Metal-Free Synthesis of 2-Substituted Quinazolines via Green Oxidation of o-Aminobenzylamines: Practical Construction of N-Containing Heterocycles Based on a Salicylic Acid-Catalyzed Oxidation System

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.

Advances in organocatalyzed synthesis of organic compounds

“…Using the activated alumina as the ller and iso-hexane for elution, column chromatography was used for purication following the reaction to produce product 27. 180 2.9.3. Synthesis of N-heteroaryl stilbenoids.…”

Metal-Free Synthesis of N-Heterocycles via Intramolecular Electrochemical C-H Aminations

“…However, the difficulty to remove the metal residues resulted from the metal catalysts largely limits the industrial use of these metal-catalyzed methodologies. To circumvent this limitation, many metal-free methodologies have been developed for the synthesis of N -heterocycles recently ( Preeti and Singh, 2021 ; Yang et al, 2021 ; Han et al, 2022 ; Yamamoto et al, 2022 ). Among them, the intramolecular C-H aminations are of high interest mainly because the prefunctionalized substrates are avoided ( Tan et al, 2020 ).…”

Aerobic oxidative synthesis of benzimidazoles by flavin photocatalysis

“…In particular, its aerobic version using molecular oxygen as an oxidant is an attractive method because of the significant economic and environmental advantages, such as sustainable abundance, safety, cost-effectiveness, atom economy, and minimal pollution. In addition to metal-catalysed systems, 2 metal-free organocatalytic methods have attracted attention, which can employ carbon nitride photocatalysts, 3 graphene oxide, 4 salicylic acid derivatives, 5 or polydopamine, 6 although they require high-pressure oxygen and/or heating conditions. Quinone-based organocatalysts have succeeded in the aerobic oxidative synthesis of benzimidazoles under relatively mild conditions (45–60 °C); 7 however, the development of novel approaches is needed.…”