Syntheses of 2,4-Substituted Quinazolines via One-Pot Three-Component Reactions Based on Manganese Dioxide/tert-Butyl Hydrogen Peroxide Co-Oxidation Using Alcohols

Abstract

Quinazolines and their derivatives occur in various natural products and pharmaceuticals, and thus, various methods of synthesizing quinazolines have been explored. They have traditionally been synthesized via two-component reactions, but these strategies often suffer from the unavailability of the starting materials and limited substrate scopes. To overcome these problems, three-component reactions using additional N sources were developed. Aldehydes were initially used in these reactions, but alcohols are greener and less toxic than aldehydes. However, the previously reported methods involving the use of alcohols require the utilization of transition metal catalysts, ultrahigh temperatures, and extended durations. Thus, an efficient, practical method of synthesizing quinazolines using alcohol is desirable. A facile one-pot three-component method of synthesizing quinazolines utilizing alcohols, 2-aminobenzoketones, and ammonium acetate is reported for the first time, using active MnO₂ and tert-butyl hydrogen peroxide (TBHP) as synergistic oxidants. MnO₂ and TBHP play dual roles: First, they oxidize the alcohol to the aldehyde and then facilitate the transformation of the intermediate into the product. During alcohol oxidation, the synergistic effect of MnO₂ and TBHP is particularly evident. The aldehydes generated in situ via alcohol oxidation undergo immediate subsequent reactions, thereby minimizing their volatilization and side reactions, such as oxidation and polymerization.