Applicability Aspects of Transition Metal‐Catalyzed Aromatic Amination Protocols in Medicinal Chemistry

Abstract

The application of palladium-and coppercatalyzed reactions for the aromatic amination of pharmacologically relevant scaffolds is investigated. The focus is set on the scope of several protocols for the introduction of amines of broad structural diversity, allowing for the synthesis of numerous derivatives of one biological hit structure for screening in biological assay systems. Thus, attaining optimized yields and TONs had not a major priority, most important were practical aspects, that is no further purification and drying of reagents and solvents had to be envisaged, ideally only a few transition metalbased protocols had to be applied for synthesizing structurally diverse compounds in sufficient amounts (several milligrams) for screening without any finetuning of conditions and catalytic systems.

Applications of Palladium-Catalyzed C–N Cross-Coupling Reactions

“… 320 Amide coupling and subsequent reductive amino cyclization reactions could be carried out in a single flask and gave rise to a series of benzo-fused heterocycles in 43–94% yield with complete regiocontrol. Although 2-halonitroarenes are often problematic substrates for Pd-catalyzed amidation reactions, 41 , 321 the use of Pd(TFA) 2 /( R )- L6 322 successfully transformed 386 and substituted amides into intermediate 387 . The use of weak base in the reaction was crucial due to the presence of the base-sensitive nitro group.…”

Biaryl Phosphane Ligands in Palladium‐Catalyzed Amination

“…Scientists at 4SC investigated aromatic amination reactions on a range of substrates (Scheme 45). [204] JohnPhos was the most versatile ligand, but dppf, binap, and XantPhos were most successful for particular substrate classes. The JohnPhos system could be used in synthesizing a library of compounds in a parrallel synthesizer.…”

“…[204] JohnPhos as ligand was the most versatile, but dppf, BINAP and Xantphos were most successful for particular substrate classes. The JohnPhos system was practical in synthesizing a library of compounds in a parrallel synthesizer.…”

Biarylphosphanliganden in der palladiumkatalysierten Aminierung

“…Wissenschaftler von 4SC erforschten die aromatischen Aminierungen einer Reihe von Substraten (Schema 45). [204] JohnPhos war der vielseitigste Ligand, während dppf, Binap und Xantphos bei bestimmten Substratklassen erfolgreicher waren. Das JohnPhos-System war zweckmäßig zur automatisierten Parallelsynthese einer Verbindungsbibliothek.…”