Herein we describe our efforts to elucidate the key mechanistic aspects of the previously reported enantioselective photochemical α-alkylation of aldehydes with electron-poor organic halides. The chemistry exploits the potential of chiral enamines, key organocatalytic intermediates in thermal asymmetric processes, to directly participate in the photoexcitation of substrates either by forming a photoactive electron donor–acceptor complex or by directly reaching an electronically excited state upon light absorption. These photochemical mechanisms generate radicals from closed-shell precursors under mild conditions. At the same time, the ground-state chiral enamines provide effective stereochemical control over the enantioselective radical-trapping process. We use a combination of conventional photophysical investigations, nuclear magnetic resonance spectroscopy, and kinetic studies to gain a better understanding of the factors governing these enantioselective photochemical catalytic processes. Measurements of the quantum yield reveal that a radical chain mechanism is operative, while reaction-profile analysis and rate-order assessment indicate the trapping of the carbon-centered radical by the enamine, to form the carbon–carbon bond, as rate-determining. Our kinetic studies unveil the existence of a delicate interplay between the light-triggered initiation step and the radical chain propagation manifold, both mediated by the chiral enamines.

We report here the first asymmetric catalytic alkylation of unmodified ketones with alkyl halides. This metalfree approach, which requires light in order to proceed, provides a rare example of highly enantioselective photochemical catalytic processes. An easily available cinchona-based primary amine catalyst guides both the stereoselectivity-defining event and, through the transient formation of photon-absorbing chiral electron donor-acceptor complexes, the photo-activation of the substrates.

A metal-free, photochemical strategy for the direct alkylation of indoles was developed. The reaction, which occurs at ambient temperature, is driven by the photochemical activity of electron donor-acceptor (EDA) complexes, generated upon association of substituted 1H-indoles with electron-accepting benzyl and phenacyl bromides. Significant mechanistic insights are provided by the X-ray single-crystal analysis of an EDA complex relevant to the photoalkylation and the determination of the quantum yield (Φ) of the process.

A combination of electrochemical, spectroscopic, computational, and kinetic studies has been used to elucidate the key mechanistic aspects of the previously reported enantioselective iminium ion trapping of photochemically generated carbon-centered radicals. The process, which provides a direct way to forge quaternary stereocenters with high fidelity, relies on the interplay of two distinct catalytic cycles: the aminocatalytic electron-relay system, which triggers the stereoselective radical trap upon iminium ion formation, and the photoredox cycle, which generates radicals under mild conditions. Critical to reaction development was the use of a chiral amine catalyst, bearing a redox-active carbazole unit, which could rapidly reduce the highly reactive and unstable intermediate generated upon radical interception. The carbazole unit, however, is also involved in another step of the electron-relay mechanism: the transiently generated carbazole radical cation acts as an oxidant to return the photocatalyst into the original state. By means of kinetic and spectroscopic studies, we have identified the last redox event as being the turnover-limiting step of the overall process. This mechanistic framework is corroborated by the linear correlation between the reaction rate and the reduction potential of the carbazole unit tethered to the aminocatalyst. The redox properties of the carbazole unit can thus be rationally tuned to improve catalytic activity. This knowledge may open a path for the mechanistically driven design of the next generation of electron-relay catalysts.

The development of an intermolecular and enantioselective aza-Wacker reaction is described. Using indoles as the N-source, a selection of alkenols as the coupling partner enables selective β-hydride elimination towards the alcohol. This strategy preserves the newly formed stereocenter by preventing the formation of traditionally observed enamine products. Allylic and homoallylic alcohols with a variety of functional groups are compatible with the reaction in high enantioselectivity. Isotopic-labeling experiments support a syn amino-palladation mechanism for this new class of aza-Wacker reactions.