Synthesis Of4(3H)-Quinazolinones

Quinazolinones are a class of nitrogen-containing heterocycles with a diverse range of pharmacological activities. Such as anticancer, antitumor, antihypertensive, antimicrobial, etc. Meanwhile, a large number of natural products contain quinazolinone structure, such as echinozolinone, chrysogine, glycosminine, rutaecarpine, febrifugine. Predictably, studies and synthesis of quinazolinones has a very important significance.It has been more than a century since the initial study on synthesis of quinazolinones. Recently, researchs on quinazolinones are active. There are a number of synthetic methods of quinazolinones. One of the most general one is cyclocondensation of anthranilamides with aldehydes in the presence of various promoting agents, such as CuCl2in ethanol, Pd(OAc)2and TPPMS in water, KMnO4under microwave irradiation. However, most of these methodologies have some drawbacks, such as, using stoichiometric or expensive catalyst, and often involve harsh reaction conditions. Hence, to explore some new method, such as to discover a cost-saving catalyst, also has certain significance.We select anthranilamide and aldehyde as the raw material of synthetic quinazolinones. After a series of trials and studies, we demonstrate for the first time that vanadyl acetylacetonate could be used as an efficient catalyst for the synthesis of4(3H)-quinazolinones at low catalyst loading (only1mol%). First, determine the optimized conditions of the reaction. The optimized conditions were as follows: Anthranilamide:benzaldehyde:catalyst=1:1:0.01, DMA as solvent, under air at120℃for15hours in a open test tube. Under the conditions,97%yield was obtained. Secondly, with the optimized reaction in hand, different substrates were investigated, such as:4-methylbenzaldehyde,p-fluorobenzaldehyde,4-(N,N’-dimethyl)benzaldehy -de,3,5-di-tert-butylsalicylaldehyde, furtural,2-amino-N-propylbenzamide,2-amino-N-benzylbenzamide, etc. All of these substates afforded the corresponding4(3H)-quinazolinones with pretty good yields.Considering the toxicity of VO(acac)2, in the further study on synthesis of4(3H)-quinazolinone derivatives. We found another reaction system with recyclable copper(II) oxide powder (CuO) as catalyst for synthesis of4(3H)-quinazolinones. First of all, optimize the reaction system, and the optimal reaction condition is Anthranilamide:benzaldehyde:catalyst=1:1:0.03, DMA as solvent, with air at120℃for24hours in the open system with a high yeild (97%). Subsequently, a series of anthranilamides and aldehydes were investigated under the optimized conditions, all of these obtained good to excellent yields. The reuse of CuO was also been studied, we found that after recycling it is still having a good catalytic efficiency.In conclusion, the reaction systems in the above using transition metals as catalyst have several prominent features include easy operation, mild experimental conditions, low catalyst loading and good to excellent yields. And we has provided some new synthetic methods of quinazolinones with potential application values.