A convenient proline catalysed Paal–Knorr synthesis of highly substituted pyrrole: construction of a pyrrolo[2,1-a]isoquinoline scaffold

Abstract

Pyrroles are a fundamental class of heterocyclic compounds that play a crucial role in many biologically active natural products and synthetic pharmaceuticals. Their unique electronic properties and structural versatility make them indispensable for the development of molecules with significant therapeutic potential. In this work, we introduce a novel approach to the formation of the pyrrole core, catalysed by L-proline, employing Paal–Knorr synthesis as the key transformation. This innovative method facilitates the efficient construction of the core structure while allowing for the introduction of diverse substituents, leading to the synthesis of over 20 highly functionalized pyrrole derivatives. Building upon this pyrrole core synthesis, we have extended our strategy to the construction of the pyrrolo[2,1-a]isoquinoline scaffold, an essential structural motif present in several alkaloids and pharmacologically active compounds. This scaffold is notable for its biological relevance, particularly in anti-cancer and anti-inflammatory applications. Our method showcases the versatility of the Paal–Knorr synthesis, enabling precise construction of the pyrrolo[2,1-a]isoquinoline core, starting from substituted chalcones. The synthetic route offers a reliable pathway for constructing complex heterocyclic structures, advancing our understanding of pyrrole and isoquinoline chemistry and providing valuable insights for the development of new therapeutic agents.