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Molecular Ring Remodeling through C-C Bond Cleavage
Single-carbon-atom transfer reactions offer a powerful strategy for constructing complex molecular architectures by sequential assembly of substituents around the atomic carbon core. However, the limited availability of atomic carbon sources has significantly hindered progress in this field. Herein, we demonstrate a single-carbon atom transfer reaction utilizing commercially available TMSCF2Br as an atomic carbon equivalent. Through a cascade of 1,6-addition and TBAF-catalyzed intramolecular cyclization with para-quinone methides (p-QMs), gem-difluorinated spiro[2.5]octa-4,7-dien-6-ones were efficiently formed. These spirocyclic intermediates exhibit remarkable electrophilicity, enabling stereoselective capture of diverse nucleophiles to access fluorinated alkenes with excellent stereocontrol. The resulting fluoroalkenes serve as versatile platforms for constructing tetrasubstituted alkenes via nucleophilic vinylic substitution (SNV), achieving excellent stereoselectivities. In the presence of a 1,3-bisnucleophile, for example a C2-substituted acetoacetate ester, cyclic 2-methylene-2,3-dihydrofuran was generated via a sequential SNV reaction with excellent stereoselectivities. Moreover, a computational study and a control experiment provide insight into the mechanism of the reaction.
Skeletal editing of aromatic heterocycles represents a straightforward approach to rapidly expand the accessible chemical space. While notable progress has been made on the direct modification of various nitrogen‐ and oxygen‐heterocycles, editing of prevalent sulfur‐containing heteroarenes, especially for single‐atom insertion, remains exceedingly rare. This disparity is primarily attributed to the sulfur atom's inherent nucleophilicity and high susceptibility to oxidation. Here we present a conceptually distinct photocatalytic strategy that enables the insertion of a boron atom into a diverse range of thiaarenes, furnishing previously inaccessible cyclic thioborane scaffolds and synthetically valuable alkyl boronates in an efficient manner. Furthermore, mechanistic studies have revealed that the boron insertion step proceeds through an unprecedented mechanism.
Skeletal editing of aromatic heterocycles represents a straightforward approach to rapidly expand the accessible chemical space. While notable progress has been made on the direct modification of various nitrogen‐ and oxygen‐heterocycles, editing of prevalent sulfur‐containing heteroarenes, especially for single‐atom insertion, remains exceedingly rare. This disparity is primarily attributed to the sulfur atom's inherent nucleophilicity and high susceptibility to oxidation. Here we present a conceptually distinct photocatalytic strategy that enables the insertion of a boron atom into a diverse range of thiaarenes, furnishing previously inaccessible cyclic thioborane scaffolds and synthetically valuable alkyl boronates in an efficient manner. Furthermore, mechanistic studies have revealed that the boron insertion step proceeds through an unprecedented mechanism.
Aromatic compounds are used across chemistry and materials science as a result of their stability, characteristic interactions, defined molecular shape and the numerous approaches for their synthesis by a diversity of cyclization reactions¹. By contrast, the cleavage of inert aromatic carbon–carbon bonds remained largely unfeasible owing to the unfavourable energetics of disrupting aromaticity on ring opening. For non-aromatic structures, alkene metathesis catalysed by transition-metal alkylidenes is established as one of the most versatile carbon–carbon bond-forming and -breaking reactions2,3. However, despite remarkable advancements, strategies to open aromatic compounds by metathesis remain elusive⁴. Here we report aromatic ring-opening metathesis (ArROM) for the cleavage of aromatic rings, including tetraphene, naphthalene, indole, benzofuran and phenanthrenes, by using Schrock–Hoveyda molybdenum catalysts. The reactions for each ring system proceed through unique alkylidene intermediates. We further show the possibility for stereoselective ArROM with exquisite catalyst control over the configuration of atropisomers. ArROM is, therefore, a viable and efficient approach to catalytically transform and interconvert various aromatics without the requirement for any reagents or photoexcitation.
