Copper-Catalyzed Remote C(sp³)–H Amination of Carboxamides

Abstract

Here we report a method for the site-selective intermolecular C­(sp3)–H amination of carboxamides by merging transition-metal catalysis and the hydrogen atom transfer strategy. The reaction proceeds through a sequence of favorable single-electron transfer, 1,5-hydrogen atom transfer, and C–N cross-coupling steps, thus allowing access to a series of desired products. This reaction could accommodate a wide diversity of nitrogen nucleophiles as well as demonstrate excellent chemoselectivity and functional group compatibility.

Copper-Catalyzed N-Directed Distal C(sp3)–H Sulfonylation and Thiolation with Sulfinate Salts

“…Under the standard conditions, substrate 1at can undergo a cascade process to afford the cyclized product 4 that would support the involvement of a series of radical intermediates (Scheme ). Based on the above observations and previous reports, − , a plausible mechanism for the transformation is depicted in Scheme . The catalysis is initiated by the single electron transfer of copper­(I) complex A to 1 , thus generating the copper­(II) complex B and the nitrogen-centered radical D .…”

“…The Hofmann–Löffler–Freytag (HLF) reaction, first developed for the preparation of N -heterocycles, has recently proven as a practical and powerful approach to enable distal C­(sp 3 )–H functionalization . Note that the copper-catalyzed redox manner has been broadly employed in these HLF-type reaction while using nucleophiles as the cross-coupling partners. − Inspired by these reports, we envisioned that the combination of 1,5-HAT (1,5-hydrogen atom transfer) with the sulfonylation of alkyl radicals might achieve the remote C­(sp 3 )–H sulfonylation of amine derivatives via copper catalysis with sulfinates as the nucleophiles (Scheme c).…”

Copper-catalyzed radical relay in C(sp3)–H functionalization

“…Liu and coworkers merged C–N bond cross-coupling with the Hofmann–Löffler–Freytag reaction and realized intermolecular C(sp 3 )–H amination of carboxamides (Scheme 29). 83 This transformation utilized copper as a catalyst to convert N -fluorocarboxamides into a wide range of distal aminated carboxamides with various nucleophiles such as aryl/aliphatic amines, indoles, and imines. The reaction was initiated by an in situ generated Cu( i )–N complex which reduced the N–F substrates to generate amidyl radicals, triggering 1,5-HAT.…”

Recent Advances in Copper‐Catalyzed C−N Bond Formation Involving N‐Centered Radicals

“…In the same year, Liu and co‐workers published a regio‐ and chemo‐selective Cu‐catalyzed intermolecular C(sp 3 )−H amination strategy of N ‐fluorocarboxamides (Scheme 19). [28] This approach was not only suitable for the metal‐catalyzed HLF reaction but also for C(sp 3 )−N coupling. More importantly, γ ‐and δ ‐aminated carboxamides were afforded by using this method, indicating that this method not only solved the difficulty of competitive cyclization leading to heterocycles, but also overcame the challenges of the C(sp 3 )−N reductive elimination.…”