Yamamoto Yuki, Yamakawa Chihiro, Nishimura Riku, Dong Chun-Ping, Kodama Shintaro, Nomoto Akihiro, Ueshima Michio, Ogawa Akiya
Department of Applied Chemistry, Graduate School of Engineering, Osaka Prefecture University, Osaka, Japan.
Front Chem. 2022 Feb 23;9:822841. doi: 10.3389/fchem.2021.822841. eCollection 2021.
Conventional quinazoline synthesis methods involve a highly multistep reaction, and often require excess amounts of substrate to control the product selectivity, leading to significant resource wastage. Hence, in this study, from the viewpoint of green chemistry, we developed a novel metal-free synthetic method for 2-substituted quinazoline derivatives by the 4,6-dihydroxysalicylic acid-catalyzed oxidative condensation of -aminobenzylamines and benzylamines using atmospheric oxygen. In this system, the use of a catalytic amount of BF‧EtO (10 mol%) as a Lewis acid successfully led to the efficient oxidative condensation and intramolecular cyclization of these amines, followed by aromatization to afford the corresponding 2-arylquinazolines in up to 81% yield with excellent atom economy and environmental factor. Furthermore, to expand this green oxidation method to gram-scale synthesis, we investigated the development of an oxidation process using salicylic acid itself as an organocatalyst, and established a method for the practical green synthesis of a series of nitrogen-containing heterocycles. We expect that the findings will contribute to the development of practical synthesis methods for pharmaceutical manufacturing and industrial applications, along with further advancements in green chemistry.
传统的喹唑啉合成方法涉及高度多步反应，并且通常需要过量的底物来控制产物选择性，导致大量资源浪费。因此，在本研究中，从绿色化学的角度出发，我们开发了一种新颖的无金属合成方法，用于通过4,6-二羟基水杨酸催化的邻氨基苄胺和苄胺与大气中的氧气进行氧化缩合反应来合成2-取代喹唑啉衍生物。在该体系中，使用催化量的BF‧EtO（10 mol%）作为路易斯酸成功地实现了这些胺的高效氧化缩合和分子内环化，随后进行芳构化反应，以高达81%的产率得到相应的2-芳基喹唑啉，具有出色的原子经济性和环境因子。此外，为了将这种绿色氧化方法扩展到克级规模合成，我们研究了使用水杨酸本身作为有机催化剂的氧化过程的开发，并建立了一系列含氮杂环化合物的实用绿色合成方法。我们期望这些发现将有助于药物制造和工业应用的实用合成方法的发展，以及绿色化学的进一步进步。
