Evaluation of Cyclic Amides as Activating Groups in N–C Bond Cross-Coupling: Discovery of <i>N</i>-Acyl-δ-valerolactams as Effective Twisted Amide Precursors for Cross-Coupling Reactions
Md. Mahbubur Rahman, Daniel J. Pyle, Elwira Bisz, Błażej Dziuk, Krzysztof Ejsmont, Roger A. Lalancette, Qi Wang, Hao Chen, Roman Szostak, Michal Szostak
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 N-acyl-imides, N-acyl-lactams, and N-acyl-oxazolidinones bearing five- and 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+χN) 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.