C–H Xanthylation: A Synthetic Platform for Alkane Functionalization

Abstract

Intermolecular functionalizations of aliphatic C–H bonds offer unique strategies for the synthesis and late-stage derivatization of complex molecules, but the chemical space accessible remains limited. Herein, we report a transformation significantly expanding the chemotypes accessible via C–H functionalization. The C–H xanthylation proceeds in useful chemical yields with the substrate as limiting reagent using blue LEDs and an easily prepared N-xanthylamide. The late-stage functionalizations of complex molecules occur with high levels of site selectivity, and a variety of common functionality is tolerated in the reaction. This approach capitalizes on the versatility of the xanthate functional group via both polar and radical manifolds to unlock a wide array of C–H transformations previously inaccessible in synthesis.

A General Approach to Site‐Specific, Intramolecular C−H Functionalization Using Dithiocarbamates

“…From the outset, we anticipated that this strategy would require a different dithiocarbonyl derivative from the xanthate used in the intermolecular C–H functionalization, [7] as amine and xanthate functionality are generally incompatible with each other owing to the electrophilicity of the thiocarbonyl group resulting in rapid degradation of the xanthate. [8,9] We thus considered a less electrophilic dithiocarbonyl derivative–a dithiocarbamate–as the transfer group for our studies.…”

“…[7] For example, while the intermolecular C–H xanthylation of linear substrates favors functionalization at the most distal methylene site, a mixture of regioisomers is still observed. In cases where complete site specificity is desired, the present approach provides a useful alternative.…”

“…The reaction of the N -dithiocarbamate derived from rimantadine delivered 13 as the sole product in good yield, with no functionalization of the adamantyl core that is the major product of intermolecular C–H functionalization of related substrates. [6a,6b,7,18] A gemfibrozil derived substrate afforded 14 , demonstrating successful C–H dithiocarbamylation in the presence of an electron-rich arene prone to react with the strong oxidants common to HLF-type reactions. The C–H functionalization of substrates derived from the amino acids norleucine and valine provided products 12 and 15 , respectively, with functionalizations at either secondary or primary C–H sites, providing avenues for unnatural amino acid synthesis.…”

A General Approach to Site‐Specific, Intramolecular C−H Functionalization Using Dithiocarbamates

“…[5] Moreover,t he marked reliance on C À Hh alogenation (or subsequent intramolecular aminations) in these processes ultimately has limited the synthetic scope and value of these reactions. [6,7] In particular, we recently reported aC ÀHxanthylation as asynthetic platform unlocking adiverse array of aliphatic C À Htransformations. [6,7] In particular, we recently reported aC ÀHxanthylation as asynthetic platform unlocking adiverse array of aliphatic C À Htransformations.…”

“…[2,3,5] Prior efforts from our laboratory have demonstrated the utility of functionalized amides to achieve site-selective, intermolecular CÀHf unctionalizations. [7] We hypothesized that asite-specific,intramolecular variant of this transformation would offer significant advantages over standard HLF-type reactions as the impressive synthetic versatility of dithiocarbonyl products would allow access to ad iverse range of derivatives via both polar and radical processes.A ss uch, we considered ac onvergent approach involving coupling of as uitable functionalized amine and ac arboxylic acid ( Figure 1). [7] We hypothesized that asite-specific,intramolecular variant of this transformation would offer significant advantages over standard HLF-type reactions as the impressive synthetic versatility of dithiocarbonyl products would allow access to ad iverse range of derivatives via both polar and radical processes.A ss uch, we considered ac onvergent approach involving coupling of as uitable functionalized amine and ac arboxylic acid ( Figure 1).…”