Multidimensional Screening Accelerates the Discovery of Rhodium Catalyst Systems for Selective Intra- and Intermolecular C–H Amidations

Abstract

We report herein a series of tailored CpXRh­(LX)Cl catalyst systems for the outer-sphere C–H amidations discovered by high-throughput experimentation. Using a diverse repertoire of Cp-tunable group 9 [CpXMCl2]2 precatalysts in combination with bidentate LX-type co-ligands, we have established a premixing protocol for the fast and convenient in situ generation of an array of half-sandwich metal complexes. Benefitting from the designed multidimensional approach to simultaneously screen the metal center, CpX, LX-type co-ligands, and nitrene precursors, optimal CpXRh­(III)­(LX) catalysts were quickly identified for intra- and intermolecular C–H amidations and also for an enantioselective transformation using N-tosyloxycarbamates as the nitrenoid precursor.

Nitrene transfer reaction with hydroxylamine derivatives

“…Recently, the Chang group established a high-throughput experimentation (HTE) approach to quickly identify the optimal reaction parameters for outer-sphere C–H amidation reactions (Scheme 5). 22 With this approach, they soon identified that Cp X Rh(LX) bearing a bidentate LX-type co-ligand were effective catalysts for intra- and intermolecular C–H amination reactions by utilizing N -tosyloxycarbamates as nitrenoid sources. Moreover, this parallel screening approach enabled a quick identification of a chiral catalyst with l -prolinamide as a ligand for asymmetric C–H amidation.…”

Recent developments for intermolecular enantioselective amination of non-acidic C(sp3)–H bonds

“…Intramolecular C(sp 3 )–H amination methods can lead to valuable changes in site- and chemo-selectivity compared to intermolecular variants. 12–14 Nonetheless, intermolecular reactions often place less restrictions on the substrates than intramolecular reactions and thus have more potential for generality and late-stage functionalization. Hence, we will focus on intermolecular enantioselective C(sp 3 )–H amination reactions rather than intramolecular reactions.…”

The Indenyl Effect: Accelerated C−H Amidation of Arenes via Ind*RhIII Nitrene Transfer Catalysis**

“…1,4,2‐dioxazol‐5‐ones have been successfully engaged as N ‐donor sources in C−H amidation reactions (including stereo‐ and enantioselective variants) to access pharmaceutically relevant N ‐aryl amides, oxazoles, and lactams [6] . Such transformations have been realised via inner‐sphere mechanisms involving strongly‐ or weakly‐coordinating directing groups [7] and outer‐sphere mechanisms [5b, 6b, 8] …”