Pd(ii)-Catalyzed [4 + 1 + 1] cycloaddition of simple o-aminobenzoic acids, CO and amines: direct and versatile synthesis of diverse N-substituted quinazoline-2,4(1H,3H)-diones

Abstract

The mild, efficient, and straightforward synthesis of pharmaceutically and biologically active N3-substituted and N1,N3-disubstituted quinazoline-2,4-(1H,3H)-diones from simple and readily available substrates has been a huge challenge. Described here is a Pd(II)-catalyzed [4 + 1 + 1] modular synthesis of diverse quinazoline-2,4-(1H,3H)-diones through one-pot cascade reactions of cyclocondensation of o-(alkyl)aminobenzoic acids with CO, amidation of the intermediate isatoic anhydrides with amines, and unprecedented carbonylation of the resulting o-aminobenzamides with CO under 1 atm and 60 °C conditions. The chemoselective and versatile multicomponent reaction allows for the diversities of the products including N3-substituted and N1,N3-disubstituted products, and even makes the substituents on N1,N3 the same or different from each other, which cannot be achieved by most traditional synthetic strategies.