate bearing a -Me group was examined, and an 82% yield of 4b was isolated, which is the same efficiency as 4a. When 2-aminobenzamides 1 carried halogen substituents including Cl or Br, the anticipated products (4c-4f) were also obtained in good yields ranging from 80% to 92%. However, the strong electron-donating substituent gave the corresponding product 4g with a moderate yield of 76%, while the strongly electron-withdrawing substituent did not obtain the target product 4h due to the weak nucleophilic activity of the amino group. Finally, when the -NH2 group was replaced by -NHMe, the target product 4i was not obtained. The scope and limitations of different substrates with 2-aminobenzamides 1 and terminal alkynes 2 were also tested. As shown in Scheme 3, 2-aminobenzamides 1 exhibit the same electronic effect when 1-(benzyloxy)-4-ethynylbenzene is involved as a terminal alkyne in this reaction. The effect of the -Me group on the reaction is relatively small (4j−4l), the halogen groups are the most effective (4m−4q), and the strong electron-donating group is poor (4r). Expectedly, with R 2 bearing an n-butyl or R 3 bearing a -Me group, the corresponding quinazolin-4(3H)-one derivatives 4s or 4t are formed in an excellent yield of 98% and 93%, respectively. Disappointingly, the natural product 2-(4-hydroxyben- The scope and limitations of different substrates with 2-aminobenzamides 1 and terminal alkynes 2 were also tested. As shown in Scheme 3, 2-aminobenzamides 1 exhibit the same electronic effect when 1-(benzyloxy)-4-ethynylbenzene is involved as a terminal alkyne in this reaction. The effect of the -Me group on the reaction is relatively small (4j-4l), the halogen groups are the most effective (4m-4q), and the strong electron-donating group is poor (4r). Expectedly, with R 2 bearing an n -butyl or R 3 bearing a -Me group, the corre-sponding quinazolin-4(3H)-one derivatives 4s or 4t are formed in an excellent yield of 98% and 93%, respectively. Disappointingly, the natural product 2-(4-hydroxybenzyl)quinazolin-4(3H)-one (HBQ, Figure 1, III) was not obtained when the R 2 group changed to H of 1a, which shows that the proton in this situation interferes with the reaction.   Although the natural product HBQ cannot be directly obtained by the above method, it can be obtained by a simple reduction of product 4j and can also be prepared in large quantities under mild conditions (Scheme 4). What is interesting to us is that there was no sulfonyl group in the target products, and we could detect the other undesired product TsNH2, which we compared with standard samples by thin-layer chromatography (TLC) and confirmed by NMR. Moreover, unlike the other products, compound 4i, which was difficult to synthesize (Scheme 2), was What is interesting to us is that there was no sulfonyl group in the target products, and we could detect the other undesired product TsNH 2 , which we compared with standard samples by thin-layer chromatography (TLC) and confirmed by NMR. Moreover, unlike the other products, compound 4i, which was difficult to synthesize (Scheme 2), was unaromatized. Therefore, we concluded that the product had aromatic properties. To confirm this fact and elucidate the mechanism, an intermolecular control experiment was performed under the optimized reaction condition (Table 1, entry 5). As shown in Scheme 5, N-Phenylbenzamide 5 and benzylamine 6 were tested for the intermolecular reaction. After being detected by TLC and confirmed by NMR, the N-sulfonylamidine product, which has been reported previously [41], was formed instead of the desired compound 7. The above experiments show that aromaticity is indispensable.

ER REVIEW 6 of 13
unaromatized. Therefore, we concluded that the product had aromatic properties. To confirm this fact and elucidate the mechanism, an intermolecular control experiment was performed under the optimized reaction condition (Table 1, entry 5). As shown in Scheme 5, N-Phenylbenzamide 5 and benzylamine 6 were tested for the intermolecular reaction. After being detected by TLC and confirmed by NMR, the N-sulfonylamidine product, which has been reported previously [41], was formed instead of the desired compound 7. The above experiments show that aromaticity is indispensable.

Scheme 5. Control experiment.
Based on the above experiments, a possible reaction pathway for the synthesis of quinazolin-4(3H)-one 4a was proposed (Scheme 6). According to the previous proposal [41][42][43][44][45][46][47][48][49][50], N-sulfonylketenimine A was generated first by the reaction of TsN3 and 2a. Then, A underwent a nucleophilic addition reaction with 1a to generate the intermediate B. Subsequently, intermediate B underwent an intramolecular cascade addition to generate the intermediate C. Lastly, the desired product 4a and product TsNH2 were obtained by aromatization of intermediate C. We could not detect intermediates B and C during the experiment, which indicated that the procedure from B to 4a was fast and almost simultaneous. The sulfonyl group was eliminated through the power of aromatization and activated the decomposition of the terminal alkynes into TsNH2 and N2. Lastly, the desired product 4a and product TsNH 2 were obtained by aromatization of intermediate C. We could not detect intermediates B and C during the experiment, which indicated that the procedure from B to 4a was fast and almost simultaneous. The sulfonyl group was eliminated through the power of aromatization and activated the decomposition of the terminal alkynes into TsNH 2 and N 2 .
intermediate C. Lastly, the desired product 4a and product TsNH2 were obtained by aromatization of intermediate C. We could not detect intermediates B and C during the experiment, which indicated that the procedure from B to 4a was fast and almost simultaneous. The sulfonyl group was eliminated through the power of aromatization and activated the decomposition of the terminal alkynes into TsNH2 and N2. Scheme 6. Plausible reaction mechanism.

General Information
The 1 H NMR spectra were recorded on a Bruker DPX 400 MHz spectrometer in CDCl3. Chemical shifts are reported in ppm with the internal TMS signal at 0.0 ppm as a standard. The spectra were interpreted as s, singlet; bs, broad singlet; d, doublet; t, triplet; q, quartet; m, multiplet; dd, double doublet; ddd, double double doublet; dt, double triplet; ddt, double double triplet; tt, triple triplet; td, triple doublet. Coupling constant(s) J are reported in Hz and relative integrations are reported. The 13 C NMR (100 MHz) spectra Scheme 6. Plausible reaction mechanism.

General Information
The 1 H NMR spectra were recorded on a Bruker DPX 400 MHz spectrometer in CDCl 3 . Chemical shifts are reported in ppm with the internal TMS signal at 0.0 ppm as a standard. The spectra were interpreted as s, singlet; bs, broad singlet; d, doublet; t, triplet; q, quartet; m, multiplet; dd, double doublet; ddd, double double doublet; dt, double triplet; ddt, double double triplet; tt, triple triplet; td, triple doublet. Coupling constant(s) J are reported in Hz and relative integrations are reported. The 13 C NMR (100 MHz) spectra were recorded on a Bruker DPX 400 MHz spectrometer in CDCl 3 . Chemical shifts are reported in ppm with the internal chloroform signal at 77.16 ppm as a standard and HBQ using CD 3 OD residual nondeuterated solvent as internal standard (CD 3 OD: δ 3.31 for 1 H and 49.00 ppm for 13 C). Melting points were obtained in open capillary tubes using the SGW X-4 micro melting point apparatus and were uncorrected. IR spectra were obtained with the Bruker Tensor-27 FT-IR spectrometer. Mass spectra were recorded on a TOF mass spectrometer. The starting materials, 2-amino-N-benzylbenzamide derivatives 1, were all known and prepared according to the literature procedures [50,51]. Terminal alkynes 2, TsN 3 3a, and other reagents were purchased from Adamas-beta and other suppliers and used without further purification.