Photochemical Iron-Catalyzed Decarboxylative Azidation via the Merger of Ligand-to-Metal Charge Transfer and Radical-Ligand-Transfer Catalysis
Shih-Chieh Kao, Kang-Jie Bian, Xiaowei Chen, Ying Chen, Angel A. Marti, and Julian G. West*
Decarboxylative functionalization is a powerful approach to access diverse products, with ligand-to-metal charge transfer (LMCT) using earth abundant 3d metals emerging as a leading strategy for reaction design. 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 LMCT/RPC 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, earth-abundant iron nitrate catalyst in the presence of a simple nucleophilic azide source allows for a diverse array of carboxylic acids to be converted to corresponding organic azides directly with broad functional group tolerance, mild conditions and high efficiency. Intriguingly, no additional external oxidant is required for this reaction to proceed, simplifying the reaction protocol. 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. Together, we present a simple photocatalytic decarboxylative azidation reaction that reveals iron nitrate as a uniquely privileged species for oxidative LMCT photocatalysis.
Vitamin B12 and Hydrogen Atom Transfer Cooperative Catalysis as a Hydride Nucleophile Mimic in Epoxide Ring Opening
Brian E. Funk, Martin Pauze, Yen-Chu Lu, Austin J. Moser, Gemma Wolf, and Julian G. West*
Epoxide ring opening reactions have long been utilized to furnish alcohol products that are valuable in many subfields of chemistry. Conventionally, epoxide ring opening involves ionic attack by a nucleophile driven by release of strain in the three-membered ring system. While many epoxide opening reactions are known, the hydrogenative opening of epoxides via ionic means remains challenging due to 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, here 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. Notably, this reaction proceeds in wet methanol and uses metallic zinc as the terminal reductant, providing the desired alcohol products under exceptionally mild conditions. Further, our reaction is tolerant of a number of functional and protecting groups that would typically be susceptible to reduction or cleavage by hydrides, and preliminary mechanistic experiments are consistent with a radical process.
Recent advances in base metal-catalyzed cooperative transfer hydrogenation and hydrodeuteration of alkenes
Hai N. Tran and Julian G. West*
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.
Tetrahedron Lett. 2023, Accepted. DOI: 10.1016/j.tetlet.2023.154404 (invited contribution to special issue in Honor of Prof. John Wood)
Photochemical diazidation of alkenes enabled by ligand-to-metal charge transfer and radical ligand transfer
Kang-Jie Bian†, Shih-Chieh Kao†, David Nemoto Jr., Xiaowei Chen, and Julian G. West* († equal contribution)
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.
Chemoselective Decarboxylative Protonation Enabled by Cooperative Earth-Abundant Element Catalysis
Yen-Chu Lu and Julian G. West*
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.
HAT lessons help hydrogen hop, skip, and jump
Sarah R. Buzsaki†, Kang-Jie Bian†, and Julian G. West* († equal contribution)
Nagib, RajanBabu, et al. share a clever approach to remote desaturation triggered by metal-catalyzed 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.
Trends. Chem. 2022, Accepted. DOI:10.1016/j.trechm.2022.09.001 (invited spotlight article)
Ring-Opening Fluorination via C–C Bond Cleavage: An Efficient Approach to Diverse Fluorinated Molecules
Yen-Chu Lu and Julian G. West*
The unique and desirable properties of fluorinated compounds in pharmaceutical, agrochemical, and materials sciences has driven the development of remote fluorination methods. In particular, the C–C cleavage/fluorination of cyclic molecules recently emerged as one of the most reliable approaches, allowing the efficient construction of otherwise inaccessible fluorinated molecules. While serving as a powerful platform, many ring-opening fluorination methods have relied on the use of expensive and/or low atom-economical electrophilic fluorine sources and often require precious metals such as silver or iridium, impeding their general applications in synthesis and 18F radioisotope studies. In this Perspective, we summarize the recent efforts on the C–C deconstructive fluorination methods, including our new approaches to synthesize remotely-fluorinated ketones, followed by future opportinities of this field toward better sustainability and positron emission tomography (PET) compatibility using earth-abundant element catalysts and simple nucleophilic fluoride salts as fluorine sources.
Tetrahedron Chem. 2022, 2, 100020. (invited perspective article)
Modular Difunctionalization of Unactivated Alkenes Through Bio-Inspired Radical Ligand Transfer Catalysis
Kang-Jie Bian, David Nemoto Jr., Shih-Chieh Kao, Yan He, Yan Li, Xi-Sheng Wang,*, Julian G. West*
Development of visible light-mediated atom transfer radical addition (ATRA) 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-existed (pseudo-)halide on the alkyl halide source cannot be incorporated into target molecules in a one-step, economic fashion. Inspired by 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 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. Broad scope (97 examples, including drugs/natural product motifs), mild conditions and excellent chemo-selectivity 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.
