Fe/Thiol Cooperative Hydrogen Atom Transfer Olefin Hydrogenation: Mechanistic Insights That Inform Enantioselective Catalysis.

Asymmetric hydrogenation of activated olefins using transition metal catalysis is a powerful tool for the synthesis of complex molecules, but traditional metal catalysts have difficulty with enantioselective reduction of electron-neutral, electron-rich, and minimally functionalized olefins. Hydrogenation based on radical, metal-catalyzed hydrogen atom transfer (mHAT) mechanisms offers an outstanding opportunity to overcome these difficulties, enabling the mild reduction of these challenging olefins with selectivity that is complementary to traditional hydrogenations with H2. Further, mHAT presents an opportunity for asymmetric induction through cooperative hydrogen atom transfer (cHAT) using chiral thiols. Here, we report insights from a mechanistic study of an iron-catalyzed achiral cHAT reaction and leverage these insights to deliver stereocontrol from chiral thiols. Kinetic analysis and variation of silane structure point to the transfer of hydride from silane to iron as the likely rate-limiting step. The data indicate that the selectivity-determining step is quenching of the alkyl radical by thiol, which becomes a more potent H atom donor when coordinated to iron(II). The resulting iron(III)-thiolate complex is in equilibrium with other iron species, including FeII(acac)2, which is shown to be the predominant off-cycle species. The enantiodetermining nature of the thiol trapping step enables enantioselective net hydrogenation of olefins through cHAT using a commercially available glucose-derived thiol catalyst with up to 80:20 enantiomeric ratio. To the best of our knowledge, this is the first demonstration of asymmetric hydrogenation via iron-catalyzed mHAT. These findings advance our understanding of cooperative radical catalysis and act as a proof of principle for the development of enantioselective iron-catalyzed mHAT reactions.

RECENT ADVANCES IN BASE METAL-CATALYZED COOPERATIVE TRANSFER HYDROGENATION AND HYDRODEUTERATION OF ALKENES.

Catalytic alkene hydrogenation is a powerful method that has been widely used in the syntheses of valuable products ranging from commodity chemicals to pharmaceuticals. Hydrogenation has also been a key strategy for selectively introducing heavy hydrogen isotopes to small molecules, a key strategy for metabolism studies and even the synthesis of "heavy drugs," where the hydrogen isotope is a key element of the active pharmaceutical ingredient. Traditional hydrogenations with pressurized H2 gas are atom economic but often require complex reaction setups or expensive metal catalysts. Further, use of diatomic hydrogen necessarily limits the ability to incorporate different hydrogen isotopes at each alkene position, with H2, D2, and T2 each resulting in compete labeling of the alkene. In response to these challenges, a recent and growing movement has sought to develop transfer hydrogenation methods using non-H2 hydrogen sources and earth abundant element catalysts to simplify reaction operation. Excitingly, recent developments have delivered transfer hydrogenations that proceed using cooperative hydrogen donor reagents, permitting the controllable incorporation of different hydrogen isotopes at each position of the alkene via reagent control. In this Digest, we disclose recent advances in Earth-abundant metal-catalyzed cooperative transfer hydrogenation of alkenes with various combinations of two distinct transfer hydrogen reagents as non-H2 hydrogen sources.

Chemoselective Decarboxylative Protonation Enabled by Cooperative Earth-Abundant Element Catalysis.

Decarboxylative protonation is a general deletion tactic to replace polar carboxylic acid groups with hydrogen or its isotope. Current methods rely on the pre-activation of acids, non-sustainable hydrogen sources, and/or expensive/highly oxidizing photocatalysts, presenting challenges to their wide adoption. Here we show that a cooperative iron/thiol catalyst system can readily achieve this transformation, hydrodecarboxylating a wide range of activated and unactivated carboxylic acids and overcoming scope limitations in previous direct methods. The reaction is readily scaled in batch configuration and can be directly performed in deuterated solvent to afford high yields of d-incorporated products with excellent isotope incorporation efficiency; characteristics not attainable in previous photocatalyzed approaches. Preliminary mechanistic studies indicate a radical mechanism and kinetic results of unactivated acids (KIE=1) are consistent with a light-limited reaction.

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.

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.

Hydrogenation of Alkenes via Cooperative Hydrogen Atom Transfer.

Radical hydrogenation via hydrogen atom transfer (HAT) to alkenes is an increasingly important transformation for the formation of thermodynamic alkane isomers. Current single-catalyst methods require stoichiometric oxidant in addition to hydride (H-) source to function. Here we report a new approach to radical hydrogenation: cooperative hydrogen atom transfer (cHAT), where each hydrogen atom donated to the alkene arrives from a different catalyst. Further, these hydrogen atom (H•) equivalents are generated from complementary hydrogen atom precursors, with each alkane requiring one hydride (H-) and one proton (H+) equivalent and no added oxidants. Preliminary mechanistic study supports this reaction manifold and shows the intersection of metal-catalyzed HAT and thiol radical trapping HAT catalytic cycles to be essential for effective catalysis. Together, this unique catalyst system allows us to reduce a variety of unactivated alkene substrates to their respective alkanes in high yields and diastereoselectivities and introduces a new approach to radical hydrogenation.

