Mechanistic Insight into Cu-Catalyzed C–N Coupling of Hindered Aryl Iodides and Anilines Using a Pyrrol-ol Ligand Enables Development of Mild and Homogeneous Reaction Conditions

Abstract

Mechanistic studies of the Cu-catalyzed C−N coupling of sterically hindered aryl iodides with sterically hindered anilines are carried out to shed light on how a recently reported pyrrol-ol ligand affects the reaction. Kinetic, spectroscopic, and computational tools help to probe the nature of the active catalyst species and the rate-determining step in the cycle. In contrast to most known Cu systems, oxidative addition is found to precede coordination of the amine. These studies help to design an efficient process under mild conditions using a fully homogeneous system as well as protocols that enable high yields by temperature scanning and controlled addition of the base. The insights obtained for the XX-type ligand may lead to a general approach for challenging substrate classes in Cu-catalyzed coupling reactions.

Bayesian Optimization as a Sustainable Strategy for Early-Stage Process Development? A Case Study of Cu-Catalyzed C–N Coupling of Sterically Hindered Pyrazines

“…12 ligands ( L1–12 ). These are well representative of the diverse classes which were reported to be effective in Cu-catalyzed C–N couplings. ,,,,,− Furthermore, these are all commercially available and relatively inexpensive.…”

“…The catalyst loading was fixed at 5 mol %. 12 ligands ( L1–12 ). These are well representative of the diverse classes which were reported to be effective in Cu-catalyzed C–N couplings. ,,,,,− Furthermore, these are all commercially available and relatively inexpensive. Two ligand loadings (5 or 10 mol %). Eight bases. Three base stoichiometries (1, 1.5, or 2.0 equiv). Six non-hazardous solvents. Two molarities (0.5 or 1 M). Two temperatures (60 or 80 °C). Two stoichiometries for 2a (1.1 or 1.5 equiv). …”

“…seems to require a specific copper source and a dedicated ligand . Furthermore, literature precedents mainly focus on relatively simple substrates, whereas examples of more challenging coupling partners typically found in discovery programs (e.g., sterically hindered, , containing multiple nitrogens which can chelate the metal center and inhibit its catalytic activity), are rarer. Finally, although a growing number of experimental protocols are being reported for aryl bromides, these are not very general, and aryl chlorides are even less reactive.…”

Cu Oxamate-Promoted Cross-Coupling of α-Branched Amines and Complex Aryl Halides: Investigating Ligand Function through Data Science

“…In this regard, we were inspired by the oxamate-based ligand class originally developed by Ma and co-workers that has enabled the use of Ullmann-type reactions for druglike aryl halides. , For example, ligands L1 – 4 promote the coupling of an unbranched secondary amine, piperidine, with a set of informer aryl halides that represent druglike compounds in relatively high yield (Figure B) . In terms of Cu-catalyzed cross-coupling of α-branched amines and aryl halides, Shekar and Cook reported a study on the cross-coupling of hindered aryl iodides with α-branched amines using a pyrrole-ol ligand, , and the Buchwald lab recently reported a novel diamine ligand system to promote such couplings at reduced temperature . These elegant studies represent the state-of-the-art in Cu-catalyzed cross-coupling of α-branched amines and aryl halides.…”

Cross-coupling by a noncanonical mechanism involving the addition of aryl halide to Cu(II)

“…However, a variety of ligands proposed to bind as dianions also have been reported recently to generate catalysts for cross-coupling reactions that are challenging to achieve (Fig. 1C) (14)(15)(16). In particular, catalysts containing diamides derived from oxalic acid (oxalamide ligands), reported by Dawei Ma (17)(18)(19)(20)(21)(22)(23), are more active than any previous copper catalysts and enable reactions of unactivated, electron-rich aryl bromides and of aryl chlorides ( 6), but no mechanistic explanation of the high activity of the catalyst has been reported.…”