Photocatalytic, modular difunctionalization of alkenes enabled by ligand-to-metal charge transfer and radical ligand transfer.

Ligand-to-metal charge transfer (LMCT) is a mechanistic strategy that provides a powerful tool to access diverse open-shell species using earth abundant elements and has seen tremendous growth in recent years. However, among many reaction manifolds driven by LMCT reactivity, a general and catalytic protocol for modular difunctionalization of alkenes remains unknown. Leveraging the synergistic cooperation of iron-catalyzed ligand-to-metal charge transfer and radical ligand transfer (RLT), here we report a photocatalytic, modular difunctionalization of alkenes using inexpensive iron salts catalytically to function as both radical initiator and terminator. Additionally, strategic use of a fluorine atom transfer reagent allows for general fluorochlorination of alkenes, providing the first example of interhalogen compound formation using earth abundant element photocatalysis. Broad scope, mild conditions and versatility in converting orthogonal nucleophiles (TMSN3 and NaCl) directly into corresponding open-shell radical species are demonstrated in this study, providing a robust means towards accessing vicinal diazides and homo-/hetero-dihalides motifs catalytically. These functionalities are important precursors/intermediates in medicinal and material chemistry. Preliminary mechanistic studies support the radical nature of these transformations, disclosing the tandem LMCT/RLT as a powerful reaction manifold in catalytic olefin difunctionalization.

Photocatalytic hydrofluoroalkylation of alkenes with carboxylic acids.

Incorporation of fluoroalkyl motifs in pharmaceuticals can enhance the therapeutic profiles of the parent molecules. The hydrofluoroalkylation of alkenes has emerged as a promising route to diverse fluoroalkylated compounds; however, current methods require superstoichiometric oxidants, expensive/oxidative fluoroalkylating reagents and precious metals, and often exhibit limited scope, making a universal protocol that addresses these limitations highly desirable. Here we report the hydrofluoroalkylation of alkenes with cheap, abundant and available fluoroalkyl carboxylic acids as the sole reagents. Hydrotrifluoro-, difluoro-, monofluoro- and perfluoroalkylation are all demonstrated, with broad scope, mild conditions (redox neutral) and potential for late-stage modification of bioactive molecules. Critical to success is overcoming the exceedingly high redox potential of feedstock fluoroalkyl carboxylic acids such as trifluoroacetic acid by leveraging cooperative earth-abundant, inexpensive iron and redox-active thiol catalysis, enabling these reagents to be directly used as hydroperfluoroalkylation donors without pre-activation. Preliminary mechanistic studies support the radical nature of this cooperative process.

Radical ligand transfer: a general strategy for radical functionalization.

The place of alkyl radicals in organic chemistry has changed markedly over the last several decades, evolving from challenging-to-generate "uncontrollable" species prone to side reactions to versatile reactive intermediates enabling construction of myriad C-C and C-X bonds. This maturation of free radical chemistry has been enabled by several advances, including the proliferation of efficient radical generation methods, such as hydrogen atom transfer (HAT), alkene addition, and decarboxylation. At least as important has been innovation in radical functionalization methods, including radical-polar crossover (RPC), enabling these intermediates to be engaged in productive and efficient bond-forming steps. However, direct engagement of alkyl radicals remains challenging. Among these functionalization approaches, a bio-inspired mechanistic paradigm known as radical ligand transfer (RLT) has emerged as a particularly promising and versatile means of forming new bonds catalytically to alkyl radicals. This development has been driven by several key features of RLT catalysis, including the ability to form diverse bonds (including C-X, C-N, and C-S), the use of simple earth abundant element catalysts, and the intrinsic compatibility of this approach with varied radical generation methods, including HAT, radical addition, and decarboxylation. Here, we provide an overview of the evolution of RLT catalysis from initial studies to recent advances and provide a conceptual framework we hope will inspire and enable future work using this versatile elementary step.

Photochemical diazidation of alkenes enabled by ligand-to-metal charge transfer and radical ligand transfer.

Vicinal diamines are privileged synthetic motifs in chemistry due to their prevalence and powerful applications in bioactive molecules, pharmaceuticals, and ligand design for transition metals. With organic diazides being regarded as modular precursors to vicinal diamines, enormous efforts have been devoted to developing efficient strategies to access organic diazide generated from olefins, themselves common feedstock chemicals. However, state-of-the-art methods for alkene diazidation rely on the usage of corrosive and expensive oxidants or complicated electrochemical setups, significantly limiting the substrate tolerance and practicality of these methods on large scale. Toward overcoming these limitations, here we show a photochemical diazidation of alkenes via iron-mediated ligand-to-metal charge transfer (LMCT) and radical ligand transfer (RLT). Leveraging the merger of these two reaction manifolds, we utilize a stable, earth abundant, and inexpensive iron salt to function as both radical initiator and terminator. Mild conditions, broad alkene scope and amenability to continuous-flow chemistry rendering the transformation photocatalytic were demonstrated. Preliminary mechanistic studies support the radical nature of the cooperative process in the photochemical diazidation, revealing this approach to be a powerful means of olefin difunctionalization.

Modular Difunctionalization of Unactivated Alkenes through Bio-Inspired Radical Ligand Transfer Catalysis.

Development of visible light-mediated atom transfer radical addition of haloalkanes onto unsaturated hydrocarbons has seen rapid growth in recent years. However, due to its radical chain propagation mechanism, diverse functionality other than the pre-existing (pseudo-)halide on the alkyl halide source cannot be incorporated into target molecules in a one-step, economic fashion. Inspired by the prominent reactivities shown by cytochrome P450 hydroxylase and non-heme iron-dependent oxygenases, we herein report the first modular, dual catalytic difunctionalization of unactivated alkenes via manganese-catalyzed radical ligand transfer (RLT). This RLT elementary step involves a coordinated nucleophile rebounding to a carbon-centered radical to form a new C-X bond in analogy to the radical rebound step in metalloenzymes. The protocol leverages the synergetic cooperation of both a photocatalyst and earth-abundant manganese complex to deliver two radical species in succession to minimally functionalized alkenes, enabling modular diversification of the radical intermediate by a high-valent manganese species capable of delivering various external nucleophiles. A broad scope (97 examples, including drugs/natural product motifs), mild conditions, and excellent chemoselectivity were shown for a variety of substrates and fluoroalkyl fragments. Mechanistic and kinetics studies provide insights into the radical nature of the dual catalytic transformation and support radical ligand transfer (RLT) as a new strategy to deliver diverse functionality selectively to carbon-centered radicals.