Skeletal editing of single-atom insertion to basic chemicals has been demonstrated as an efficient strategy for the discovery of structurally diversified compounds. Previous endeavors in skeletal editing have successfully facilitated the insertion of boron, nitrogen, and carbon atoms. Given the prevalence of oxygen atoms in biologically active molecules, the direct oxygenation of C-C bonds through single-oxygen-atom insertion like Baeyer-Villiger reaction is of particular significance. Herein, we present an approach for the skeletal modification of styrenes using O2 via oxygen insertion, resulting in the formation of aryl ether frameworks under mild reaction conditions. The broad functional-group tolerance and the excellent chemo- and regioselectivity are demonstrated in this protocol. A preliminary mechanistic study indicates the potential involvement of 1,2-aryl radical migration in this reaction.
Alkenes are broadly used in synthetic applications, thanks to their abundance and versatility. Ozonolysis is one of the most canonical transformations that converts alkenes into molecules bearing carbon–oxygen motifs via C=C bond cleavage. Despite its extensive use in both industrial and laboratory settings, the aza version—cleavage of alkenes to form carbon–nitrogen bonds—remains elusive. Here we report the conversion of alkenes into valuable amines via complete C=C bond disconnection. This process, which we have termed ‘triazenolysis’, is initiated by a (3 + 2) cycloaddition of triazadienium cation to an alkene. The triazolinium salt formed accepts hydride from borohydride anion and spontaneously decomposes to create new C–N motifs upon further reduction. The developed reaction is applicable to a broad range of cyclic alkenes to produce diamines, while various acyclic C=C bonds may be broken to generate two separate amine units. Computational analysis provides insights into the mechanism, including identification of the key step and elucidating the significance of Lewis acid catalysis.
Hypervalent iodine reagents are versatile and readily accessible reagents that have been extensively applied in contemporary synthesis in modern organic chemistry. Among them, iodonitrene (ArI=NR), is a powerful reactive species, widely used for a single‐nitrogen‐atom insertion reaction, and skeletal editing to construct N‐heterocycles. Skeletal editing with reactive iodonitrene components has recently emerged as an exciting approach in modern chemical transformation. These reagents have been extensively used to produce biologically relevant heterocycles and functionalized molecular architectures. Recently, the insertion of a nitrogen‐atom into hydrocarbons to generate N‐heterocyclic compounds using hypervalent iodine reagents has been a significant focus in the field of molecular editing reactions. In this review, we discuss the rapidly emerging field of nitrene insertion, including skeletal editing and nitrogen insertion, using hypervalent iodine reagents to access nitrogen‐containing heterocycles, and the current mechanistic understanding of these processes.
Molecular structure-editing through nitrogen insertion offers more efficient and ingenious pathways for the synthesis of nitrogen-containing compounds, which could benefit the development of synthetic chemistry, pharmaceutical research, and materials science. Substituted amines, especially nitrogen-containing alkyl heterocyclic compounds, are widely found in nature products and drugs. Generally, accessing these compounds requires multiple steps, which could result in low efficiency. In this work, a molecular editing strategy is used to realize the synthesis of nitrogen-containing compounds using aryl alkanes as starting materials. Using derivatives of O-tosylhydroxylamine as the nitrogen source, this method enables precise nitrogen insertion into the Csp²-Csp³ bond of aryl alkanes. Notably, further synthetic applications demonstrate that this method could be used to prepare bioactive molecules with good efficiency and modify the molecular skeleton of drugs. Furthermore, a plausible reaction mechanism involving the transformation of carbocation and imine intermediates has been proposed based on the results of control experiments.
Comprehensive Summary
Nitrenes, as neutral monovalent nitrogen‐centered molecular species, can insert into various bond or remove nitrogen atoms from amines. Nitrene assisted single‐atom skeletal editing, discovered decades ago, provides an efficient approach for the precise alteration of cyclic skeletons. In this review, we briefly summarize early studies on skeletal editing of cyclic frameworks involving nitrene species, and introduce several recent important advances systematically.