Decatungstate-photocatalysed C(sp3)-H azidation
Yen-Chu Lu, Shih-Chieh Kao, and Julian G. West*
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. Interestingly, allylic and benzylic substrates cannot be azidated under these conditions, only forming dimeric products, showing a unique selectivity of this catalyst system, and preliminary mechanistic experiments implicate a radical mechanism proceeding via photo-hydrogen atom transfer (photo-HAT).
C–C Bond Fluorination via Manganese Catalysis
Yen-Chu Lu and Julian G. West*
β- and γ-Fluorinated ketones are a desirable moiety in building blocks for bioactive molecules. Recent progress in installing this functionality has centered around ring-opening carbon-carbon bond cleavage/fluorination of strained cycloalkanols, either using precious silver catalysis or superstoichiometric ceric ammonium nitrate (CAN). Careful study of these methods has allowed us to design and develop a general earth-abundant element catalyzed method for remotely-fluorinated ketone synthesis via C–C bond cleavage. Critically, use of manganese as a catalyst allows for the system to turnover with Selectfluor, permitting low catalyst loadings and high reaction efficiencies. This method allows the efficient synthesis of a wide variety of β- and γ-fluoroketones and is highly scalable, proceeding with no loss of efficiency on gram scale. Preliminary mechanistic experiments implicate a radical pathway. Together, we introduce a robust and simple approach to remote fluorination of ketones using earth abundant element catalysis with wide substrate tolerance and scalability.
Cooperative Hydrogen Atom Transfer: From Theory to Applications
P. Venkatesh Kattamuri and Julian G. West*
Hydrogen atom transfer (HAT) is one of the fundamental transformations of organic chemistry, allowing for the interconversion of open and closed shell species through the concerted movement of a proton an electron. While the value of this transformation is well-appreciated in isolation, allowing for homolytic C–H activation via abstractive HAT and radical reduction via donative HAT, cooperative HAT (cHAT) reactions, where two hydrogen atoms are removed or donated to vicinal reaction centers in succession proceeding through radical intermediates, are comparatively unknown outside of the mechanism of desaturase enzymes. This tandem reaction scheme has important ramifications in the thermochemistry of each HAT, with the bond dissociation energy of the C–H bond adjacent to the radical center being significantly lowered compared to that of the parent alkane, allowing for each HAT to be performed by different species. Here we discuss the thermodynamic basis of this bond strength differential in cHAT and demonstrate its use as a design principle in organic chemistry for both dehydrogenative (application 1) and hydrogenative (application 2) reactions. Together, we hope that this overview will highlight the exciting reactivity possible with cHAT and inspire further development using this mechanistic approach.
A Blueprint For Green Chemists: Lessons from Nature for Sustainable Synthesis
Julian G. West*
The design of new chemical reactions that are convenient, sustainable, and innovative is a preeminent concern for modern synthetic chemistry. While the use of earth abundant element catalysts remains underdeveloped by chemists, nature has developed a cornucopia of powerful transformation using only base metals, demon- strating their viability for sustainable method development. Here we show how study of nature’s approach to disparate chemical problems, from alkene desaturation to photodetection in bacteria, can inspire and enable new approaches to difficult synthetic chemistry problems past, present, and future.
Pure Appl. Chem. 2021, 93, 537–549. (invited issue recognizing winners of the IUPAC–Zhejiang Award for Advancements in Green Chemistry)
Rapid and scalable synthesis of fluoroketones via Cerium-mediated C–C bond cleavage
Yen-Chu Lu, Helen M. Jordan, and Julian G. West*
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
Chem. Commun., 2021, 57, 1871–1874.
Selected for the front cover of ChemComm.
Mild olefin formation via bio-inspired vitamin B12 photocatalysis
Radha Bam, Alexandros S. Pollatos, Austin J. Moser, and Julian G. West*
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.
Highlighted on the Organic Chemistry Portal
Hydrogenation of Alkenes via Cooperative Hydrogen Atom Transfer
P. Venkatesh Kattamuri and Julian G. West*
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.
J. Am. Chem Soc, 2020, 142, 45, 19316–19326.
Highlighted on the Organic Chemistry Portal
Fortune Favors the Well Read
Julian G. West
A contribution to Science's "Working Life" series describing how maintaining a broad knowledge across disciplines is essential to the pursuit of research.
Development of a Bio-Inspired Dual Catalytic System for Alkane Dehydrogenation
Julian G. West* and Erik J. Sorensen*
The alkene is a central functional group in organic synthesis. While myriad reliable methods exist to access this moiety from other functionalities, acceptorless dehydrogenation, or the direct synthesis of alkenes from alkanes with hydrogen gas as the sole byproduct, remains a challenging, albeit highly desirable, transformation. This essay provides an account of our recent efforts toward accessing this difficult reaction class, with particular attention paid to the diverse precedents that informed our explorations. This report highlights the benefits of maintaining a broad range of interests, and we hope that it illustrates the vast connectivity between chemical disciplines.
