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.

Enantioselective Synthesis of Secondary ß-Trifluoromethyl Alcohols via Catalytic Asymmetric Reductive Trifluoroalkylation and Diastereoselective Reduction.

Fluorinated motifs are frequently encountered in drugs and agrochemicals. Incorporating fluorine-containing motifs in drug candidates for lead optimization in pharmaceutical research and development has emerged as a powerful tool. The construction of molecules that feature a trifluoromethyl (CF3-) group on a stereogenic carbon has accumulated broad research efforts. Unlike its well-explored, biologically active methyl counterpart, asymmetric construction of ß-trifluoromethylated alcohols bearing adjacent stereocenters still remains elusive. Through retrosynthetic analysis, we posited that followed by sequential reduction of carbonyl, the initial construction of chiral α-trifluoromethylated ketones could render the desired product in a facile, one-pot fashion. Herein, we developed the first example of nickel-catalyzed asymmtric reductive cross-coupling trifluoroalkylation of acyl chlorides for enantioselective synthesis of diverse α-trifluoromethylated ketones. The one-pot reduction of these α-trifluoromethylated ketones furnished corresponding alcohols bearing ß-CF3-substituted stereogenic carbons with excellent diastereoselectivity and complete enantioselective retention. High yields/enantioselectivity, mild conditions, and good functional group compatibility are shown in the system. Utilities of the method are also illustrated by applying asymmetric, late-stage trifluoroalkylation of biologically active complex molecules, revealing tremendous potential for development of CF3-containing chiral drugs.

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.

A General and Efficient Solution to Monofluoroalkylation: Divergent Synthesis of Aliphatic Monofluorides with Modular Synthetic Scaffolds.

Monofluoroalkanes are important in many pharmaceuticals, agrochemicals and functional materials. However, the lack of easily available and transformable monofluoroalkylating reagents that facilitate a broad array of transformations has hampered the application of monofluoroalkylation. Herein, we report a general and efficient method of preparing diverse aliphatic monofluorides with monofluoroalkyl triflate as the synthetic scaffold. Using both nickel-catalyzed hydromonofluoroalkylation of unactivated alkenes and copper-catalyzed C-C bond formation, the general diversification of the monofluoroalkylating scaffold has been exhibited. The broad utility of this monofluoroalkylating reagent is shown by concise conversion into various conventional fluoroalkylating reagents and construction of monofluoro-alkoxy, -alkylamino motifs with commercially available heteroatom-based coupling partners.

Diversity-Oriented Synthesis of Aliphatic Fluorides via Reductive C(sp3 )-C(sp3 ) Cross-Coupling Fluoroalkylation.

Monofluorinated alkyl compounds are of great importance in pharmaceuticals, agrochemicals and materials. Herein, we describe a direct nickel-catalyzed monofluoromethylation of unactivated alkyl halides using a low-cost industrial raw material, bromofluoromethane, by demonstrating a general and efficient reductive cross-coupling of two alkyl halides. Results with 1-bromo-1-fluoroalkane also demonstrate the viability of monofluoroalkylation, which further established the first example of reductive C(sp3 )-C(sp3 ) cross-coupling fluoroalkylation. These transformations demonstrate high efficiency, mild conditions, and excellent functional-group compatibility, especially for a range of pharmaceuticals and biologically active compounds. Mechanistic studies support a radical pathway. Kinetic studies reveal that the reaction is first-order dependent on catalyst and alkyl bromide whereas the generation of monofluoroalkyl radical is not involved in the rate-determining step. This strategy provides a general and efficient method for the synthesis of aliphatic fluorides.

Remote azidation of C(sp3)-H bonds to synthesize δ-azido sulfonamides via iron-catalyzed radical relay.

With an iron catalyst playing dual roles as a radical initiator and terminator, we report a selective remote C-H functionalization to access δ-azido sulfonamides through a radical relay process. The reaction of N-fluorosulfonamide furnishes the corresponding products in excellent yields with high regioselective control. The key to success is the highly efficient iron-mediated redox azido transfer to the in situ generated carbon radical. The products provide incentives for drug discovery and ligand designs.

Nickel-Catalyzed Carbofluoroalkylation of 1,3-Enynes to Access Structurally Diverse Fluoroalkylated Allenes.

A nickel-catalyzed 1,4-carbofluoroalkylation of 1,3-enynes to access structurally diverse fluoroalkylated allenes has been established. This method has demonstrated high catalytic reactivity, mild reaction conditions, broad substrate scope, and excellent functional-group tolerance. The key to success is the use of a nickel catalyst to generate different fluoroalkyl radicals from readily available and structurally diverse fluoroalkyl halides to access 1,4-difunctionalization of 1,3-enynes by a radical relay. This strategy provides facile synthesis of structurally diverse multisubstituted allenes, and offers a solution for batch production of various fluorinated bioactive molecules for drug discovery by further transformations.

