Evaluation of Cyclic Amides as Activating Groups in N–C Bond Cross-Coupling: Discovery of N-Acyl-δ-valerolactams as Effective Twisted Amide Precursors for Cross-Coupling Reactions

Abstract

The development of efficient methods for facilitating N−C(O) bond activation in amides is an important objective in organic synthesis that permits the manipulation of the traditionally unreactive amide bonds. Herein, we report a comparative evaluation of a series of cyclic amides as activating groups in amide N−C(O) bond cross-coupling. Evaluation of Nacyl-imides, N-acyl-lactams, and N-acyl-oxazolidinones bearing fiveand six-membered rings using Pd(II)−NHC and Pd− phosphine systems reveals the relative reactivity order of N-activating groups in Suzuki−Miyaura cross-coupling. The reactivity of activated phenolic esters and thioesters is evaluated for comparison in O−C(O) and S−C(O) cross-coupling under the same reaction conditions. Most notably, the study reveals N-acyl-δ-valerolactams as a highly effective class of mono-N-acyl-activated amide precursors in cross-coupling. The X-ray structure of the model N-acyl-δ-valerolactam is characterized by an additive Winkler−Dunitz distortion parameter Σ(τ+χ N ) of 54.0°, placing this amide in a medium distortion range of twisted amides. Computational studies provide insight into the structural and energetic parameters of the amide bond, including amidic resonance, N/O-protonation aptitude, and the rotational barrier around the N−C(O) axis. This class of N-acyl-lactams will be a valuable addition to the growing portfolio of amide electrophiles for cross-coupling reactions by acyl−metal intermediates. Article pubs.acs.org/joc

Recent Development in the Catalytic Applications of Pd‐NHC (NHC=N‐Heterocyclic Carbene) Compounds in Amide C−N Activation Reactions

“…Szostak's research also designed N,N ‐di‐Boc‐amides [14d] and N‐benzoyl‐δ‐valerolactam [14j] as another class of activated amides for cross‐coupling reactions (Scheme 6 and 7). N,N ‐di‐Boc‐amides, a protected equivalent to unactivated primary benzamides, could be catalyzed by [Pd(NHC)(cin)Cl] and a general, mild, highly selective method for Suzuki‐Miyaura cross‐coupling of primary benzamides was developed.…”

Photoinduced carbamoylation reactions: unlocking new reactivities towards amide synthesis

“…6 Moreover, the use of bulky twisted amides added enormous value to the field of C–N bond activation through transition metal catalysis, enabling novel synthetic opportunities. 7 Amides have also an important use as directing groups on transition metal-catalyzed aromatic C–H activation strategies. 8 More recently, this ability was extended to aliphatic C–H bonds with the development of proton-coupled electron transfer (PCET) protocols enabled by photoredox catalysis.…”

Environmentally Benign Transamidation Protocol for Weakly Nucleophilic Aromatic Amines with N‐Acyl‐2‐piperidinones: Catalyst‐, Additive‐, Base‐ and Solvent‐Free Condition

“…However, in the last two decades, various strategies have been adopted to effect transamidation with aromatic amines under relatively milder conditions. For example, N‐ activation by acylation/tosylation, [12,5] N‐ activation‐metal catalyzation, [5,9,13,14] amide bond twist, [4,15] and amide bond twist‐metal catalyzation [15,16] . Most of these developed methods deploy either catalyst that is metals such as Ni, [10,17–19] Pd, [9,20,21] Ce, [22,23] Fe, [24] Cu, [25] W [6] and lanthanides [26] or activating agents to realize transamidation.…”

“…In the present study, the inherited amide bond twist of N‐ acyl‐2‐piperidinones was utilized to achieve transamidation. Recently, Szostak et al determined amide twist (τ) and Winkler−Dunitz distortion parameter (∑(τ+χ N )) for N‐ benzoyl‐2‐piperidinones as 30.3° and 54.0° respectively, placing this amide in a medium distortion range of twisted amides [16] …”