Understanding the Structure‐Activity Relationship of Ni‐Catalyzed Amide C−N Bond Activation using Distortion/Interaction Analysis

Abstract

Transition metal‐catalyzed amide C−N bond activation has emerged as a powerful strategy to utilize amides in synthetic transformations. The key mechanistic basis for the rational design of amide reagents is the structure‐activity relationship of amide C−N bond activation. In this work, the controlling factors of Ni/PCy3‐catalyzed amide C−N bond activation barrier are elucidated with density functional theory (DFT) calculations and distortion/interaction analysis. We found that the substrate distortion is the key factor that differentiates the amide reactivity in the C−N bond activation. The substrate distortion of amide is associated with two distinctive structure‐activity relationships. The general planar amides undergo a classic three‐membered ring oxidative addition to cleave the C−N bond, in which the C−N heterolytic bond dissociation energy has a linear relationship with the activation barrier. The twisted amides have a chelation‐assisted transition state for the amide C−N bond cleavage, and the twisted angle τ can serve as a predictive parameter for the reactivity of the twisted amides. The understanding of the structure‐activity relationship of amide C−N bond activation provides a rational and predictive basis for future reaction designs involving transition metal‐catalyzed amide C−N bond activation.

Ni-Catalyzed Reductive Coupling of Alkynes and Amides to Access Multi-Functionalized Indoles

“…The reaction between 1a and 2a was attempted in the presence of 10 mol% Ni­(COD) 2 and various ligands in 2,2,2-trifluoroethanol (TFE) at 80 °C to afford the corresponding 2-CF 3 - and 3-phenylalkenyl-substituted indole 3aa . As expected, N -heterocyclic carbene (NHC) ligands ( L1 and L2 ) were found to be relatively less efficient in this transformation, as these ligands are prone to undergoing oxidative addition to amides . Mono- or bidentate phosphine ligands ( L3 – L7 ) and bidentate N ∧ N ligands ( L8 – L10 ) were also not suitable choices.…”

“…However, despite their natural abundance and remarkable stability, amide functional groups have never been employed as electrophilic π-donors in the reductive coupling with alkynes. The intrinsic ability of amide groups to undergo oxidative addition by Ni(0) complexes, leading to C–N bond cleavage, might have hindered the exploration of their potential as electrophilic π-components in reductive coupling processes (Scheme b) …”

Classes of Amides that Undergo Selective N–C Amide Bond Activation: The Emergence of Ground-State Destabilization

“…Among amide activation strategies in organic synthesis, direct transition-metal insertion and transition metal-free addition are widely applied in amide bond activation. − Spectroscopic, crystallographic, and computation techniques have been used to garner structural and energetic parameters of ground-state destabilization of the amide bond in comparison with their planar analogues. − …”

“…The Perspective is focused on classes of amides that undergo distortion and their structural effects that enable amide bond activation. For mechanistic studies in amide bond activation, the reader is encouraged to consult already published reviews. − …”

Distinguishing Competing Mechanistic Manifolds for C(acyl)–N Functionalization by a Ni/N-Heterocyclic Carbene Catalyst System

“…While the geometric parameters for 8b , c were near-identical, complex 8d demonstrated a six-membered chelate with the two carbamate directing groups. Although such chelates have been described for phosphine-based catalyst systems, computational studies of NHC-based catalyst systems have instead invoked three-centered oxidative addition with disagreement over the role of directing-group assistance or chelation post-oxidative addition. , Other chelating groups are expected to perform similarly; see the Supporting Information for the oxidative addition product derived from a 2-pyridyl substituted benzamide.…”