Palladium- and Manganese-catalysed Synthesis of N-heterocycles

Abstract

Access to a wide range of functionalized N-heterocyclic compounds is essential for efficient drug discovery programs. A key challenge remains the lack of simple synthetic methods using readily available starting materials. Metal-catalysed dehydrogenative coupling has proven particularly effective in providing catalytic pathways for converting alcohols and amines into valuable products, particularly in the synthesis of imines, which are crucial intermediates in the formation of nitrogen-containing compounds. Additionally, incorporating dehydrogenative coupling into multicatalytic processes offers a convenient strategy for N-heterocyclic synthesis. This work explores the development of dehydrogenative coupling strategies for nitrogen-containing compounds and their implementation in multicatalytic approaches. Key findings include the conversion of primary alcohols with aniline and aminopyridines, achieving up to 99% yield of imines using only 3 mol% of a manganese- tricarbonyl complex with a bidentate triazole ligand system. For the more challenging secondary alcohols, a simple method for imine synthesis is described, utilizing Pd(OAc)₂ as catalyst in an acceptorless dehydrogenative coupling strategy, without any base additives. Sequential reactions with Pd(OAc)₂ led to the formation of indoles, representing a significant advance in the synthesis of N-heterocycles. Furthermore, by modifying the reaction conditions, this catalytic system enabled the selective formation of secondary amines through a borrowing hydrogen strategy. Finally, the thesis explores the dialkylation of diamines and diols using a Mn(I)-tricarbonyl complex with bis(1,2,3-triazol-5-ylidene) ligands, achieving yields of up to 99%. The catalytic activity was further demonstrated in the synthesis of 1,2,3,4-tetrahydroquinoxalines, a class of compounds with significant pharmacological activity. Additionally, an unprecedented route for the synthesis of indoline was developed using a bimetallic manganese/palladium catalytic system combining primary alcohols and amines.