The construction and manipulation of amine-containing architectures is of importance to academic and industrial development and discovery programs. The photochemical single-electron reduction of imine derivatives to generate α-amino radical intermediates has emerged as a powerful umpolung strategy for opening up underexplored routes to such amine motifs. Furthermore, these radicals have been shown to engage in a wide variety of chemistry, including radical–radical coupling, addition to electrophiles, and reductive amination chemistry. The concept has also begun to see application to iminium ion intermediates and the extension to enantiocontrolled C–C bond formation. This Perspective covers recent efforts in this synthetic strategy to simple and complex amine structures alike.

A visible-light-mediated photocatalytic umpolung synthesis of 1,3-diamines from in situ-generated imines and dehydroalanine derivatives is described. Pivoting on a key nucleophilic addition of photocatalytically generated α-amino radicals to electron-deficient alkenes, this three-component coupling reaction affords 1,3-diamines efficiently and diastereoselectively. The mild protocol tolerates a wide variety of functionalities including heterocycles, pinacol boronates, and aliphatic chains. Application to biologically relevant α-amino-γ-lactam synthesis and extension to 1,3-aminoalcohols is also demonstrated.

The photocatalytic construction of C(sp 3)-rich α-tertiary dialkyl ethers through the reductive αfunctionalization of alkyl enol ether substrates with conjugated alkenes in the presence of a Hantzsch ester terminal reductant under blue LED irradiation, is described. Pivoting on oxocarbenium ion generation via an initial TMSClfacilitated protic activation of the enol ether substrate, subsequent single electron transfer delivers the key nucleophilic αoxy tertiary radical capable of productively combining with a variety of alkene substrates. The new reductive functionalization strategy was simple to perform, efficient, broad in scope with respect to both alkene acceptor and enol ether donor fragments and delivered a wide range of complex α-tertiary dialkyl ether architectures. Scheme 4. Proposed mechanism for the photocatalytic α-functionalization of enol ethers Single electron transfer from the iridium(II) species (E°1/2 =-1.37 V) to the oxocarbenium ion (E°1/2 (calc) =-1.12 V) gives rise to the nucleophilic α-oxy radical 31 which then undergoes Giese-type addition with the conjugated alkene to produce the γ-amino radical. Subsequent intramolecular HAT and then intermolecular HAT permits termination, delivering the α-tertiary dialkyl ether 3a. This HAT can take place from either HE radical cation (shown, Scheme 4, right), or HEH•, rendering either HP+ or HE radical cation as the potential respective proton sources for the corresponding mechanisms (see ESI for more details). Aligned to previous investigations, the pathway shown is most likely in operation. 32 In conclusion, a mild photocatalytic reductive αfunctionalization of alkyl enol ethers has been developed. Through Lewis acid-assisted protic activation of the enol ether to generate the corresponding oxocarbenium ion and subsequent single electron reduction, we have identified a new approach to access the α-oxy dialkyl radical. This reactive intermediate was shown to engage in Giesetype coupling reactions with a wide range of alkene substrates to deliver 33 examples of α-tertiary dialkyl ether architectures. Work to understand the source of the acidity and applying this concept to further reaction systems is currently underway.

A general photocatalytic reductive strategy for the construction of unsymmetrical α-tertiary dialkyl ethers is reported. By merging Lewis acid-mediated ketal activation and visible-light photocatalytic reduction, in situ generated α-alkoxy radicals can engage in addition reactions with a variety of olefinic partners. Good reaction efficiency is demonstrated with a range of ketals of aromatic and aliphatic ketones. Extension to acetal substrates is also described, demonstrating the overall synthetic utility of this methodology for complex ether synthesis.