Scope and Optimization of the Double Knorr Cyclization: Synthesis of Novel Symmetrical and Unsymmetrical Tricyclic 1,8-Diazaanthraquinones

The Knorr cyclization of β-ketoanilides to form 2-quinolones in the presence of acid is well documented chemistry. Double Knorr cyclization is rare, with very few examples appearing in the literature to date. The double Knorr methodology can provide access to tricyclic 1,8-diazaanthraquinones, a scaffold seen in the diazaquinomycin family. The optimized synthesis of diazaquinomycin A and structural analogues thereof via double Knorr cyclization of di-β-ketoanilide precursor substrates is reported. The scope and generality of the double Knorr cyclization were investigated along with an optimization study. The double Knorr cyclization was found to be sensitive to steric bulk on precursor substrates. In addition, the presence of a 5-hydroxy group on the 1,3-di-β-ketoanilide facilitated the double Knorr cyclization, possibly due to its stabilizing effect on the carbocation intermediates formed during the reaction.