Mechanistic Study of Suzuki–Miyaura Cross‐Coupling Reactions of Amides Mediated by [Pd(NHC)(allyl)Cl] Precatalysts

Abstract

We report a combined experimental and computational investigation of the Suzuki–Miyaura cross‐coupling of amides enabled by [Pd(NHC)(allyl)Cl] precatalysts. Most crucially, mechanistic details pertaining to the Pd0/NHC catalytic cycle were elucidated by computational methods. Mechanistic insights shed light on the role of each ligand about the metal. Sterics play a key role in the initial activation of the catalyst. As a key insight, we have shown that water participates in the activation of the Pd‐NHC catalytic system. Easier activation has led to effect room temperature cross‐coupling of a broad range of amides through selective N−C bond scission under the mildest conditions reported to date. The use of sterically hindered [Pd(IPr*)(cin)Cl] reported herein for the first time in the amide cross‐coupling indicates that increasing flexible steric bulk of the isopropyl wingtip groups of the NHC ligand provides a modular scaffold for promoting amide cross‐coupling in high yields. The precatalytic pathway involving both NHC ligands as well as the catalytic cycle beginning from the Pd0 species are discussed. The mechanistic details provide insight into the amide bond twist (distortion) that leads to N−C cross‐coupling reactions and is required for the efficient N−C bond activation.

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

“…[17] Unlike THF, 2-MeTHF is produced from bioresources, furfural or levulinic acid, which is indispensable in decreasing waste generation in chemical and pharmaceutical sectors. [21] We focused our efforts on the Suzuki-Miyaura cross-coupling of N-Boc activated secondary amides [8] (Ar = Ph, R = Ph, RE = 9.7 kcal/mol; RE = resonance energy; Winkler-Dunitz parameters: τ = 18.8°; χ N = 18.9°) using various Pd-NHC precatalysts. 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. It is now established that the rate-determining step in amide cross-coupling involves transmetallation, [21] while electronic-substitution of the amide affects amidic resonance. [18c] We note that under the standard conditions (eq 1, 1 a, [Pd(IPr)(cin)Cl], 3 mol%, 2-MeTHF, RT), 98% yield is obtained using 1.2 equiv.…”

“…Water helps to activate the Pd-NHC catalyst system. [21] We focused our efforts on the Suzuki-Miyaura cross-coupling of N-Boc activated secondary amides [8] (Ar = Ph, R = Ph, RE = 9.7 kcal/mol; RE = resonance energy; Winkler-Dunitz parameters: τ = 18.8°; χ N = 18.9°) using various Pd-NHC precatalysts. 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.)…”

Recent Advances in the Metal‐Catalyzed Activation of Amide Bonds

“…In 2017, Szostaka nd co-workers elucidated detailedm echanistic aspects of the Suzuki-Miyaura cross-coupling reaction mediated by [Pd(NHC)(allyl)Cl] by using experimental and computational methods. [59] They found that the cross-couplingr eactions of amides were not restricted to boron precursors, and reported the first example of using organozinc reagents as a cross-coupling partner. Furthermore, Shi and Szostak also reported an ickel-catalyzed Negishic ross-coupling reactiono fNacylglutarimides with arylorganozinc reagents (Scheme 23).…”

Palladium‐catalysed room‐temperature Suzuki–Miyaura coupling in water extract of pomegranate ash, a bio‐derived sustainable and renewable medium

“…Palladium catalysts with appropriate ligands and bases in organic or biphasic media assist as common systems for SMC reactions . The frequently employed ligands for this purpose include phosphines, palladacycles, sterically crowded N ‐heterocyclic carbenes, imines and oximes . These ligands are highly active and enhance the rate of oxidative addition (usually the rate‐determining step) in catalytic cycles .…”