Photoredox-Mediated Remote C(sp³)–H Heteroarylation of N-Alkyl Sulfonamides

Abstract

A Minisci-type δ-selective C­(sp3)–H heteroarylation of sulfonyl-protected primary aliphatic amines with N-heteroarenes under photoredox-catalyzed conditions was developed. The reaction typically uses a slight excess of amine reactant. The use of benziodoxole acetate (BI-OAc) oxidant and hexafluoroisopropanol solvent is critical to achieve high yield. Besides methylene C–H bonds, heteroarylation reactions of δ methyl C–H bonds also worked under more forced conditions. The reactions show a broad scope for both amine and N-heteroarene substrates, offering a straightforward method for synthesis of complex δ-heteroarylalkylmines from simple precursors.

Hexafluoroisopropanol: the magical solvent for Pd-catalyzed C–H activation

“… 10 Probably, due to the same reason, the solvent is found to be way more efficient than any other polar solvents in a recent δ-C–H heteroarylation of protected aliphatic amines via [1,5]HAT ( Scheme 1B , eqn (1)). 11 Because of the high reactivity of the radical cations, the whole catalysis predominantly depends on the reaction media. It has been observed that non-nucleophilic HFIP can easily solvate the counter anions by H-bonding interactions, thus leaving the radical cations free.…”

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

“…We previously reported a photoredox-mediated method for δ-C(sp 3 )−H heteroarylation of sulfonyl-protected primary alkyl amines with N-heteroarenes using benziodoxole acetate oxidant. 9,10 directly oxidized by single electron transfer (SET) to generate an N-radical, which triggers the subsequent 1,5-HAT and Minisci-type arylation. 9,11 Encouraged by these results, we wondered whether a similar alkyl radical via 1,5-HAT can be trapped by suitable fluorination reagents to give the fluorination product.…”

“…9,10 directly oxidized by single electron transfer (SET) to generate an N-radical, which triggers the subsequent 1,5-HAT and Minisci-type arylation. 9,11 Encouraged by these results, we wondered whether a similar alkyl radical via 1,5-HAT can be trapped by suitable fluorination reagents to give the fluorination product. As shown in Table 1, we were pleased to find that reaction of p-methoxyphenyl (PMP) sulfonyl pentylamine 1 with 2.5 equiv of Selectfluor I (BF 4 ) and 1.0 mol % of Ru(bpy) 3 Cl 2 photocatalyst under the irradiation of household compact fluorescent lamp (CFL, 23 W) in the mixed solvents of hexafluoroisopropanol (HFIP) 12 and water (4.6/1) at 30 °C for 12 h gave the desired monofluorination product 2m along with a small amount of difluorination 2d in 70% isolated yield (entry 1).…”

“…Based on this evidence and the related work by Knowles, Rovis, and our group, the following mechanism is proposed for this reaction system (Scheme 4B). 9,11 Upon photoexcitation, Ru(II) can be oxidized by Selectfluor or its derived intermediate via SET to form a Ru(III) species. The sulfonamide substrate 1 can be directly oxidized by Ru(III) via SET or proton-coupled electron transfer process to form N-radical 26 and Ru(II).…”

“…As shown in Scheme A, the treatment of N -fluorosulfonamide intermediate 25 under our typical photoredox conditions in the absence of Selectfluor reagent did not form any δ-fluorination product 2m . Based on this evidence and the related work by Knowles, Rovis, and our group, the following mechanism is proposed for this reaction system (Scheme B). , Upon photoexcitation, Ru­(II) can be oxidized by Selectfluor or its derived intermediate via SET to form a Ru­(III) species. The sulfonamide substrate 1 can be directly oxidized by Ru­(III) via SET or proton-coupled electron transfer process to form N-radical 26 and Ru­(II) .…”