Remote, Late-Stage Oxidation of Aliphatic C–H Bonds in Amide-Containing Molecules

Abstract

Amide-containing molecules are ubiquitous in natural products, pharmaceuticals, and materials science. Due to their intermediate electron-richness, they are not amenable to any of the previously developed N-protection strategies known to enable remote aliphatic C—H oxidations. Using information gleaned from a systematic study of the main features that makes remote oxidations of amides in peptide settings possible, we developed an imidate salt protecting strategy that employs methyl trifluoromethanesulfonate (MeOTf) as a reversible alkylating agent. The imidate salt strategy enables, for the first time, remote, non-directed, site-selective C(sp3)—H oxidation with Fe(PDP) and Fe(CF3PDP) catalysis in the presence of a broad scope of tertiary amides, anilide, 2-pyridone, and carbamate functionality. Secondary and primary amides can be masked as N-Ns amides to undergo remote oxidation. This novel imidate strategy facilitates late-stage oxidations in a broader scope of medicinally important molecules and may find use in other C—H oxidations and metal-mediated reactions that do not tolerate amide functionality.

Activation and Deactivation Strategies Promoted by Medium Effects for Selective Aliphatic C−H Bond Functionalization

“…[5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20] Ther eagents that are typically involved in these processes include heteroatomcentered radicals and radical ions,p hotoexcited species and photocatalysts (carbonyl compounds,polyoxometalates), biocatalysts (cytochrome P450 and oxygenases) and bioinspired catalysts,a swell as closed-shell species such as dioxiranes. [5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20] Ther eagents that are typically involved in these processes include heteroatomcentered radicals and radical ions,p hotoexcited species and photocatalysts (carbonyl compounds,polyoxometalates), biocatalysts (cytochrome P450 and oxygenases) and bioinspired catalysts,a swell as closed-shell species such as dioxiranes.…”

“…[5,[8][9][10][23][24][25][26][27] Hydrogen bonding and Brønsted and Lewis acid-base interactions have also been employed to promote the deactivation of CÀHb onds that are in the a position to basic centers,o rt he activation of CÀHb onds that are in the a position to acidic groups,b ye lectrophilic HATr eagents. [5,[8][9][10][23][24][25][26][27] Hydrogen bonding and Brønsted and Lewis acid-base interactions have also been employed to promote the deactivation of CÀHb onds that are in the a position to basic centers,o rt he activation of CÀHb onds that are in the a position to acidic groups,b ye lectrophilic HATr eagents.…”

“…Among the available methods for the site-selective functionalization of aliphatic CÀHb onds,t hose based on hydrogen atom transfer (HAT) to radical or radical-like species play an important role. [5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20] Ther eagents that are typically involved in these processes include heteroatomcentered radicals and radical ions,p hotoexcited species and photocatalysts (carbonyl compounds,polyoxometalates), biocatalysts (cytochrome P450 and oxygenases) and bioinspired catalysts,a swell as closed-shell species such as dioxiranes.…”

“…consequently allow functionalization at remote positions. [5,[8][9][10][23][24][25][26][27] Hydrogen bonding and Brønsted and Lewis acid-base interactions have also been employed to promote the deactivation of CÀHb onds that are in the a position to basic centers,o rt he activation of CÀHb onds that are in the a position to acidic groups,b ye lectrophilic HATr eagents. This indicates that the properties of the reaction medium can be used as an extremely powerful method to alter both the reactivity and site selectivity in HAT-based C À Hf unctionalization procedures.…”

Anwendung von Mediumeffekten in Aktivierungs‐ und Deaktivierungsstrategien zur selektiven Funktionalisierung aliphatischer C‐H‐Bindungen

“…Für die regioselektive Funktionalisierung aliphatischer C‐H‐Bindungen spielen insbesondere solche Methoden eine wichtige Rolle, die auf dem Wasserstoffatomtransfer (HAT) auf Radikale oder radikalartige Spezies beruhen . Die an diesen Prozessen normalerweise beteiligten Reagenzien sind Heteroatom‐zentrierte Radikale und radikalische Ionen, photoangeregte Spezies und Photokatalysatoren (Carbonylverbindungen, Polyoxometallate), Biokatalysatoren (Cytochrom P450 und Oxygenasen) und bioinspirierte Katalysatoren sowie Spezies mit abgeschlossenen Schalen, wie Dioxirane.…”