Quinazolin-4(3 H )-ones: A Tangible Synthesis Protocol via an Oxidative Oleﬁn Bond Cleavage Using Metal-Catalyst Free Conditions

: An e ﬃ cient and selective oxidative procedure for the synthesis of quinazolinones from readily available o -aminobenzamides and styrenes was developed. A number of potentially pharmacologically relevant quinazolinones were prepared using metal- and catalyst-free conditions. The synthesis procedure highlights the sustainable operation, low-priced, free from perilous materials, green solvent and environmental a ﬀ ability. The synthesized products were isolated in moderate to excellent yields.


Introduction
Oxidative cleavage of unsaturated hydrocarbons is one of the most significant and efficient approaches to produce carbonyl compounds in organic chemistry, petrochemical industry as well as the conversion of biomass [1][2][3][4]. Aldehydes and ketones are important precursors to acids and alcohols as well as widely used in pharmaceutical, agriculture and most importantly in the fine chemical industry. The direct oxidative cleavage of olefins is still a challenge and greatly dependent on the use of conventional methods, for instance using ozone [5][6][7][8], KMnO 4 [9,10], oxone [11,12], NaIO 4 [13], OsO 4 [14], high valance I 2 [15,16], m-chloroperbenzoic acid, etc. [17,18]. However, these methods suffer from the long reaction period, over oxidation, low selectivity, limited substrate scope, poor functional group tolerance and environment unfriendliness.
There is need for development of environment benign synthetic methodologies, procedures not requiring use of hazardous materials and expensive reagents. In order to match the request of green chemistry some methodologies were developed for the oxidation of alkenes using the palladium catalyst under high pressure of oxygen [19]. Our group has also developed several metal-free oxidative methodologies [20][21][22]. Although these methodologies show progress towards oxidative cleavage of unsaturated hydrocarbons, nevertheless, there is still much room for the development of synthetic methodologies that provide the generality of substrate scope for the synthesis of fine chemical building blocks.
Nevertheless, most of the reported work depend on expensive metals, ligands, higher temperature and special equipment, etc. which, as a result, limit the synthesis of biologically active compounds because of the presence of metal impurities in the products. Therefore, a significant need for improvement of environmentally benign methodologies for the preparation of quinazolinones under metal-based-catalyst free reaction conditions is still needed. Based on our continuing interest in the maturity of green, novel and sustainable synthetic methodologies for fine chemicals [63][64][65] as well as pharma related products where we have developed methodology for the synthesis of quinazolinones by reaction of 2-aminobenzamides and benzylic alcohols [66]. Thus, we report a metal-catalyst-free, synthesis of quinazolin-4(3H)-ones from o-aminobenzamide and direct oxidation-cyclization of in situ prepared aldehydes from styrenes. General preparation; characterization of the synthesized compounds and figures of the NMR spectra can be seen in supplementary material.
Appl. Sci. 2020, 10, x FOR PEER REVIEW 3 of 11 Nevertheless, most of the reported work depend on expensive metals, ligands, higher temperature and special equipment, etc. which, as a result, limit the synthesis of biologically active compounds because of the presence of metal impurities in the products. Therefore, a significant need for improvement of environmentally benign methodologies for the preparation of quinazolinones under metal-based-catalyst free reaction conditions is still needed. Based on our continuing interest in the maturity of green, novel and sustainable synthetic methodologies for fine chemicals [63][64][65] as well as pharma related products where we have developed methodology for the synthesis of quinazolinones by reaction of 2-aminobenzamides and benzylic alcohols [66]. Thus, we report a metal-catalyst-free, synthesis of quinazolin-4(3H)-ones from o-aminobenzamide and direct oxidationcyclization of in situ prepared aldehydes from styrenes. General preparation; characterization of the synthesized compounds and figures of the NMR spectra can be seen in supplementary material.

Model Reaction for Synthesis of Quinazolin-4(3H)-one
Initially, o-aminobenzamide 1 and styrene 2 in the presence of an oxidant TBHP (70% in H2O, 5.8 eq., 1.5 mL w.r.t 2) were employed as a model reaction for screening the best reaction conditions. As shown in Table 1, different reaction parameters, oxidant, solvent, temperature, additive and time were screened. To our contentment, as expected, desired product 3, was obtained in 56% yield using a neat reaction, without solvent (Table 1, entry 1). The lower yields of the anticipated product 3 were

Model Reaction for Synthesis of Quinazolin-4(3H)-one
Initially, o-aminobenzamide 1 and styrene 2 in the presence of an oxidant TBHP (70% in H 2 O, 5.8 eq., 1.5 mL w.r.t 2) were employed as a model reaction for screening the best reaction conditions. As shown in Table 1, different reaction parameters, oxidant, solvent, temperature, additive and time were screened. To our contentment, as expected, desired product 3, was obtained in 56% yield using a neat reaction, without solvent ( the addition of p-TsOH showed the improvement in yield (Table 1, entry 7). Several screenings were performed by varying the amounts of the additives, temperatures and time and it was observed that DTBP (1.1 eq, TsOH 0.33 eq) furnished the improved yield (

