Advancing Meta-Selective C–H Amination through Non-Covalent Interactions

Abstract

Regioselective C−H amination of simple arenes is highly desirable, but accessing meta-sites of ubiquitous arenes has proven challenging due to the lack of both electronic and spatial preference. This study demonstrates the successful use of various privileged nitrogen-containing functionalities found in pharmaceutical compounds to direct meta-C−H amination of arenes, overcoming the long-standing requirement for a redundant directing group. The remarkable advancements in functional group accommodation for precise regiochemical control were achieved through the discovery of an unprecedented organo-initiator and the strategic utilization of non-covalent interactions. This protocol has been successfully applied in the concise synthesis and late-stage derivatization of drug molecules, which would have been otherwise challenging to achieve.

Synthesis of N–H Aziridines from Unactivated Olefins Using Hydroxylamine-O-Sulfonic Acids as Aminating Agent

“…Aziridines, recognized as the smallest nitrogen-containing heterocyclic compounds, are a “privileged scaffold” extensively found in natural products and pharmaceuticals, such as Mitomycin A (antitumor agents), Azicemicin A (antimicrobial antibiotic), and FR-66979 (antitumor antibiotic) (Scheme a). − Notably, as a crucial building block, various methods for synthesizing aziridines have emerged. − These primarily include (1) intramolecular cyclization of amino or azido alcohols, (2) addition of carbene equivalent to imine, and (3) addition of nitrene equivalent to olefin . Transforming simple olefins into high-value-added aziridines, given that the significance of olefins as a chemical feedstock, represents a challenging and significant task.…”

“…Transforming simple olefins into high-value-added aziridines, given that the significance of olefins as a chemical feedstock, represents a challenging and significant task. However, most of the research studies on alkene aziridination have predominantly focused on the syntheses of activated aziridination compounds, where R is an electron-withdrawing group (Scheme b, R = EWG). ,, Typically, these reactions generally require transition metal catalysis. Conversely, the synthesis of free N–H aziridines has garnered relatively less attention, probably due to the scarcity of suitable nitrene precursors and approaches. − In a seminal study in 2014, the Kürti, Falck, and Ess group reported a rhodium-catalyzed N–H aziridination of alkenes utilizing O -(2,4-dinitrophenyl)­hydroxylamines (DPHs) as the aminating reagent (Scheme c, left) .…”

Palladium-Catalyzed para-Selective C–H Olefination and Acetoxylation of Benzylamines Enabled by an Unmasked Benzoyl Template

“…Meanwhile, designs of directing templates based on the distance, conformation, and geometry enabled palladium-catalyzed meta -selective C–H functionalization of benzylamines . In addition, remote meta -selective C–H functionalization of benzylamines has also been achieved through the norbornene relay palladation process, a non-covalent interaction between the substrate and linker, including the use of distal-directing ligands or an organo-initiator . Notwithstanding the vast advance, the success in this field was exclusively limited to ortho - or meta -C–H functionalization, while palladium-catalyzed remote para -C–H functionalization of benzylamines has hitherto not been achieved to date …”