Photoredox-Mediated Mono- and Difluorination of Remote Unactivated Methylene C(sp³)–H Bonds of N-Alkyl Sulfonamides

Abstract

A photoredox-mediated δ-C(sp 3 )−H fluorination of sulfonyl-protected primary alkylamines with Selectfluor is developed. The reaction can proceed in excellent monofluorination selectivity for amine substrates without α substituent. For α-substituted substrates, a slightly modified reaction conditions with two rounds of operation gives the δ,δ-difluorination products in good yield. Mechanistic studies suggest SET oxidation of sulfonamide group directly generates the key sulfonamide N radical intermediate, which triggers a 1,5-HAT process to form the δ alkyl radical.

Fluorinated Cycloalkyl Building Blocks for Drug Discovery

“…Other recent approaches included δ-fluorination of nonactivated CÀ H bonds via the O- [62,63] or N-radical [163,164] generation and further [1,5]…”

“…Other recent approaches included δ‐fluorination of non‐activated C−H bonds via the O ‐ [62,63] or N ‐radical [163,164] generation and further [1,5] hydrogen shift as shown in Scheme 16 (Schemes 41424344; compare with Schemes 17 and 18).…”

“…[163] Also, γ-fluorocyclohexyl derivatives 206 and 208 were formed in 34 % and 80 % yield, respectively, in the Rucatalyzed photoredox fluorination reaction (Scheme 66). [164] The latter method did not work, however, for the synthesis of the corresponding δ-fluorocyclohexylamine derivative. In both cases, initial formation of N-centered radical was postulated, followed by [1,5] H-shift and further reaction with the fluorine source (see also Scheme 16).…”

Cu-Catalyzed Intermolecular γ-Site C–H Amination of Cyclohexenone Derivatives: The Benefit of Bifunctional Ligands

“…As a highly active species, N-centered radicals have the advantages of simplicity and efficiency in building diverse C–N bonds . However, the process involving radicals for site-selective C–N bond formation will remain challenging , for the following reasons: (I) the N radical was difficult to be generated by cleavage of the strong N–H bond under mild conditions compared to the weak N–X (X = O, S, N, and halogen) bond . (II) An N-centered radical could not be readily generated in situ and provided an appropriate situation in the intermolecular cross-coupling manner to achieve site-selective C–N bond construction simultaneously.…”

δ-C–H Halogenation Reactions Enabled by a Nitrogen-Centered Radical Precursor

“…In 2018, Leonori used a novel hydroxylamine-based precursor to generate nitrogen-centered radicals for HAT reactions; however, only one example of remote fluorination of a sulfonamide was presented, targeting a tertiary C–H bond. More recently, Chen disclosed a δ-C–H fluorination reaction of p -methoxybenzenesulfonamides using a proton-coupled electron transfer (PCET) strategy , for nitrogen-centered radical generation; however, this reaction was effective only with electron-rich sulfonamides. Meanwhile, Muñiz demonstrated a radical crossover strategy for the remote fluorination of tolylsulfonamides using a combination of iodine and a hypervalent iodine oxidant to generate the initial nitrogen-centered radical, followed by oxidation of the remote carbon radical to a carbocation and trapping with nucleophilic fluoride.…”