Mechanistic studies on intramolecular C–H trifluoromethoxylation of (hetero)arenes via OCF₃-migration

Abstract

The one-pot two-step intramolecular aryl and heteroaryl C-H trifluoromethoxylation recently reported by our group has provided a general, scable, and operationally simple approach to access a wide range of unprecedented and valuable OCF3-containing building blocks. Herein we describe our investigations to elucidate its reaction mechanism. Experimental data indicates that the O-trifluoromethylation of N-(hetero)aryl-N-hydroxylamine derivatives is a radical process, whereas the OCF3-migration step proceeds via a heterolytic cleavage of the N–OCF3 bond followed by rapid recombination of a short-lived ion pair. Computational studies further support the proposed ion pair reaction pathway for the OCF3-migration process. We hope that the current study would provide useful insights for the development of new transformations using versatile N-(hetero)aryl-N-hydroxylamine synthons.

Synthesis of Tri‐ and Difluoromethoxylated Compounds by Visible‐Light Photoredox Catalysis

“…Stern–Volmer quenching experiments indicated that the deprotonated N ‐phenyl‐ N ‐hydroxylamide 2.1 ( E 1/2 red = +0.62 V vs. SCE) quenched *Ru(bpy) 3 2+ efficiently ( k q =7.84×10 9 m −1 s −1 ), while there was no observable quenching with the N ‐phenyl‐ N ‐hydroxylamide 2.2 and perfluoroisopropyl iodide ( 2.3 ; Scheme a). Furthermore, Ngai and co‐workers observed that the OR F migration was slower when electron‐deficient aromatic substrates were used, which was consistent with their previous observations and proposal of an ionic OR F ‐migration pathway . Based on this data, a reductive quenching photocatalytic cycle for selective O−R F bond formation and the subsequent OR F migration were proposed as outlined in Scheme b. Excitation of Ru(bpy) 3 2+ with visible light produces a long‐lived photoexcited *Ru(bpy) 3 2+ ( t 1/2 =1.10 μs), which is reductively quenched by 2.1 to give the N ‐hydroxyl radical 2.4 and Ru(bpy) 3 + .…”

Selective C–O bond formation via a photocatalytic radical coupling strategy: access to perfluoroalkoxylated (ORF) arenes and heteroarenes

“…We also observed that the OR F migration is slower with more electron deficient aromatics, which is consistent with our previous observations and suggests an ionic OR F -migration pathway. 36 Based on these results, a detailed description of our proposed photocatalytic cycle for selective O–R F bond formation and the consequent OR F -migration is outlined in Fig. 2b .…”

“…Subsequent radical–radical coupling between Ib and ˙R F affords O -perfluoroalkylated N -phenyl- N -hydroxylamide Ic , which undergoes heterolytic N–OR F bond cleavage 47 , 48 followed by recombination of the resulting short-lived ion pair ( Id ) and then tautomerization to yield the final perfluoroalkoxylated arene product. 36 …”

“…CF 3 I costs $83 mol –1 ). 35 Based on our prior mechanistic studies, 36 selective O–R F bond formation is feasible if N -hydroxyl and R F radicals are generated simultaneously. 37 Although direct single electron transfer (SET) from N -(hetero)aryl- N -hydroxylamides to R F –I is kinetically and thermodynamically unfavorable, we hypothesize that such a SET process could be facilitated by using an appropriate photoredox catalyst.…”

Synthetic Approaches to Trifluoromethoxy‐Substituted Compounds

“…[62] The OCF 3 migration step, however, is currently believed to proceed by heterolytic cleavage of the N À OCF 3 bond via formation of a nitrenium ion and a trifluoromethoxide anion.…”