Tartramide Ligands for Copper‐Catalyzed N‐Arylation at Room Temperature

Abstract

Readily accessible tartramide ligands have been demonstrated to promote copper‐catalysed N‐arylation under mild conditions. In addition, the coupling protocol employs cheap and readily available pre‐catalyst, ligand, and base (NaOH), and overcomes many current limitations often associated with Ullmann coupling: it can be run with low catalyst loadings, does not require the use of excess amine, operates at room temperature, is fully homogeneous, and displays improved tolerance to air and moisture. Detailed kinetic studies using reaction progress kinetic analysis (RPKA) methods have provided insight into the factors influencing the reaction rate in terms of impact of ligand structure, reactant/catalyst dependence and catalyst (in)stability. These kinetic insights have been used in a quality‐by‐design approach for further optimization of the reaction protocol. The reaction scope was extended to 22 examples, showing broad applicability for a wide range of substituted aryl iodides with both primary and secondary amines.

On the mechanism of benzimidazole synthesis via copper-catalysed intramolecular N-arylation

“…It is noteworthy that this behaviour therefore differs to that observed for intermolecular Ullmann aminations where generally first order reactions in [Cu] have been reported and where amide coordination/deprotonation and aryl halide activation occurs at the same copper centre. 22,24,25…”

“…It is noteworthy that this behaviour therefore differs to that observed for intermolecular Ullmann aminations where generally first order reactions in [Cu] have been reported and where amide coordination/deprotonation and aryl halide activation occurs at the same copper centre. 22,24,25 A "same excess" experiment was carried out to investigate potential catalyst deactivation and/or inhibition. This experiment involved reducing [TBPM] 0 and [1b] 0 in 0.0250 M increments, whilst keeping the excess [e] constant at 0.0500 (Fig.…”

“…Over recent years, studies on the mechanism of the intermolecular N-arylation (Ullmann amination) reaction by our group and others has led to a much improved understanding of these systems. [20][21][22][23][24][25][26] However, to date, mechanistic studies on related intramolecular Ullmann reactions are rare, and advances in the understanding and methodology for intermolecular coupling has yet to be fully transitioned to these intramolecular systems.…”

Facile Synthesis Hyper-Crosslinked PdFe Bimetallic Polymer as Highly Active Catalyst for Ullmann Coupling Reaction of Chlorobenzene

“…Organic synthesis heavily relies on carbon–carbon coupling reactions as a versatile tool to produce complex structures from easily accessible building blocks in diverse ways [ 1 , 2 , 3 ]. While significant progress has been made in transition metal-catalyzed cross-coupling reactions between aryl halides and organometallic reagents, such as Suzuki, Stille, Negishi, and Hiyama coupling reactions, in the past few decades [ 4 , 5 , 6 , 7 ], Ullmann biaryl synthesis remains a straightforward method because of its effectiveness and minimization of undesirable by-products, facilitating the synthesis of various biaryl groups from aryl halides, without the requirement of preformed organometallic species [ 8 , 9 , 10 , 11 , 12 ]. However, the traditional Ullmann coupling reaction has been carried out under harsh reaction conditions, such as high temperature, extended reaction times, use of toxic solvents, and strong bases [ 13 , 14 ].…”

Oxalamide/Amide Ligands: Enhanced and Copper-Catalyzed C–N Cross-Coupling for Triarylamine Synthesis

“…This concept has received extensive attention from both academia and the pharmaceutical industry. Quite a few novel oxalic diamides and amides have been identified for copper-catalyzed C–S, C–O, and C–N cross-couplings via the combination of high-throughput experimentation and rational ligand evolution . Notably, the Hartwig group reported a class of ligands based on oxalohydrazide cores that generated long-lived copper catalysts for C–O cross-coupling .…”