C–N cross-coupling is one of the most valuable and widespread transformations in organic synthesis. Largely dominated by Pd- and Cu-based catalytic systems, it has proven to be a staple transformation for those in both academia and industry. The current study presents the development and mechanistic understanding of an electrochemically driven, Ni-catalyzed method for achieving this reaction of high strategic importance. Through a series of electrochemical, computational, kinetic, and empirical experiments, the key mechanistic features of this reaction have been unraveled, leading to a second generation set of conditions that is applicable to a broad range of aryl halides and amine nucleophiles including complex examples on oligopeptides, medicinally relevant heterocycles, natural products, and sugars. Full disclosure of the current limitations and procedures for both batch and flow scale-ups (100 g) are also described.

The direct union of primary, secondary, and tertiary carboxylic acids with a chiral glyoxylate-derived sulfinimine provides rapid access into a variety of enantiomerically pure α-amino acids (>85 examples). Characterized by operational simplicity, this radical-based reaction enables the modular assembly of exotic α-amino acids, including both unprecedented structures and those of established industrial value. The described method performs well in high-throughput library synthesis, and has already been implemented in three distinct medicinal chemistry campaigns.

In this communication, a new photocatalytic strategy for the addition of alkyl-radical derivatives to N-sulfinimines with complete diastereoselectivity and moderate to good yields is presented. This is the first asymmetric photocatalytic addition to N-sulfinimines under visible light irradiation with smooth conditions and functional group tolerance.Enantiopure sulfinimines, or N-sulfinyl imines, have been used in the asymmetric synthesis of diverse chiral amino derivatives, e.g. a-branched amines, a-and b-amino acids, and a-and b-amino phosphonic acids.1 The N-sulfinyl group is one of the best chiral auxiliaries for imines because the CQN bond is activated for nucleophilic addition, diastereofacial selectivity is provided, and it is easily removable under mild acidic conditions. However, most reactions with N-sulfinimines employ organometallic compounds such as organolithium or Grignard reagents under very restrictive conditions (low temperature and minimal functional group tolerance). In this regard, radical reactions offer a better functional group tolerance under more suitable reaction conditions. However, only a few examples involving radical-mediated intermolecular additions to N-sulfinimines have been reported, 2-4 which are impractical because of the large amount of radical precursors and the use of toxic reagents (Bu 3 SnH). These issues are impeding a simple gateway to valuable chiral amines, and therefore a new straightforward methodology capable of overcoming these limitations is required. On the other hand, visible light photoredox catalysis has received significant attention over the past decade due to its ability to achieve bond constructions that are not possible using established procedures.5 At the same time, photoredox catalysts can also be employed to generate radicals to be used in a diverse range of proven radical strategies. This approach is based on the adeptness transition metal complexes 6 and organic dyes 7 display by engaging in SET processes following photoexcitation with visible light. Numerous photocatalytic examples of racemic radical transformations performed with imines have been published. 8 However, only one asymmetric approach has been disclosed by Ooi and co-workers (Scheme 1a). 9In Ooi's work, the addition of a-alkylamine derivatives to N-sulfonylimines to afford diamine derivatives was described. Nonetheless, no examples of visible light photocatalytic reactions with N-sulfinimines exist to the best of our knowledge. Therefore, our goal is to deliver a novel radical addition to N-sulfinimines, using photocatalysis and visible light irradiation as a viable radical-generating process, and the N-sulfinyl group as a chiral auxiliary to achieve complete stereoselectivity in the synthesis of amine derivatives (Scheme 1b).In order to achieve this goal, we performed an initial study in which the reactivity of the enantiopure N-sulfinimine 1a (R 1 = p-Tol) was tested with different radical donors (see ESI ‡Scheme 1 Previous reaction and present work of this manuscript.