Role of N-Acyl Amino Acid Ligands in Pd(II)-Catalyzed Remote C–H Activation of Tethered Arenes

Abstract

A combined experimental/computational study on the amino acid ligand-assisted Pd-catalyzed C-H bond activation reveals a mechanism in which the amino acid acts as both a dianionic bidentate ligand and a proton acceptor. This new model explains the effects of amino acids on reactivity and selectivity and unveils the dual roles of amino acids: stabilizing monomeric Pd complexes and serving as the internal base for proton abstraction.

Computational Studies of Heteroatom‐Assisted CH Activation at Ru, Rh, Ir, and Pd as a Basis for Heterocycle Synthesis and Derivatization

“…This pathway proves slightly more accessible than either ortho-C-H activation (ΔG ‡ = 32.4 kcal mol −1 ) or para-C-H activation (ΔG ‡ = 31.9 kcal mol −1 ). Note that the potential noninnocence of the N-acetyl group in C-H activation has been subsequently highlighted (see Figure 1.7) [22]. Reprotonation then facilitates N-decoordination of the MPAA ligand, and this is thought to facilitate the functionalization steps (modeled with ethylacrylate).…”

“…Supporting ligands can also play the role of the heteroatom base in C-H activation, as seen for an N-acyl monoprotected amino acid (MPAA) ligand studied by Houk, Yu, Wu, and coworkers (M06(SMD)//B3LYP calculations; see Figure 1.7a) [22]. This study also highlighted the flexibility of the directing group paradigm, with a remote cyano moiety providing access to an unusual meta selectivity in the reaction of substrate 16 with ethyl acrylate to give 17.…”

“…22 C-H activation transition state for cyclometalation of 2-phenylpyridine at {cis-Ru(Cl) 2 (IMe)} in the presence of bicarbonate base[60].…”

Factors Impacting the Mechanism of the Mono-N-Protected Amino Acid Ligand-Assisted and Directing-Group-Mediated C–H Activation Catalyzed by Pd(II) Complex

“…3c Furthermore, these findings were supported by (1) the detailed kinetic analysis of the Pd(OAc) 2 -catalyzed C−H bond olefination in the presence of MPAA ligands (such as AcIle-O−, Ac-Val-O−, Boc-Val-O−, and Boc-Ile-O−) showing that the determined overall kinetic rate law holds if the formation of two kinetically indistinguishable species, I1 and I2, is assumed; 10 (2) mass-spectrometry and isotope pattern and fragmentation analysis via collision-induced dissociation detecting the bidentate [MPAA′]−Pd(II) complex in a mixture of Pd(OAc) 2 and N-acetyl-glycine (or N-Boc-glycine); 9 (3) DFT studies by Wu, Houk, Yu, and co-workers utilizing Pd(OAc) 2 and N-acetyl-glycine (i.e., MPAA) that show that deprotonation of the N−H bond of the MPAA ligand (i.e., MPAA → MPAA′ transformation) is highly favored and leads to the formation of a stable [MPAA′]−Pd(II)−[DG-SUB] complex; 9 and (4) other experimental and computational studies that find that N−H activation likely occurs prior to C−H activation, notably C−H functionalization utilizing an acidic amide DG. 11 Comparison of the computational findings of Wu, Houk, Yu, and co-workers 9 with that of Musaev and co-workers 7 demonstrates, once again, the importance of the nature of the MPAA ligand and substrate on the mechanism of C−H activation in the [MPAA′]−Pd(II)−[DG-SUB] complex.…”

“…Indeed, by utilizing Pd(OAc) 2 (as the catalyst), N-acetylglycine (as the MPAA ligand) and MCN (as the substrate) Houk and co-workers have found the inner-sphere C−H activation pathway (pathway B in Scheme 2) to be kinetically more favored than the outer-sphere C−H activation pathway (pathway A in Scheme 2) by 12.3 kcal/mol. 9 On the other hand, studies by Musaev and co-workers of the Pd(OAc) 2 (as a catalyst), N-Boc-valine (as a MPAA ligand) and PYR (as a substrate) have shown that the formation of the experimentally reported R product via the inner-sphere C−H activation pathway requires only 4.8 kcal/mol less energy barrier than the outer-sphere C−H activation pathway. 7a One should mention that operation of the outer-sphere pathway A is expected to heavily rely on the reaction conditions such as base concentration, solvent, counterion, etc., whereas the innersphere pathway B depends more on the electronic and steric properties of the MPAA ligand (i.e., protecting group) and substrate (including Pd-DG interaction).…”