Quinazolinones represent a high value class of compounds in organic chemistry,which has a wide range of biological and pharmacological activities ^[1],including anti-bacterial ^[2],anticancer ^[3],anti-inflammatory ^[4],anti-microbial ^[5],anti-tubercular ^[6],anti-ulcer ^[7],and so on ^[8]. Additionally,they are important intermediates in natural products preparation ^[9] and applied as structural scaffold in drug discovery.

Owing to their diverse bioactivity and privileged sub-structure for drug design,the synthetic methodologies development becomes attractive and many synthetic routes have been developed ^[10a]. For example,copper-catalyzed Ullmann-type coupling reactions ^[10b],redox condensation between o-substituted nitrobenzenes with amines in the presence of iron and cobalt as catalysts ^[11],one-pot synthesis of quinazolinones from benzyl alcohols by iridium or ruthenium catalysts ^[12]. In these reactions,metal-salts turned out to be indispensable,and many metal wastes were generated. Besides,condensation between o-aminobenzamides and aldehydes with additional oxidants is also a typical method to prepare quinazolinones ^[13]. Recently,a procedure on autoxidation of benzyl amines and applied in heterocycles synthesis was developed as well ^[14a]. Five examples of quinazolinones were prepared in moderate yields under 150 ℃ with 40% AcOH as the additive. Meanwhile,we reported a procedure for the transformation of benzyl amines to the corresponding imines ^[15]. Various imines were produced in good to excellent yields under metal-free conditions and with H₂O₂ as the green oxidant. From mechanistic point of view,the oxidation of benzyl amines to the corresponding benzaldehydes should be the first step and then followed by condensation to give the imines. Hence,we believe a procedure for quinazolinones preparation with o-aminobenzamides and benzylamines as the substrates without metal catalysts and using H₂O₂ as the green oxidant should be highly realizable. Under this context,we developed this interesting metal-free and additive-free procedure for the synthesis of quinazolinones from o-aminobenzamides and benzyl amines.

A 15 mL tube was added 2-aminobenzamide (1 mmol),benzyl amine (1.5 mmol),and a stir bar. Then H₂O₂ (30 wt% in H₂O,5 equiv.) was added by a syringe at room temperature under open air. The tube was closed and kept at 120 ℃ for 20 h. The conversion and yield were determined by GC and GC-MS using hexadecane (0.1 mmol) as the internal standard.

At the beginning,substrates 1a and 2a were chosen as the starting materials. The reaction was conducted with 5 equiv. of H₂O₂ (30 wt% in H₂O) at 100 ℃ in DMSO,fortunately,25% yield of the target product 3aa was obtained (Table 1,entry 1). Encouraged by this result,we continued with the studies of different solvents which did not improve the yield significantly (Table 1,entries 2- 10). However,when we tried the reaction without solvent,the yield raised to 50% (Table 1,entry 11). Furthermore,the amount of H₂O₂ was examined,less and more H₂O₂ all decreased the yield (Table 1,entries 12 and 13). Notably,reaction temperature was found hold great influence for this transformation. 80 ℃ resulted in 46% yield (Table 1,entry 15),while 120 ℃ resulted in 71% yield (Table 1,entry 14). No better yield can be obtained under higher reaction temperature.

Table 1

Table 1 Screening of the reaction conditions.a

Table 1 Screening of the reaction conditions.a

Inspired by this result,we next investigated the substrates scope. First,o-aminobenzamide and a variety of para-substituted benzyl amines were studied (Table 2,entries 1-10). The substrates with electron-donating group,such as methyl,tert-butyl group smoothly afford the quinazolinones in 59% and 69% yield (Table 2,entries 2 and 3). However,as an electron-rich group,paramethoxybenzylamine decreased the yield of the desired product to 44% (Table 2,entry 4). A moderate product yield was generated when the substrate decorated with electron-deficient group,such as trifluoromethyl moiety (Table 2,entry 5). Moreover,benzyl amines bearing fluoro,chloro,and bromo provided the desired products with slightly lower yields (Table 2,entries 6-8). It is noteworthy that heteroaromatic substrate can also be tolerated under the standard condition,resulted the corresponding product in 65% yield (Table 2,entry 9). In addition,N-substituted benzylamine was also examined,affording the product 3aa in 45% yield (Table 2,entry 10). However,aliphatic amines such as butylamine and 2-phenylethanamine failed in our system. Additionally,no desired product was observed with N,N-dimethylbenzyl amine.

Table 2

Table 2 Synthesis of quinazolinones: substrates testing.a

Table 2 Synthesis of quinazolinones: substrates testing.a

Next,a series of o-aminobenzamides were then subjected to the optimized reaction conditions,and the results were summarized (Table 2,entries 11-14). We were delighted to find that all the oaminobenzamides examined worked well and succeeded to give the target products in moderate yields.

Regarding the reaction pathway,a possible reaction mechanism has been proposed in Scheme 1. First,benzyl amine 1 was oxidized to benzaldehyde in the presence of H₂O₂. Then,the condensation of the in situ formed aldehyde with o-aminobenzamide 2 occurred. The condensed intermediate can provide the final quinazolinone 3 after further oxidation step.

Scheme 1

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Scheme 1. Proposed reaction mechanism

In conclusion,we have developed an environmental friendly strategy for the quinazolinones preparation. With o-aminobenzamides and benzyl amines as the substrates and H₂O₂ as the green oxidants under metal-free and solvent-free conditions,a variety of quinazolinones were generated in moderate to good yields.

The authors thank the financial supports from NSFC (No. 21472174),Education Department of Zhejiang Province (No. Y201432060) and Zhejiang Sci-Tech University (Nos. 1206838-Y and 14062015-Y). X.-F. Wu appreciates the general support from Matthias Beller in LIKAT.