The Protective and Immunomodulatory Effects of Fucoidan Against 7,12-Dimethyl benz[a]anthracene-Induced Experimental Mammary Carcinogenesis Through the PD1/PDL1 Signaling Pathway in Rats.

Fucoidan is a sulfated polysaccharide that is extracted from brown algae seaweed. This study was designed to evaluate the protective and immunomodulatory effects of dietary fucoidan on 7,12-dimethyl benz[a]anthracene (DMBA)-induced experimental mammary carcinogenesis in rats. Sixty Sprague-Dawley rats were randomly assigned to four equal groups: the control group (control group), the cancer model group (model group), and the F1 and F2 groups, which were fed fucoidan at concentrations of 200 and 400 mg/kg·body weight, respectively. We found that fucoidan treatment decreased the tumor incidence and mean tumor weight and prolonged the tumor latency. Flow cytometric analyses revealed that the number of blood natural killer cells was higher after fucoidan treatment and that the proportions of CD4 and CD8 T cells were also increased. The serum levels of interleukin (IL)-6, IL-12p40, and interferon (IFN)-γ were higher in the rats treated with fucoidan compared to those of model rats. Moreover, the percentage of CD3+ Foxp3+ regulatory T cells in the blood and the levels of IL-10 and transforming growth factor ß in the serum were lower in the rats treated with fucoidan. Furthermore, fucoidan treatment decreased the expression of Foxp3 and programmed cell death 1 ligand 1 (PDL1) in tumor tissues. The levels of p-phosphatidyl inositol kinase 3 and p-AKT in tumor tissues were also lower than those of model rats. These results suggest that a fucoidan-supplemented diet can inhibit DMBA-induced tumors in rats. This study provides experimental evidence toward elucidating the immune enhancement induced by fucoidan through the programmed cell death 1/PDL1 signaling pathway. The immunomodulatory effect is one of the possible mechanisms of the protective effect of fucoidan against mammary carcinogenesis.

Simple, catalytic C(sp3)-H azidation using the C-H donor as the limiting reagent.

C-N bonds play a critical role in pharmaceutical, agrochemical, and materials sciences, necessitating ever-better methods to forge this linkage. Here we report a simple procedure for direct C(sp3)-H azidation using iron or manganese catalysis and a nucleophilic azide source. All reagents are commercially available, the experimental procedure is simple, and we can use the C-H donor substrate as the limiting reagent, a challenge for many C-H azidation methods. Preliminary experiments are consistent with a hydrogen atom transfer (HAT)/radical ligand transfer (RLT) radical cascade mechanism and a wide variety of substrates can be azidated in moderate to high yields.

Regio- and enantioselective nickel-alkyl catalyzed hydroalkylation of alkynes.

The migratory insertion of metal-hydride into alkene has allowed regioselective access to organometallics, readily participating in subsequent functionalization as one conventional pathway of hydroalkylation, whereas analogous process with feedstock alkyne is drastically less explored. Among few examples, the regioselectivity of metal-hydride insertion is mostly governed by electronic bias of alkynes. To alter the regioselectivity and drastically expand the intermediate pools that we can access, one aspirational design is through alternative nickel-alkyl insertion, providing opposite regioselectivity induced by steric demand. Leveraging in situ formed nickel-alkyl species, we herein report the regio- and enantioselective hydroalkylation of alkynes with broad functional group tolerance, excellent regio- and enantioselectivity, enabling efficient route to diverse valuable chiral allylic amines motifs. Preliminary mechanistic studies indicate the aminoalkyl radical species can participate in metal-capture and lead to formation of nickel-alkyl, of which the migratory insertion is key to reverse regioselectivity observed in metal-hydride insertion.

Remote Functionalization of Inert C(sp3)-H Bonds via Dual Catalysis Driven by Alkene Hydrofluoroalkylation Using Industrial Feedstocks.

We have developed a dual-catalytic system capable of site-selective azidation of inert C(sp3)-H bonds with concomitant and modular anti-Markovnikov alkene fluoroalkylation. The protocol leverages the synergetic cooperation of both the photocatalyst and earth-abundant iron catalyst to deliver two radical species in succession to minimally functionalized alkenes. This powerful catalyst system exhibits broad scope, mild conditions, and excellent regioselectivity for a variety of substrates and fluoroalkyl fragments. The key to this C-centered radical relay is the matched rate of both photocatalytic and iron catalytic cycles, ensuring selective azidofluoroalkylation with a broad array of fluoroalkyl sources from trivial reagents.

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.

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.

Enantioselective catalytic radical decarbonylative azidation and cyanation of aldehydes.

