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.
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.
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.
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
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.
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
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.