One-pot synthesis of phenyl- and biphenyl-linked bis-pyrrolo[3,4-b]pyridin-5-ones via a pseudo-repetitive Ugi-Zhu-5CR coupled to a double cascade process (aza-Diels-Alder/N-acylation/decarboxylation/dehydration)

Abstract

Fifteen new bis-pyrrolo[3,4-b]pyridin-5-ones were synthesized via a one-pot process composed by a pseudo-repetitive Ugi-Zhu-5CR coupled to a double cascade sequence (aza-Diels-Alder cycloaddition/N-acylation/decarboxylation/dehydration) in 39–77 % yields, and in short reaction times (only one hour per compound) despite the big size, symmetry and high complexity of the products. The reaction conditions were first optimized step-by-step, and then, the bis-heterocyclic products were synthesized in one-pot manner. It was observed that, formation of the corresponding imines and the double cascade process were carried out without external heating inputs, instead that only under constant stirring at room temperature. Reaction conditions turned out to be the friendliest (in terms of energy) with the environment in comparison with all previously published methodologies involving post-Ugi-Zhu reactions. Therefore, this work shows that pseudo-repetitive MCRs are more thermodynamically favorable compared to classic MCRs, and that they also allow rapid access to highly structurally complex molecules, exhibiting a high degree of symmetry that may play an important role in several fields of knowledge like optics, material science, agrochemistry, and medicinal chemistry.