The Uranyl Cation as a Visible-Light Photocatalyst for C(sp(3) )-H Fluorination.

The fluorination of unactivated C(sp(3) )-H bonds remains a desirable and challenging transformation for pharmaceutical, agricultural, and materials scientists. Previous methods for this transformation have used bench-stable fluorine atom sources; however, many still rely on the use of UV-active photocatalysts for the requisite high-energy hydrogen atom abstraction event. Uranyl nitrate hexahydrate is described as a convenient, hydrogen atom abstraction catalyst that can mediate fluorinations of certain alkanes upon activation with visible light.

Direct C-F bond formation using photoredox catalysis.

We have developed the first example of a photoredox catalytic method for the formation of carbon-fluorine (C-F) bonds. The mechanism has been studied using transient absorption spectroscopy and involves a key single-electron transfer from the (3)MLCT (triplet metal-to-ligand charge transfer) state of Ru(bpy)3(2+) to Selectfluor. Not only does this represent a new reaction for photoredox catalysis, but the mild reaction conditions and use of visible light also make it a practical improvement over previously developed UV-mediated decarboxylative fluorinations.

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.

Vitamin B12 and hydrogen atom transfer cooperative catalysis as a hydride nucleophile mimic in epoxide ring opening.

Epoxide ring-opening reactions have long been utilized to furnish alcohol products that are valuable in many subfields of chemistry. While many epoxide-opening reactions are known, the hydrogenative opening of epoxides via ionic means remains challenging because of harsh conditions and reactive hydride nucleophiles. Recent progress has shown that radical chemistry can achieve hydrogenative epoxide ring opening under relatively mild conditions; however, these methods invariably require oxophilic metal catalysts and sensitive reagents. In response to these challenges, we report a new approach to epoxide ring-opening hydrogenation using bio-inspired Earth-abundant vitamin B12 and thiol-centric hydrogen atom transfer (HAT) co-catalysis to produce Markovnikov alcohols under visible light irradiation. This powerful reaction system exhibits a broad substrate scope, including a number of electrophilic and reductively labile functionalities that would otherwise be susceptible to reduction or cleavage by hydride nucleophiles, and preliminary mechanistic experiments are consistent with a radical process.

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.

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.

Decatungstate-photocatalysed C(sp3)-H azidation.

C-H Azidation is an increasingly important tool for bioconjugation, materials chemistry, and the synthesis of nitrogen-containing natural products. While several approaches have been developed, these often require exotic and energetic reagents, expensive photocatalysts, or both. Here we report a simple and general C-H azidation reaction using earth-abundant tetra-n-butylammonium decatungstate as a photocatalyst and commercial p-acetamidobenzenesulfonyl azide (p-ABSA) as the azide source. This system can azidate a variety of unactivated C(sp3)-H bonds in moderate to good yields and excellent turnover numbers. Preliminary mechanistic experiments implicate a radical mechanism proceeding VIA photo-hydrogen atom transfer (photo-HAT).

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.

Rapid and scalable synthesis of fluoroketones via cerium-mediated C-C bond cleavage.

Ketones with remote fluorination are an important motif in the synthesis of bioactive molecules. Here we demonstrate that ceric ammonium nitrate (CAN) is able to produce this functionality under incredibly mild conditions and short reaction times (30 min) while eliminating the need for precious metals in previous methods. Importantly, this method allows the efficient synthesis of a wide variety of γ-fluoroketones and is highly scalable. Preliminary mechanistic studies suggest this reaction proceeds through a radical pathway.

Mild olefin formation via bio-inspired vitamin B12 photocatalysis.

Dehydrohalogenation, or elimination of hydrogen-halide equivalents, remains one of the simplest methods for the installation of the biologically-important olefin functionality. However, this transformation often requires harsh, strongly-basic conditions, rare noble metals, or both, limiting its applicability in the synthesis of complex molecules. Nature has pursued a complementary approach in the novel vitamin B12-dependent photoreceptor CarH, where photolysis of a cobalt-carbon bond leads to selective olefin formation under mild, physiologically-relevant conditions. Herein we report a light-driven B12-based catalytic system that leverages this reactivity to convert alkyl electrophiles to olefins under incredibly mild conditions using only earth abundant elements. Further, this process exhibits a high level of regioselectivity, producing terminal olefins in moderate to excellent yield and exceptional selectivity. Finally, we are able to access a hitherto-unknown transformation, remote elimination, using two cobalt catalysts in tandem to produce subterminal olefins with excellent regioselectivity. Together, we show vitamin B12 to be a powerful platform for developing mild olefin-forming reactions.