Visible-Light-Induced Alkoxyl Radicals Enable α-C(sp3)-H Bond Allylation

Abstract

SummaryThe alkoxyl radical is an essential reactive intermediate in mechanistic studies and organic synthesis with hydrogen atom transfer (HAT) reactivity. However, compared with intramolecular 1,5-HAT or intermolecular HAT of alkoxyl radicals, the intramolecular 1,2-HAT reactivity has been limited to theoretical studies and rarely synthetically utilized. Here we report the first selective 1,2-HAT of alkoxyl radicals for α-C(sp3)-H bond allylation of α-carbonyl, α-cyano, α-trifluoromethyl, and benzylic N-alkoxylphthalimides. The mechanistic probing experiments, electron paramagnetic resonance (EPR) studies, and density functional theory (DFT) calculations confirmed the 1,2-HAT reactivity of alkoxyl radicals, and the use of protic solvents lowered the activation energy by up to 10.4 kcal/mol to facilitate the α-C(sp3)-H allylation reaction.

Investigations on the 1,2-Hydrogen Atom Transfer Reactivity of Alkoxyl Radicals under Visible-Light-Induced Reaction Conditions

“…In fact, the electron paramagnetic resonance (EPR) experiment with 5,5dimethyl-pyrroline N-oxide (DMPO) 26 as the radical spin trap detected both the O-centered radical trapping adduct 27 and the α-C-centered radical trapping adduct 28, which directly confirmed the existence of the alkoxyl radical (Scheme 5a). 10 The presence of the alkoxyl radical could also be validated by the well-studied reactivity of alkoxyl radicals by the probe molecules 29 and 32. The N-alkoxylphthalimide 29 has both the -C-H and α-C-H that are prone to the intramolecular HAT, and the -C-H allylation adduct 31 could be obtained in 53% yield, together with the α-C-H allylation adduct 30 in 28% yield (Scheme 5b).…”

“…With the negative answer for the carbonyl compound as the sole reaction intermediate and the positive answer for the alkoxyl radical presence in the reaction conditions, the final and most essential question is if the 1,2-HAT of alkoxyl radical irrefutably exists? While the 1,2-HAT of alkoxyl radicals under visible-lightinduced reaction conditions was first revealed with Nalkoxylphthalimides as radical precursors, 10,12 the carbonyl compound formation in the reaction conditions complicated the mechanistic analysis. We envision the demonstration of 1,2-HAT reactivity from other alkoxyl radical precursors, especially in the absence of the carbonyl intermediate, will irrefutably validate the unusual 1,2-HAT reactivity of alkoxyl radicals.…”

“…In 2019, our group reported the first regioselective -C(sp 3 )-H allylation of N-alkoxylphthalimides under visible-light-induced reaction conditions, and the 1,2-HAT of alkoxyl radicals was proposed as the reaction mechanism. 10 However, some key questions remained to be conclusively addressed in the preliminary communication. In this account, we will discuss three key questions regarding the proposed reaction mechanism (Scheme 1c): 1) May the aldehyde/ ketone be the sole reaction intermediate?…”

“…3) Does the 1,2-HAT of alkoxyl radical irrefutably exist? As the reaction optimization and substrate scopes have been revealed in the previous communication, 10 we will briefly summarize them and will not report the whole dataset in detail (Scheme 2). In brief, the α-carbonyl, α-cyano, α-trifluoromethyl, and benzylic Nalkoxylphthalimides were suitable substrates for the α-C-H allylation (4)(5)(6)(7)(8)(9)(10)(11)(12)(13), and the photocatalyst in combination with HE was required for the reaction.…”

Toward Rational Understandings of α-C–H Functionalization: Energetic Studies of Representative Tertiary Amines

“…Because of a high efficiency and atom economy, direct C-H functionalization has become a prevalent strategy for converting readily accessible starting materials into potentially bioactive scaffolds (Blakemore et al, 2018;Qin et al, 2017;Saint-Denis et al, 2018). However, most C-H bonds are comparatively inactive, therefore substrates with a C-H bond at the a-position of some heteroatom-centered entities, such as an N-containing moiety, have attracted much attention, as a consequence of the latent stabilizing effect of the neighboring electron pair on the incipient a-radical or a-cation upon a-C-H bond scission (Campos, 2007;Chen, W. J. et al, 2018;Nakajima et al, 2016;Shi et al, 2012;Zhang et al, 2019). Among this category of Y-C-H (Y = N, O, S, P, etc.)…”