Synthesis of Quinazolin-4(3H)-one: Substrate Scope
The best optimized conditions obtained in entry 8 of Table 1, were employed to assess the substrate scope, generality and limitations of the present protocol. A reaction of o-aminobenzamide and wide range of substituted styrenes were studied under best conditions in hand. As presented in Figure 3, several substituted styrenes showed functional group tolerance under given condition and furnished the desired quinazolin-4(3H)-ones in good to high yields. Styrenes bearing common electron donating functional groups, tert-(CH3)3 (Figure 3, 3b), -OCH3 (Figure 3, 3d), which are generally sensitive to strong oxidants exhibited very good tolerance under the optimized reaction conditions and were transformed to corresponding quinazolin-4(3H)-ones providing moderate yields 65%, 50% respectively ( Figure 3). 54-56% yields were isolated in case of reaction of oaminobenzamide 1, with para-fluoro and para-chloro substituted styrenes (Figure 3, 3e, 3f)

Understanding of the Reaction Mechanism
To have better understanding of the reaction pathway, several control experiments were performed. Initially, the reaction of styrene was performed without using oxidant and oaminobenzamide, no oxidation product was detected in GC showing the starting material only. Whereas, an oxidation reaction of styrene under optimized reaction conditions (without oaminobenzamide) afforded the expected benzaldehyde in 78% GC yield ( Figure 5). Based on the above experiments a plausible reaction mechanism for the synthesis of quinazolinones from styrene and o-aminobenzamide is proposed ( Figure 5). It is established that benzaldehyde is an oxidation product of styrene which on condensation with o-aminobenzamide afforded imine intermediate that eventually, through cyclization-oxidation afforded the quinazolinone.

Understanding of the Reaction Mechanism
To have better understanding of the reaction pathway, several control experiments were performed. Initially, the reaction of styrene was performed without using oxidant and o-aminobenzamide, no oxidation product was detected in GC showing the starting material only. Whereas, an oxidation reaction of styrene under optimized reaction conditions (without o-aminobenzamide) afforded the expected benzaldehyde in 78% GC yield ( Figure 5). Based on the above experiments a plausible reaction mechanism for the synthesis of quinazolinones from styrene and o-aminobenzamide is proposed ( Figure 5). It is established that benzaldehyde is an oxidation product of styrene which on condensation with o-aminobenzamide afforded imine intermediate that eventually, through cyclization-oxidation afforded the quinazolinone.

Typical Experimental Procedure for Synthesis of Quinazolin-4(3H)-ones (Figure 3, 3-3i)
2-aminobenzamides (1.00 mmol, 136 mg), styrenes (2.0 mmol, 2.0 eq) were placed in an acepressure tube that was equipped with a stirring bar. DMSO (2 mL) and p-TsOH (0.66 mmol, 114 mg) were then added into the mixture. In the end, DTBP (2.2 mmol, 0.4 mL) added to the mixture by the syringe and ace-pressure tube sealed with Teflon cap. The final reaction mixture in the pressure tube was placed in an aluminum heating block and stirred at a temperature of 120 o C for 16 h. The reaction mixture was cooled to room temperature and worked up by diluting with ethyl acetate and washed with water. The compound was extracted with 45 mL ethyl acetate. After the solvent was evaporated in vacuum, products were purified using column chromatography on silica gel with hexane and ethyl acetate (2:1).

Typical Experimental Procedure for Synthesis of Quinazolin-4(3H)-ones
2-aminobenzamides (1.00 mmol, 136 mg), styrenes (2.0 mmol, 2.0 eq) were placed in an ace-pressure tube that was equipped with a stirring bar. DMSO (2 mL) and p-TsOH (0.66 mmol, 114 mg) were then added into the mixture. In the end, DTBP (2.2 mmol, 0.4 mL) added to the mixture by the syringe and ace-pressure tube sealed with Teflon cap. The final reaction mixture in the pressure tube was placed in an aluminum heating block and stirred at a temperature of 120 • C for 16 h. The reaction mixture was cooled to room temperature and worked up by diluting with ethyl acetate and washed with water. The compound was extracted with 45 mL ethyl acetate. After the solvent was evaporated in vacuum, products were purified using column chromatography on silica gel with hexane and ethyl acetate (2:1) (Figure 3 3.2. Typical Procedure for Synthesis of Benzothiadiazine-1,1-dioxides 2-aminobenzenesulfonamide (1.00 mmol, 172 mg), styrenes (2.0 mmol, 2.0 eq) were placed in an ace-pressure tube that was equipped with stirring bar. DMSO (2 mL) and p-TsOH (0.66 mmol, 114 mg) were then added into the mixture. At the end, DTBP (2.2 mmol, 0.4 mL) added to the mixture by the syringe and ace-pressure tube sealed with Teflon cap. The final reaction mixture in pressure tube was placed aluminum heating block and stirred at temperature of 120 • C for 20 h. The reaction mixture was cooled to room temperature and worked up by diluting with ethyl acetate and washed with water. The compound was extracted with 45 mL ethyl acetate. After the solvent was evaporated in vacuum, products were purified using column chromatography on silica gel with hexane and ethyl acetate (2:1) (Figure 4, 5-5b).

Conclusions
In conclusion, we have established an efficient, novel metal-and catalyst-free protocol for the synthesis of pharmaceutically important, potential bio-active quinazolin-4(3H)-ones and benzothiadiazine-1,1-dioxides in modest to fairly good yields. Readily accessible starting materials were applied as substrate in presence of DTBP as an oxidant and p-TsOH as an additive. Remarkable, no transition metal catalyst was used for this effective transformation.