Toward a mild dehydroformylation using base-metal catalysis
Dylan J. Abrams, Julian G. West, and Erik J. Sorensen*
Dehydroformylation, or the reaction of aldehydes to produce alkenes, hydrogen gas, and carbon monoxide, is a powerful transformation that is underdeveloped despite the high industrial importance of the reverse reaction, hydroformylation. Interestingly, nature routinely performs a related transformation, oxidative dehydroformylation, in the biosynthesis of cholesterol and related sterols under mild conditions using base-metal catalysts. In contrast, chemists have recently developed a non-oxidative dehydroformylation method; however, it requires high temperatures and a precious-metal catalyst. Careful study of both approaches has informed our efforts to design a base-metal catalyzed, mild dehydroformylation method that incorporates benefits from each while avoiding several of their respective disadvantages. Importantly, we show that cooperative base metal catalysis presents a powerful, mechanistically unique approach to reactions which are difficult to achieve using conventional catalyst design.
The Uranyl Cation as a Visible-Light Photocatalyst for C(sp3)−H Fluorination
Julian G. West, T. Aaron Bedell, and Erik J. Sorensen*
The fluorination of unactivated C(sp3)−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.
Design and synthesis of molecular scaffolds with anti-infective activity
Junjia Liu, T. Aaron Bedell, Julian G. West, and Erik J. Sorensen*
The discovery and development of new anti-infectives is an important contemporary challenge to modern society. This challenge must be met with matching creativity and enthusiasm by chemists to avoid losing the battle with emerging strains of drug-resistant microbes. A series of case studies from our lab are presented, demonstrating our continued efforts in the areas of synthetic design, total synthesis of natural products, structure revision, and bioactive scaffold diversification. Together, these are used to highlight the power and utility of chemical synthesis to uniquely address challenges in the discovery and development of novel antibiotic compounds, particularly within the context of natural products scaffolds.
The Diels–Alder Cycloaddition Reaction in the Context of Cascade Processes
Julian G. West and Erik J. Sorensen*
Contributed chapter to the Science of Synthesis Reference Library Collection "Applications of Domino Transformations in Organic Synthesis" edited by Prof. Scott A. Snyder.
The Diels–Alder cycloaddition has been a key component in innumerable, creative domino transformations in organic synthesis. This chapter provides examples of how this [4+2] cycloaddition has been incorporated into the said cascades, with particular attention to its interplay with the other reactions in the sequence. We hope that this review will assist the interested reader to approach the design of novel cascades involving the Diels–Alder reaction
Science of Synthesis, (S.A. Snyder Ed), Georg Thieme Verlag, 2016; pp 1–46.
Acceptorless dehydrogenation of small molecules through cooperative base metal catalysis
Julian G. West, David Huang, and Erik J. Sorensen*
The dehydrogenation of unactivated alkanes is an important transformation both in industrial and biological systems. Recent efforts towards this reaction have revolved around high temperature, organometallic C–H activation by noble metal catalysts that produce alkenes and hydrogen gas as the sole products. Conversely, natural desaturase systems proceed through stepwise hydrogen atom transfer at physiological temperature; however, these transformations require a terminal oxidant. Here we show combining tetra-n-butylammonium decatungstate (TBADT) and cobaloxime pyridine chloride (COPC) can catalytically dehydrogenate unactivated alkanes and alcohols under near-UV irradiation at room temperature with hydrogen as the sole by-product. This noble metal-free process follows a nature-inspired pathway of high- and low-energy hydrogen atom abstractions. The hydrogen evolution ability of cobaloximes is leveraged to render the system catalytic, with cooperative turnover numbers up to 48 and yields up to 83%. Our results demonstrate how cooperative base metal catalysis can achieve transformations previously restricted to precious metal catalysts.
Direct C-F Bond Formation Using Photoredox Catalysis
Montserrat Rueda-Becerril, Olivier Mahé, Myriam Drouin, Marek B. Majewski, Julian G. West, Michael O. Wolf, Glenn M. Sammis,* and Jean-François Paquin*
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 3MLCT (triplet metal-to-ligand charge transfer) state of Ru(bpy)32+ 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.
Photo‐fluorodecarboxylation of 2‐Aryloxy and 2‐Aryl Carboxylic Acids
Joe C.T. Leung, Claire Chatalova-Sazepin, Julian G. West, Montserrat Rueda-Becerril, Jean-François Paquin,* and Glenn M. Sammis*
Coming to light: The title reaction simply requires an aqueous alkaline solution of Selectfluor and light. The method is inexpensive and effective for a wide range of neutral and electron‐poor 2‐aryloxy and 2‐aryl acetic acids to provide fluoromethyl ethers (see scheme) and benzyl fluorides, respectively. The mechanism most likely proceeds through an initial aryl excitation with a subsequent single‐electron transfer.