Visible‐Light‐Mediated Remote Aliphatic C−H Functionalizations through a 1,5‐Hydrogen Transfer Cascade

Abstract

A redox‐neutral, light‐mediated functionalization of unactivated C(sp3)−H bonds via iminyl radicals is presented here. A 1,5‐H transfer followed by the functionalization of a C(sp2)−H bond takes place in aqueous media producing a variety of elaborated fused ketones. Mechanistic investigations have revealed 1,5‐H transfer as the reversible, rate‐determining step in this transformation. Divergent scaffolds are also accessible via C(sp3)−N bond formation upon a careful choice of the reaction additives.

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

“…[2,3] With few exceptions, [3b,4] am ajor limitation of this approach in complex synthesis is the use of strong oxidants to generate unstable halogenated NÀXd erivatives. [2,3,5] Prior efforts from our laboratory have demonstrated the utility of functionalized amides to achieve site-selective, intermolecular CÀHf unctionalizations. [2,3,5] Prior efforts from our laboratory have demonstrated the utility of functionalized amides to achieve site-selective, intermolecular CÀHf unctionalizations.…”

“…[15] We began with simple aliphatic substrates to identify suitable conditions for the C À Hf unctionalization. [2][3][4][5] TheC À Hd ithiocarbamylation is not limited to methylene functionalization, as primary CÀHf unctionalization was successful (entries 7a nd 8) in contrast to related reactions that require an electron-withdrawing group on nitrogen to achieve primary functionalization. Arange of different Nalkyl hexanamides worked well in the reaction (entries 1-4), with the nPr amide substrate for 3 providing the 1,6functionalization isomer as aminor product.…”

“…[1] Thev enerable Hofmann-Lçffler-Freytag (HLF) reaction and related variants are prototypical examples of transformations of this type that proceed via intramolecular hydrogen atom transfer of reactive nitrogen-centered radicals. [2,3] With few exceptions, [3b,4] am ajor limitation of this approach in complex synthesis is the use of strong oxidants to generate unstable halogenated NÀXd erivatives. [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.…”

“…[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. [2,3,5] Prior efforts from our laboratory have demonstrated the utility of functionalized amides to achieve site-selective, intermolecular CÀHf unctionalizations. [6,7] In particular, we recently reported aC ÀHxanthylation as asynthetic platform unlocking adiverse array of aliphatic C À Htransformations.…”

“…Site-specific functionalization of the amine coupling partner was also facile under these conditions (entries 5a nd 6), which is aunique feature of our approach as compared to standard HLF-type transformations that often require specific N-substitution (e.g., Ts). [2][3][4][5] TheC À Hd ithiocarbamylation is not limited to methylene functionalization, as primary CÀHf unctionalization was successful (entries 7a nd 8) in contrast to related reactions that require an electron-withdrawing group on nitrogen to achieve primary functionalization. [3c, 17] Cyclic substrates also reacted efficiently in as ite-specific manner to deliver products bearing 1,2-or 1,3-substitution in good yields (entries 9a nd 10).…”