A Formal γ-C-H Functionalization of Carboxylic Acids Guided by Metal-Nitrenoids as an Unprecedented Mechanistic Motif.

Harnessing the key intermediates in metal-catalyzed reactions is one of the most essential strategies in the development of selective organic transformations. The nitrogen group transfer reactivity of metal-nitrenoids to ubiquitous C-H bonds allows for diverse C-N bond formation to furnish synthetically valuable aminated products. In this study, we present an unprecedented reactivity of iridium and ruthenium nitrenoids to generate remote carbocation intermediates, which subsequently undergo nucleophile incorporation, thus developing a formal γ-C-H functionalization of carboxylic acids. Mechanistic investigations elucidated a unique singlet metal-nitrenoid reactivity to initiate an abstraction of γ-hydride to form the carbocation intermediate that eventually reacts with a broad range of carbon, nitrogen, and oxygen nucleophiles, as well as biorelevant molecules. Alternatively, the same intermediate can lead to deprotonation to afford ß,γ-unsaturated amides in a less nucleophilic solvent.

Enantioselective Access to Spirolactams via Nitrenoid Transfer Enabled by Enhanced Noncovalent Interactions.

Described herein is the Ir-catalyzed enantioselective access to chiral spirolactam products via the nitrenoid transfer to aromatic ipso-carbons. The key strategy for precise stereocontrol is to enhance the secondary attractive and repulsive interactions between the chiral catalyst and substrates by the introduction of a traceless O-silyl achiral auxiliary, thus effectively differentiating two prochiral faces of arenol-derived 1,4,2-dioxazol-5-one substrates.

Revisiting Arene C(sp2 )-H Amidation by Intramolecular Transfer of Iridium Nitrenoids: Evidence for a Spirocyclization Pathway.

Two mechanistic pathways, that is, electrocyclization and electrophilic aromatic substitution, are operative in most intramolecular C-H amination reactions proceeding by metal nitrenoid catalysis. Reported here is an alternative mechanistic scaffold leading to benzofused δ-lactams selectively. Integrated experimental and computational analysis revealed that the reaction proceeds by a key spirocyclization step followed by a skeletal rearrangement. Based on this mechanistic insight, a new synthetic route to spirolactams has been developed.

Selective formation of γ-lactams via C-H amidation enabled by tailored iridium catalysts.

Intramolecular insertion of metal nitrenes into carbon-hydrogen bonds to form γ-lactam rings has traditionally been hindered by competing isocyanate formation. We report the application of theory and mechanism studies to optimize a class of pentamethylcyclopentadienyl iridium(III) catalysts for suppression of this competing pathway. Modulation of the stereoelectronic properties of the auxiliary bidentate ligands to be more electron-donating was suggested by density functional theory calculations to lower the C-H insertion barrier favoring the desired reaction. These catalysts transform a wide range of 1,4,2-dioxazol-5-ones, carbonylnitrene precursors easily accessible from carboxylic acids, into the corresponding γ-lactams via sp3 and sp2 C-H amidation with exceptional selectivity. The power of this method was further demonstrated by the successful late-stage functionalization of amino acid derivatives and other bioactive molecules.