Research and development of four component quinazoline synthesis reaction without metal by Professor Deng Guojun of Xiangtan University

Quinazoline compounds, especially polysubstituted quinazoline, have a wide range of biological activities, such as anti-cancer, anti HIV, anti-inflammatory, antibacterial, anti tuberculosis and so on Since quinazoline derivatives have a variety of pharmaceutical applications and biological values, a variety of efficient methods for the preparation of quinazoline derivatives have been reported However, for most of the polysubstituted quinazoline derivatives, they need to use highly functionalized aniline derivatives or other activated intermediates, which leads to their long synthesis route, limited substrate range and increased synthesis difficulty Therefore, it is necessary to prepare nitrogen-containing heterocycles by functionalization of amino ortho-c-h bond from cheap and easily obtained aniline Recently, the group of Deng Guojun, Professor of Xiangtan University, has synthesized multi substituted quinazoline derivatives through four component reactions of aniline, aromatic aldehyde and ammonium iodide under simple reaction conditions In this strategy, two equivalent aromatic aldehydes participate in the cyclization process, and ammonium iodide is also one of the nitrogen sources The above four components can selectively construct the target quinazoline product in a "one pot" process without any expensive reagents or metal catalysts Relevant articles were published on greenchem (DOI: 10.1039/c8gc02654h) (source: Green chem.) in order to determine the optimal reaction conditions, the author initially studied aniline 1a and benzaldehyde 2A as model substrates (Table 1) First of all, the author screened several ammonium salts in toluene to find a suitable nitrogen source Among them, the efficiency of ammonium iodide was the highest, and the target product 3AA was obtained in 50% yield, while ammonium bromide was used as the nitrogen source to obtain only a small amount of product The solvent plays an important role in the reaction, and the yield can be increased to 67% by using chlorobenzene as solvent It is gratifying that the yield of the reaction can be as high as 97% when the same amount of DMSO is added to the reaction When the reaction is carried out in air, the yield of the product is low (source: Green chem.) after obtaining the optimal conditions, the author used a variety of aromatic amines to investigate the substrate range and universality of the four component reaction (Table 2) The product 3ba - 3Na can be obtained from aniline with donor group or halogen in good yield The corresponding quinoxaline 3oa - 3qa can be obtained successfully even if there are two methyl anilines Similarly, 3ra and 3sa were obtained from 1-naphthylamine and 2-naphthylamine substrates in 70% and 78% yields, respectively 5-quinoline amine and other heteroaromatic amines can also be successfully coupled with benzaldehyde and ammonium iodide to obtain the corresponding product 3ta with a yield of 40% It is worth noting that the substrate containing free amino group can also be compatible with the reaction system, and the corresponding products 3ua and 3VA can be obtained in 61% and 43% yields respectively (source: Green chem.) then, the author continued to investigate the substrate range of various aromatic aldehydes (Table 3) Benzaldehyde with electron donating groups (such as methyl, tert butyl, etc.) and electron absorbing groups (such as chlorine and bromine) can react smoothly to obtain corresponding substituted quinazoline products (3ae-3af and 3ai-3ak), with a yield of 40% to 92% When the substituent is located in the neighborhood, there is a spatial effect, which leads to a decrease in the yield of the product (3Al - 3AO) Most benzaldehyde with two substituents can get the regioselective product (3aP - 3av) with good yield (source: Green chem.) surprisingly, when 2 equivalent iron is used as reducing agent, the stable and easily available nitroaromatics can also react directly with scheme 2 The products 3ba, 3EA and 3PA can be obtained by the reaction of nitroaromatics with methyl, tert butyl and 2,4-dimethyl substituents and benzaldehyde In addition, in the present system, 2-aminobenzaldehyde 5 can be obtained in medium yield (source: Green chem.) based on the above results and related research, the author proposed a reasonable reaction mechanism (scheme 3) The condensation of aniline with benzaldehyde produces imine intermediate a, which can be detected during the reaction At the same time, the condensation reaction of benzaldehyde and ammonium iodide yields imine intermediate B After two steps of domino reaction, cyclization of a and B resulted in intermediate D The final product 2,4-diphenylquinozoline was obtained by oxidative dehydrogenation of D (source: Green chem.) Summary: Professor Deng Guojun's research group has developed a four-component synthesis method of substituted quinazoline under simple reaction conditions with readily available aniline, aromatic aldehyde and ammonium iodide as raw materials In the absence of metal, the ortho-c-h bond in aniline can be functionalized directly and used for further cyclization Four component mixtures can selectively construct target products in a "one pot" without any expensive reagents or metal catalysts The reaction has good functional group tolerance and a wide range of substrates.