Directed γ-C(sp³)–H Alkylation of Carboxylic Acid Derivatives through Visible Light Photoredox Catalysis

Abstract

Visible light photoredox catalysis enables direct γ-Csp3-H alkylation of saturated aliphatic carbonyl compounds. Electron-deficient alkenes are used as the coupling partners in this reaction. Distinguished site selectivity is controlled by the predominant 1,5-hydrogen atom transfer (HAT) of an amidyl radical generated in situ.

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

“…[1] The venerable Hofmann-Löffler-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] a major limitation of this approach in complex synthesis is the use of strong oxidants to generate unstable halogenated N–X derivatives. [5] Moreover, the marked reliance on C–H halogenation (or subsequent intramolecular aminations) in these processes ultimately has limited the synthetic scope and value of these reactions.…”

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

“…[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.…”

“…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).…”

Copper‐Catalyzed Arylation of Remote C(sp3)−H Bonds in Carboxamides and Sulfonamides

“…Therelatively harsh reaction conditions and the instability of the N-haloamines have nevertheless limited to some extent its synthetic applications.Amajor breakthrough addressing this issue came in 1980 when Suµrez and co-workers reported adirect conversion of 1b into the corresponding pyrrolidines 2 using as toichiometric amount of iodine and phenyliodine diacetate as oxidants. [2,3] Subsequently,s ilver salt catalyzed, iodine-catalyzed, and triiodide-mediated versions of the HLF reaction were developed by the groups of Li, [4] Shi, [5] MuÇiz, [6] and Nagib, [7] respectively.M ore recently,t he groups of Knowles [8] and Rovis [9] independently developed ap hotoredox-catalyzed remote functionalization of simple carboxamides and sulfonamides.I nt hese latter examples,t he Ccentered radical B was trapped by aMichael acceptor leading to 3.C losely related to the HLF reaction, the group of Yu reported metal-catalyzed g-halogenation of imides to give 4, [10] while Shi [11] and Nevado [12] described aneophyl-type 1,4-Ct oNaryl migration for the generation of the carbon radicals.…”