Abstract
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 o-aminobenzylamines and benzylamines using atmospheric oxygen. In this system, the use of a catalytic amount of BF3‧Et2O (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.
Highlights
In recent years, with advancements in pharmaceuticals and functional materials, the demand for a higher purity of the basic molecules constituting these materials has increased (Kündig, 2006; Ojima, 2017; Blakemore et al, 2018; Campos et al, 2019; Garcia-Martinez, 2021)
Considering that the oxidation system used 4,6dihydroxysalicylic acid, we first investigated the reaction of benzylamine 1a (3.0 mmol) with o-aminobenzylamine 2a in the presence of the organocatalyst (10 mol%)
In the absence of the organocatalyst or under a N2 atmosphere, the yield of 3aa significantly decreased. These results strongly suggest that the organocatalytic oxidation of benzylamines using 4,6-dihydroxysalicylic acid as the catalyst is one of the key steps in this oxidative cyclization reaction
Summary
With advancements in pharmaceuticals and functional materials, the demand for a higher purity of the basic molecules constituting these materials has increased (Kündig, 2006; Ojima, 2017; Blakemore et al, 2018; Campos et al, 2019; Garcia-Martinez, 2021). To mitigate the environmental impact of manufacturing processes, it is essential to develop resource-recyclable and highly atom-economical synthetic methods (Horvάth and Anastas, 2007; Sheldon, 2012; Hayashi, 2016; Horvάth, 2018) In this context, we recently succeeded in constructing an environmentally friendly metal-free oxidation catalyst system using oxygen (or air) at ambient pressure as an oxidant. Unstable imines can be prepared and used directly for the one-pot synthesis of various functional molecules, providing a series of innovative catalytic oxidation processes This metal-free imine synthesis method enables the one-pot synthesis of important heterocyclic compounds, and the highly selective onepot reactions (e.g., the Ugi reaction) of multicomponent linkages (Dong, et al, 2017; Kumazawa, et al, 2018; Dong et al, 2019; Yamamoto et al, 2021). To further elucidate the versatility of this metal-free imine synthesis method, we attempted one-pot synthesis for reactions that are typically multistep, and succeeded in the metal-free synthesis of quinazoline derivatives (Wang and Gao, 2013; Faisal and Saeed, 2021), which are one of the heterocycles forming the basis of pharmaceuticals, agrochemicals, and functional materials (eq 2)
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