Physical organic approaches to selective C–H amidation reactions by designing tailored iridium catalysts

Abstract

Cyclopentadienyl ($Cp^X$)-based group 9 transition-metal complexes have been under spotlight for C–H functionalization reactions. Especially, iridium-catalyzed C–H amination draws special attention since the process provides synthetically useful nitrogen-containing compounds in bioactive molecules, natural products, and materials. While a diverse range of catalytic transformation has been established, selective C–H amination in presence of competing reactive units is still elusive. In this context, described herein is the development of highly selective C–H amidation reactions utilizing newly developed iridium catalysts.

First, Cp$^*$Ir(III)-catalyzed C–H amidation has been established using dioxazolone as a nitrene precursor. The C–H aminations using organic azide have a limited flexibility due to intrinsic instability of these compounds. Stoichiometric experiments and Density Functional Theory (DFT) calculation in this study led us to conclude that dioxazolones are much more efficient than acyl azides in a C–N coupling step. Importantly, higher reactivity of iridium-dioxazolone system enables the development of efficient catalytic C–H amidation with a broad range of challenging substrates.

Second, a new catalytic platform for C–N bond formation has been developed using Cp$^*$-based iridium catalysts in combination with LX chelators. Using the highly reactive metal-nitrenoid intermediate, aromatic C($sp^2$)–H bonds were readily amidated in intramolecular manner leading to benzo-fused $\delta$-lactams. In particular, X-ray crystallographic analysis revealed that the reaction mode is different from widely-accepted pathways. Based on this mechanistic insight, a new synthetic route to diverse spirolactams has also been established.

Third, highly selective nitrenoid transfer is enabled by cooperative two-point modulation of ligands in the $Cp^X$Ir(III)($\kappa^2$-chelate) catalyst system. Using statistical analysis of catalysts’ structural effects, the underlying chemoselectivity trends was successfully interrogated in a quantitative manner. The resultant multivariate regression model predicts the reaction outcomes from a large set of catalyst candidates without experimental hit-or-miss cycles. On the basis of the quantitative analysis, a new catalytic platform is now established for the unique lactam formation, leading to the unprecedented chemoselective reactivity toward a diverse array of competing sites.