Empowered by the ubiquity of carbonyl functional groups in organic compounds, decarbonylative functionalization was prevalent in the construction of complex molecules. Under this context, asymmetric decarbonylative functionalization has emerged as an efficient pathway to accessing chiral motifs. However, ablation of enantiomeric control in a conventional 2e transition metal-catalyzed process was notable because of harsh conditions (high temperatures, etc.) that are usually required. To address this challenge and use readily accessible aldehyde directly, we report the asymmetric radical decarbonylative azidation and cyanation. Diverse aldehydes were directly used as alkyl radical precursor, engaging in the subsequent inner-sphere or outer-sphere ligand transfer where functional motifs (CN and N3) could be incorporated in excellent site- and enantioselectivity. Mild conditions, broad scope, excellent regioselectivity (driven by polarity-matching strategy), and enantioselectivity were shown for both transformations. This radical decarbonylative strategy using aldehydes as alkyl radical precursor has offered a powerful reaction manifold in asymmetric radical transformations to construct functional motifs regio- and stereoselectively.

Photochemical iron-catalyzed decarboxylative azidation via the merger of ligand-to-metal charge transfer and radical ligand transfer catalysis.

Ligand-to-metal charge transfer (LMCT) using stoichiometric copper salts has recently been shown to permit decarboxylative C-N bond formation via an LMCT/radical polar crossover (RPC) mechanism; however, this method is unable to function catalytically and cannot successfully engage unactivated alkyl carboxylic acids, presenting challenges to the general applicability of this approach. Leveraging the concepts of ligand-to-metal charge transfer (LMCT) and radical-ligand-transfer (RLT), we herein report the first photochemical, iron-catalyzed direct decarboxylative azidation. Simply irradiating an inexpensive iron nitrate catalyst in the presence of azidotrimethylsilane allows for a diverse array of carboxylic acids to be converted to corresponding organic azides directly with broad functional group tolerance and mild conditions. Intriguingly, no additional external oxidant is required for this reaction to proceed, simplifying the reaction protocol. Finally, mechanistic studies are consistent with a radical mechanism and suggest that the nitrate counteranion serves as an internal oxidant for turnover of the iron catalyst.

HAT Lessons Help Hydrogen Hop, Skip, and Jump.

Nagib and Rajanbabu share a clever approach to remote desaturation triggered by metal-catalysed hydrogen atom transfer (mHAT) to an alkene, followed by intramolecular 1,6-HAT, and terminated via mHAT. This method both realizes a valuable synthetic transformation and provides multiple lessons for the design of HAT-mediated reactions.

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.

Asymmetric construction of allylicstereogenic carbon center featuring atrifluoromethyl group via enantioselective reductive fluoroalkylation.

Emerging as a powerful tool for lead optimization in pharmaceutical research and development, to develop the facile, general protocols that allows the incorporation of fluorine-containing motif in drug candidates has accumulated enormous research interest in recent years. Among these important motifs, the incorporation of strategic motif CF3 on aliphatic chain especially with the concomitant construction of trifluoromethylated alkanes bearing a CF3-substituted stereogenic carbon, is of paramount importance. Herein, we disclose an asymmetric nickel-catalyzed reductive trifluoroalkylation of alkenyl halides for enantioselective syntheses of diverse α-trifluoromethylated allylic alkanes, offering a general protocol to access the trifluoromethyl analogue to chiral α-methylated allylic alkanes, one of the most prevalent key components among natural products and pharmaceuticals. Utilities of the method including the application of the asymmetric trifluoroalkylation on multiple biologically active complex molecules, derivatization of transformable alkenyl functionality were demonstrated, providing a facile method in the diversity-oriented syntheses of CF3-containing chiral drugs and bioactive-molecules.

Orexin-B exerts excitatory effects on nigral dopaminergic neurons and alleviates motor disorders in MPTP parkinsonian mice.

The study aimed to investigate the effects of orexin-B in Parkinson's disease. The present study showed that orexin-B exerted marked excitatory effects via orexin-2 receptor on the nigral dopaminergic neurons in MPTP parkinsonian mice, while blocking orexin-2 receptor decreased the firing rate of dopaminergic neurons significantly. Furthermore, intracerebroventricular application of orexin-B relieved the degeneration of dopaminergic neurons, increased the general spontaneous activity and alleviated motor coordination in MPTP parkinsonian mice. The present study suggests that orexin-B could exert protective effects on dopaminergic neurons and improve motor disorders in parkinsonian mice. Such protective effects of orexin-B on Parkinson's disease may be partially attributed to the excitatory effects on the nigral dopaminergic neurons.

Copper-catalyzed monochloromethylazidation to access transformable terminal alkyl chlorides using stoichiometric BrCH2Cl.

Efficient copper-catalyzed 1,2-difunctionalization of alkenes with commercially available BrCH2Cl as a chloromethylating source was carried out, in which mild conditions, high reactivity, excellent functional-group tolerance, and late-stage modification of a bioactive molecule are demonstrated. This strategy offers a solution for the diverse syntheses of nitrogen-containing terminal alkyl chlorides, a common synthetic handle that is promising for multiple derivatizations. Mechanistic studies indicate that a chloromethyl radical is involved in the catalytic cycle.