N-Ammonium Ylide Mediators for Electrochemical C–H Oxidation

Abstract

The site-specific oxidation of strong C­(sp3)–H bonds is of uncontested utility in organic synthesis. From simplifying access to metabolites and late-stage diversification of lead compounds to truncating retrosynthetic plans, there is a growing need for new reagents and methods for achieving such a transformation in both academic and industrial circles. One main drawback of current chemical reagents is the lack of diversity with regard to structure and reactivity that prevents a combinatorial approach for rapid screening to be employed. In that regard, directed evolution still holds the greatest promise for achieving complex C–H oxidations in a variety of complex settings. Herein we present a rationally designed platform that provides a step toward this challenge using N-ammonium ylides as electrochemically driven oxidants for site-specific, chemoselective C­(sp3)–H oxidation. By taking a first-principles approach guided by computation, these new mediators were identified and rapidly expanded into a library using ubiquitous building blocks and trivial synthesis techniques. The ylide-based approach to C–H oxidation exhibits tunable selectivity that is often exclusive to this class of oxidants and can be applied to real-world problems in the agricultural and pharmaceutical sectors.

Electronic control over site-selectivity in hydrogen atom transfer (HAT) based C(sp3)–H functionalization promoted by electrophilic reagents

“…60 In a more recent study, 1-pentylbenzoate was reacted with the N-trimethylammonium 2-trifluoromethylbenzamidyl radical generated electrochemically by oxidation of the N-trimethylammonium ylide precursor (2-CF 3 C 6 H 4 CON À N + Me 3 ) in the presence of air. 30 Formation of the ketoesters deriving from functionalization at C-3 and C-4 in a 1 : 4.5 ratio was observed. The results were compared with those obtained in oxidations promoted by other popularized systems, namely electrochemically generated ABCO + (described above), TFDO, H 2 O 2 / [Fe(pdp)] (FeO), photoexcited TBADT (DT*) and H 5 IO 6 /cis-[Ru(dtbpy) 2 Cl 2 ] (RuO).…”

“…The oxygenation of 2-methyl-1-pentyl pivalate and of 4-methyl-1-pentyl benzoate was investigated employing an electrochemically generated N-trimethylammonium 2-trifluoromethylbenzamidyl radical as the HAT reagent in the presence of air, with comparison to the corresponding oxidations promoted by other popularized systems (ABCO + , FeO, TFDO, DT*, RuO; see above). 30 With the former substrate, selective ketonization at the most remote C-4 secondary site was observed in low yield and mass balance (scheme 88a). Product mixtures deriving from oxygenation at C-2 and C-4 or C-2, C-3 and C-4 were observed in the corresponding oxidations promoted by ABCO + , FeO and TFDO.…”

“…29 A new class of HAT reagents that offers the opportunity to broadly diversify both structure and reactivity has been recently developed, and consists in N-ammonium amidyl radicals that can be conveniently generated electrochemically by oxidation of N-ammonium ylide precursors (Scheme 8). 30 These reagents have been shown to promote HAT from the C-H bonds of different substrate classes with tunable site selectivity, governed by the structure of the ylide precursor.…”

Novel Strategies in C-H Oxidations for Natural Product Diversification—A Remote Functionalization Application Summary

“…Recently, Baran group reported a new class of reactive radicals with tunable reactivity and selectivity for unactivated C−H oxidation. ( Baran et al, 2021 ) Figure 1B . N-ammonium ylides-mediated electrochemical C-H oxidation worked with a wide range of substrates and revealed their unusual and often unique selective properties.…”

Synthesis of <i>N</i>-Aminated Salts of Aliphatic <i>tert</i>-Amines, (Trialkyl)amidines, and (Pentaalkyl)guanidines by Electrophilic Amination in an Ethereal Solvent

“…This is because the resulting N-aminated products are useful precursors of amine imide derivatives, i.e., nitrogen ylides, which exhibit unique reactivities and properties. [1][2][3][4][5] Thus far, various reagents and routes for EA reactions are being developed [6][7][8][9] to overcome the drawbacks associated with the traditional chloramine (NH 2 Cl) reagent, 10,11) including its low reactivity and handling difficulty (preparation in a diluted solution immediately before use). O-(Mesitylenesulfonyl) hydroxylamine (MSH) 12,13) is a commonly used EA reagent, whose utility was established by Tamura et al [14][15][16][17] MSH offers the advantages of high reactivity and sufficient solubility in common organic solvents.…”