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.

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Herein we report the first example of (hetero)arylation of ammonia using a monoligated palladium-NHC complex. The new, rationally designed, precatalyst (DiMeIHept Cl )Pd(allyl)Cl featuring highly branched alkyl chains has been shown to be effective in selective aminations across a range of challenging substrates, including nitrogencontaining heterocycles and those featuring base-sensitive functionality. The less bulky Pd-PEPPSI-IPent Cl precatalyst performs well for ortho-substituted aryl halides, giving monoarylated products in high yield with good selectivity.

The relative rates of arylation of primary alkylamines with different Pd-NHCcatalysts have been measured, as have the relative rates of arylation of the secondary aniline product in an attemptt ou nderstand the key ligand design features necessary to have high selectivity for the monoarylated amine product. As the substituents on the N-aryl ring of the NHC increaseinsize, selectivity for monoarylation increases and this is furthere nhanced by chlorinating the back of the NHC ring. Computations have been performed on the catalytic cycleo ft his transformation in order to understand the selectivity obtained with the different catalysts.Supporting information and the ORCID identification number(s) for the author(s) of this articlecan be found under: https://doi.

Coupling of Ph3SiNH2 with aryl halides by using Pd‐PEPPSI‐IPentCl {dichloro(3‐chloropyridyl)[4,5‐dichloro‐1,3‐bis(2,6‐dipent‐3‐ylphenyl)imidazol‐2‐ylidene]palladium(II)} yields triphenylsilyl‐protected anilines. These triphenylsilyl protected anilines can be isolated, alkylated without over‐alkylation, and the protecting group can be removed under mild acidic conditions or in the presence of fluoride to afford the secondary aniline product.