2.2 1,5‐HAT process in HLF reaction.Scheme 2.3 Geometrical factors, polar and enthalpic effects in 1,5‐HAT process.Source: (a) Katohgi et al. [9] and (c) Luo [10].
Polar effects. Nitrogen radicals are reactive intermediates with distinct and different philicities based on their substitution patterns. There are four general classes: (i) iminyl, (ii) amidyl (including carbamoyls, sulfamidyls, and phosphoramidyls), (iii) aminyl, and (iv) aminium radicals (Scheme 2.3b). The philicity and the hybridization of these species change significantly: iminyl radicals [11] are σ‐radicals with ambiphilic character, while all the others are π‐radicals with the amidyls [12] and the aminiums [13] being electrophilic and the aminyls [14] slightly nucleophilic.
Although the 1,5‐HAT process goes via a sterically favorable six‐membered ring transition state, polar effects have a strong interplay in its stabilization [15]. This means that when the innate polarity of the H‐atom matches the one of the nitrogen radical, then a charge transfer stabilization takes place, leading to a more facile 1,5‐HAT process. As an example, the general amidyl radical 9 would undergo selective abstraction from the α‐O‐methylene group rather than the α‐ester one, as transition state 10 enables a better stabilization of polar effects than transition state 11.
Enthalpic effects. The exothermicity, hence the feasibility, of 1,5‐HAT reactions is dictated by the relative energy difference between the sp3 C—H bond broken and the N—H bond formed [16]. In general, N—H bonds have higher bond‐dissociation energy (BDEs) than sp3 C—H bonds, which facilitate 1,5‐HAT reactivities (Scheme 2.3c) [10]. This is particularly evident for the reaction of amidyl and aminium radicals, which lead to the formation of very strong N—H bonds. Iminyl radicals have witnessed a more limited application in radical relay strategies owing to the weaker nature of their corresponding N—H bonds, which makes 1,5‐HAT possible mostly from activated or tertiary sp3 centers. Aminyl radicals are the only class of nitrogen radicals that are not used in these processes owing to their weaker N—H bonds and also to negative polar effects.
2.3 Photoinduced Strategies
2.3.1 Reductive Strategies
2.3.1.1 1,5‐HAT via Iminyl Radicals
Iminyl radicals have been identified as powerful reactive intermediates for a number of reactions such as intramolecular cyclization but also radical ring opening and 1,5‐HAT. In this case, the pioneering work of Forrester [17–20] has clearly demonstrated their ability to partake into radical transposition, but the harsh chemical methods for their generation limited applications in mainstream organic synthesis.
The Leonori group recently reported that iminyl (and amidyl radicals) can be generated upon visible light irradiation from easy‐to‐make O‐aryl oximes [21] via oxidative quenching photoredox cycles and also via the formation of electron donor–acceptor (EDA) complex with tertiary amines [22–24]. These strategies have been adopted by others in the subsequent development of interrupted HLF‐type reactions.
Fu and coworkers described a photochemical intramolecular α‐N sp3 C–H imination based on O‐aryl oximes 12 for the preparation of functionalized imidazoles 13 (Scheme 2.4) [25]. In this case, the authors exploited the known ability of these derivatives to undergo EDA complex formation with a tertiary amine in an intramolecular setting (12). This EDA complex underwent photoinduced single‐electron transfer (SET) and fragmentation across the weak N—O bond to give the iminyl 14. This slightly nucleophilic radical was then able to trigger a polarity‐matched 1,5‐HAT from the α‐N sp3 carbon providing 15. An ionic intramolecular cyclization, followed by aromatization, delivered the desired products 13. This methodology can only be used to assemble five‐membered ring systems and is limited on having an aryl substituent on the oxime. However, the site of 1,5‐HAT could be embedded into a further cyclic system, thus leading to interesting bicyclic structures.
Scheme 2.4 Photochemical intramolecular C(sp3)–H imination of tertiary aliphatic amines containing β‐O‐aryl oximes.
Source: Modified from Li et al. [25].
More recently, Wu and coworkers have demonstrated that similar O‐aryl oximes 16 can also undergo EDA complex formation with 1,4‐diazabicyclo[2.2.2]octane (DABCO)·(SO2)217 and that this can be used for iminyl radical generation upon visible light irradiation (Scheme 2.5) [26]. This step was followed by a 1,5‐HAT process, and the resulting carbon radical was able to intercept SO2 en route to products 18. In this way, a rare example of amino‐sulfonylation of unactivated sp3 C—H bonds was achieved, leading to the assembly of biologically relevant 1,2‐thiazine dioxides.
The ability of iminyl radicals to undergo 1,5‐HAT has been recently employed for the conversion of activated acyclic O‐acyl oximes 19 into a variety of cyclic ketones 20 (Scheme 2.6). In this work, Nevado and coworkers described a redox‐neutral process, where the SET reduction of radical precursor 19 was performed by a visible‐light‐excited Ir(III) photocatalyst [27]. In this case, the authors used O‐acyl oximes that have a reduction potential accessible by many photoexcited catalysts [28]. This SET led to the corresponding iminyl radical 21 that underwent selective 1,5‐HAT. The distal carbon radical 22 was exploited in an intramolecular cyclization onto the (hetero)aromatic substituent. Oxidation of intermediate 23 by the Ir(IV) catalyst gave the imine 24, which, upon hydrolysis, delivered a variety of fused bicyclic ketones in high yields. The six‐membered ring radical cyclization enabled excellent control of relative stereochemistry when substituents were present.
Scheme 2.5 Photoinduced aminosulfonylation of C(sp3)—H bonds with sulfur dioxide.
Source: Modified from Li et al. [26].
Scheme 2.6 Redox neutral remote functionalization of C(sp3)—H bonds via iminyl radicals.
Source: Modified from Shu and Nevado [27].
The direct installation of vinyl groups onto unactivated sp3 C—H bonds is a transformation with powerful applications as the olefin functionality can
