Photocatalytic Vicinal Aminopyridylation of Methyl Ketones by a Double Umpolung Strategy

Abstract

A photocatalytic double umpolung strategy for the vicinal aminopyridylation of ketones was developed using pyridinium N−N ylides. The inversion of the polarity of the pyridinium N−N ylides by single‐electron oxidation successfully enables radical‐mediated 1,3‐dipolar cycloadditions with enolsilanes formed in situ from ketones, followed by homolytic cleavage of the N−N bond. Intriguingly, the nucleophilic amino and electrophilic pyridyl groups in the ylides can be installed at the nucleophilic α‐position and electrophilic carbonyl carbon, respectively, which are typically inaccessible by their innate polarity‐driven reactivity. This method accommodates a broad scope, and the utility was further demonstrated by the late‐stage functionalization of complex biorelevant molecules. Moreover, the strategy can be successfully applied to enamides.

N-Functionalized Pyridinium Salts: A New Chapter for Site-Selective Pyridine C–H Functionalization via Radical-Based Processes under Visible Light Irradiation

“…A similar strategy using N-aminopyridinium ylides 73 was applicable to the aminopyridylation of ketones through an umpolung approach (Figure 14b). 44 In this mechanism, as Naminopyridinium ylide 73 is oxidized by a photocatalyst, radical intermediate 75 undergoes radical addition to in-situgenerated enol silane. The resulting α-silyloxy carbon radical is rapidly intercepted intramolecularly at the C2 position to form a five-membered cycloadduct.…”

Divergent reactivity of sulfinates with pyridinium salts based on one-versustwo-electron pathways

“… 14,15 We envisioned that sulfinates could also serve as a new type of electron-donor for delivering such a radical-based reactivity with N -activated pyridinium salts. 16,17 Combined with an alkene moiety, the generated sulfonyl radicals could be embraced in the three-component assembly process 18 without the need of external photocatalysts and oxidants, which is preferable from the viewpoint of green chemistry. If successful, such a modular approach would enable the net addition of pyridyl and sulfonyl moieties across double bonds and further expand the synthetic horizon of sulfinates ( Scheme 1b , top).…”

Site-Selective, Photocatalytic Vinylogous Amidation of Enones

“…Significant advances have been made in the field of photoredox catalysis, and a great deal of effort has been spent on expanding the utility of radicals in organic synthesis. − In vinylogous transformations, substrates that bear a leaving group at the functionalized position have been mainly utilized. , However, despite the broad application of nitrogen-centered radicals in synthetic chemistry, − their reactivity in vinylogous reactions has rarely been explored. ,− We have recently reported that electrophilic nitrogen-centered radicals generated from N -aminopyridinium salts are trapped by enol equivalents to give α-amido carbonyl compounds in excellent yields . On the basis of the vinylogy principle, we hypothesized that photocatalytic amidation at the γ-position of the enone system with electrophilic amidyl radicals should also be feasible.…”

“… 29 , 30 However, despite the broad application of nitrogen-centered radicals in synthetic chemistry, 42 − 46 their reactivity in vinylogous reactions has rarely been explored. 44 , 46 − 49 We have recently reported that electrophilic nitrogen-centered radicals generated from N -aminopyridinium salts are trapped by enol equivalents to give α-amido carbonyl compounds in excellent yields. 50 On the basis of the vinylogy principle, we hypothesized that photocatalytic amidation at the γ-position of the enone system with electrophilic amidyl radicals should also be feasible.…”