Diversity in Heterocycle Synthesis Using α-Iminocarboxylic Acids: Decarboxylation Dichotomy

Despite the structural similarity with imines, alpha-iminocarboxylic acids have seldom been used in heterocycles synthesis. The reactions of ortho-substituted anilines and arylglyoxylic acids in DMSO at 40 degrees C gave various benzo-fused five- to six-membered N-heterocycles in good to excellent yields. The reaction proceeds via intramolecular Michael addition of alpha-iminocarboxylic acids, generated in situ, with an ortho-substituted nucleophile, yielding an isolable unprecedented tetrahedral carboxylic acids, which upon decarboxylation without any aid of additional reagents forms the N-heterocycles. DMSO is crucial in this reaction, perhaps because of improved solubility and the ease of decarboxylation of these tetrahedral carboxylic acids. However, a copper-catalyzed reaction of ortho-substituted anilines and 2-bromoarylglyoxylic acids gave a dibenzo-fused seven-membered N-heterocycle under a basic reaction condition. Unlike intramolecular cyclization with alpha-iminocarboxylic acids in the first case, alpha-iminocarboxylic acid undergoes a competitive decarboxylation under the copper-catalyzed conditions, which upon subsequent heteroarylation form the heterocycles. Taken together, the study described herein represents two different modes of decarboxylation observed with alpha-iminocarboxylic acids, leading to the synthesis of divergent heterocycles and pharmaceuticals, which remained unexplored previously.

Automated summary

This study demonstrates two different modes of decarboxylation observed with alpha-iminocarboxylic acids, leading to the synthesis of divergent heterocycles and pharmaceuticals. DMSO plays a crucial role in the reaction, while under copper-catalyzed conditions, a competitive decarboxylation leads to the formation of different products.