Photoinduced Remote Functionalization of Amides and Amines Using Electrophilic Nitrogen Radicals

Abstract

The selective functionalization of C(sp3)−H bonds at distal positions to functional groups is a challenging task in synthetic chemistry. Reported here is a photoinduced radical cascade strategy for the divergent functionalization of amides and protected amines. The process is based on the oxidative generation of electrophilic amidyl radicals and their subsequent transposition by 1,5‐H‐atom transfer, resulting in remote fluorination, chlorination and, for the first time, thioetherification, cyanation, and alkynylation. The process is tolerant of most common functional groups and delivers useful building blocks that can be further elaborated. The utility of this strategy is demonstrated through the late‐stage functionalization of amino acids and a dipeptide.

Generation and Reactivity of Amidyl Radicals: Manganese‐Mediated Atom‐Transfer Reaction

“…We first addressed remote C(sp 3 ) À H chlorination of amine substrates, since alkyl chlorides are very important and versatile synthetic intermediates for organic synthesis. [16] The groups of Studer, [17] Leonori, [18] and Yu [19] have recently achieved elegant amidyl radical directed remote C(sp 3 )ÀH chlorinations by cleaving NÀS, NÀO, and NÀCl bonds with the help of LPO radical initiator and precious photoredox catalysts. [20,21] Obviously, developing alternative methods that feature a cheap catalytic system and operate under mild conditions to realize site-selective distal C(sp 3 )ÀH chlorination would be very fascinating.…”

“…Furthermore, a range of sulfonamides bearing electrondonating and electron-withdrawing substituents on the aromatic ring all proceeded efficiently to afford products 13-17 in 64-82 % yields. A heteroarene such as thiophene was compatible (18). Alkyl-substituted sulfonamides proved to be viable substrates (19).…”

Generation and Reactivity of Amidyl Radicals: Manganese‐Mediated Atom‐Transfer Reaction

“…We first addressed remote C(sp 3 )−H chlorination of amine substrates, since alkyl chlorides are very important and versatile synthetic intermediates for organic synthesis . The groups of Studer, Leonori, and Yu have recently achieved elegant amidyl radical directed remote C(sp 3 )−H chlorinations by cleaving N−S, N−O, and N−Cl bonds with the help of LPO radical initiator and precious photoredox catalysts . Obviously, developing alternative methods that feature a cheap catalytic system and operate under mild conditions to realize site‐selective distal C(sp 3 )−H chlorination would be very fascinating.…”

Dual Photoredox/Copper Catalysis for the Remote C(sp3)−H Functionalization of Alcohols and Alkyl Halides by N‐Alkoxypyridinium Salts

“…To extend the application scope of this dual catalytic approach, cyanation of N ‐alkoxypyridinium salts 4 was next investigated. Replacing TMSN 3 by TMSCN under otherwise identical conditions converted 4 a to 4‐cyano‐4‐phenylbutan‐1‐ol ( 6 a ) in 73 % yield (Scheme ) . Screening the copper salts and the ligand structures (See the Supporting Information) did not improve the reaction outcome and the azidation conditions were directly exploited for the scope of this novel cyanation reaction.…”