Designing Pd–N-Heterocyclic Carbene Complexes for High Reactivity and Selectivity for Cross-Coupling Applications

Abstract

Over the past decade, the use of Pd-NHC complexes in cross-coupling applications has blossomed, and reactions that were either not previously possible or possible only under very forcing conditions (e.g., > 100 °C, strong base) are now feasible under mild conditions (e.g., room temperature, weak base). Access to tools such as computational chemistry has facilitated a much greater mechanistic understanding of catalytic cycles, which has enabled the design of new NHC ligands and accelerated advances in cross-coupling. With these elements of rational design, highly reactive Pd-NHC complexes have been invented to catalyze the selective formation of single products in a variety of transformations that have the potential to afford multiple compounds (e.g., isomers). Pd-NHC catalysts may be prepared as stable Pd(II) precatalysts that are readily reduced to the active Pd(0) species in the presence of an organometallic cross-coupling partner or nucleophile possessing β-hydrogens. It has been found from computational and experimental results that Pd-NHC complexes bearing a single bulky NHC ligand are well-suited to tackle challenging cross-coupling reactions. N-Aryl-substituted imidazole-2-ylidenes with branched alkyl chains at the ortho positions of the aryl group are effective for the challenging couplings of hindered biaryls, secondary alkyl organozincs, electron-deficient anilines, α-amino esters, primary alkylamines, and ammonia. The bulk of the NHC has been tuned by increasing the size of the alkyl groups at the ortho positions and substituting the NHC core with chlorine substituents. All of the cross-coupling transformations studied benefit from the increased bulk when the ortho groups are changed from methyl to 2-propyl to 3-pentyl. However, there is a limit to the positive effect of steric bulk, as some reactions do not benefit from the increased size of the 4-heptyl group compared with 3-pentyl. Thus, there is an optimum size for the NHC ligand that depends upon whether reactivity (turnover frequency and turnover number), selectivity, or both are needed to obtain the desired reaction outcome. In the cases that we have studied, reactivity and selectivity increase together (i.e., the fastest catalyst is also the most selective), allowing cross-couplings to be carried out under mild conditions to obtain one product with high selectivity. This Account focuses on seminal literature reports that have disclosed new Pd-NHC complexes that have led to significant breakthroughs in efficacy for challenging couplings while demonstrating high selectivity for the desired target. These catalysts have been used widely in materials science, pharmaceutical, and agrochemical applications.

2‐Methyltetrahydrofuran (2‐MeTHF): A Green Solvent for Pd−NHC‐Catalyzed Amide and Ester Suzuki‐Miyaura Cross‐Coupling by N−C/O−C Cleavage

“…The use of [Pd(IPr)(1-t-Bu-ind)Cl] [23] gave slightly better reactivity in this instance. The use of [Pd(IPr)(1-t-Bu-ind)Cl] [23] gave slightly better reactivity in this instance.…”

“…Water helps to activate the Pd-NHC catalyst system. Finally, we established that the reaction could be carried our with other commercially-available Pd(II) À NHC precatalysts (Pd-PEPPSI-IPr, [23] 95%; Pd(IPr)(1-t-Bu-ind)Cl, [24] 92%) ( Figure 2), highlighting the potential of 2-MeTHF as a general solvent for amide bond cross-coupling. The optimized process (eq 1) employs [Pd(IPr)(cin)Cl] (3 mol%) (cin = cinnamyl) [22] in the presence of K 2 CO 3 (3 equiv.)…”

“…Importantly, the cross-coupling could be carried out efficiently using only a slight excess of boronic acid (1.2 equiv.). Finally, we established that the reaction could be carried our with other commercially-available Pd(II) À NHC precatalysts (Pd-PEPPSI-IPr, [23] 95%; Pd(IPr)(1-t-Bu-ind)Cl, [24] 92%) ( Figure 2), highlighting the potential of 2-MeTHF as a general solvent for amide bond cross-coupling. It also should be noted that the amount of waste is an important consideration in evaluating sustainability in addition to the toxicity of solvents and reagents used.…”

A Path to More Sustainable Catalysis: The Critical Role of LiBr in Avoiding Catalyst Death and its Impact on Cross‐Coupling

“…Cross-coupling has become one of the most relied upon transformationsi nt he fine chemical sector. [1] Indeed,t he metal-catalyzed formation of CÀC, 2 CÀN, 3 and CÀS 4 bonds is used widely in discovery and increasingly in manufacturing as efficacious catalysts becomea vailable. [2][3][4] Key to the success of cross-coupling reactions is the role that variousa dditives play, such as bases and salts.…”

Preparation of Poly(Bulky N‐Heterocyclic Carbene) as the Self‐Supporting Catalyst toward Suzuki–Miyaura Reaction

“…Since the (IPr)Pd(acac)Cl was synthesized in 2005 ( Figure a), NHC‐based palladium catalysts have been developed greatly owing to its excellent catalytic activity in the cross‐coupling reaction. Some groups, for example, Nolan, Organ, Buchwald, and İsmail Özdemir, made great progress in structure design and synthesis methods of bulky NHCs. A series of ligands have been synthesized, such as Pd‐PESSI‐Ipent (Figure b), Pd(ITent)(cin)Cl (Figure c), and so on.…”