The molecular structure‐editing through selective C−C bond cleavage allows for the precise modification of molecular structures and opens up new possibilities in chemical synthesis. By strategically cleaving C−C bonds and editing the molecular structure, more efficient and versatile pathways for the synthesis of complex compounds could be designed, which brings significant implications for drug development and materials science. o‐Aminophenethyl alcohols and amines are the essential key motifs in bioactive and functional material molecules. The traditional synthesis of these compounds usually requires multiple steps which could generate inseparable isomers and induce low efficiencies. By leveraging a molecular editing strategy, we herein reported a selective ring‐opening amination of isochromans and tetrahydroisoquinolines for the efficient synthesis of o‐aminophenethyl alcohols and amines. This innovative chemistry allows for the precise cleavage of C−C bonds under mild transition metal‐free conditions. Notably, further synthetic application demonstrated that our method could provide an efficient approach to essential components of diverse bioactive molecules.
The achievement of directly activating and utilizing bulk small molecules has remained a longstanding objective in the field of chemical synthesis. The present work reports a catalytic activation method for bulk chemical nitromethane (MeNO2). This method combines homogeneous Lewis acid with recyclable heterogeneous Brønsted acid catalysis, featuring practicality, sustainability, and low cost, thus solving the inherent drawbacks of previous Nef processes where stoichiometric reductants or activators were required. By combining the advantages of both homo‐ and heterogeneous catalysts, this chemistry may not only offer new opportunities for the further development of MeNO2 as a nitrogen source for organic synthesis, but also promote the catalysis design in synthetic chemistry.
When searching for the ideal molecule to fill a particular functional role (for example, a medicine), the difference between success and failure can often come down to a single atom¹. Replacing an aromatic carbon atom with a nitrogen atom would be enabling in the discovery of potential medicines², but only indirect means exist to make such C-to-N transmutations, typically by parallel synthesis³. Here, we report a transformation that enables the direct conversion of a heteroaromatic carbon atom into a nitrogen atom, turning quinolines into quinazolines. Oxidative restructuring of the parent azaarene gives a ring-opened intermediate bearing electrophilic sites primed for ring reclosure and expulsion of a carbon-based leaving group. Such a ‘sticky end’ approach subverts existing atom insertion–deletion approaches and as a result avoids skeleton-rotation and substituent-perturbation pitfalls common in stepwise skeletal editing. We show a broad scope of quinolines and related azaarenes, all of which can be converted into the corresponding quinazolines by replacement of the C3 carbon with a nitrogen atom. Mechanistic experiments support the critical role of the activated intermediate and indicate a more general strategy for the development of C-to-N transmutation reactions.
Nitrogen scanning in aryl fragments is a valuable aspect of the drug discovery process, but current strategies require time-intensive, parallel, bottom-up synthesis of each pyridyl isomer because of a lack of direct carbon-to-nitrogen (C-to-N) replacement reactions. We report a site-directable aryl C-to-N replacement reaction allowing unified access to various pyridine isomers through a nitrene-internalization process. In a two-step, one-pot procedure, aryl azides are first photochemically converted to 3 H -azepines, which then undergo an oxidatively triggered C2-selective cheletropic carbon extrusion through a spirocyclic azanorcaradiene intermediate to afford the pyridine products. Because the ipso carbon of the aryl nitrene is excised from the molecule, the reaction proceeds regioselectively without perturbation of the remainder of the substrate. Applications are demonstrated in the abbreviated synthesis of a pyridyl derivative of estrone, as well as in a prototypical nitrogen scan.
The Baeyer-Villiger oxidation represents a valuable reaction that enables the conversion of ketones into esters or lactones. Here, we present a novel and efficient approach utilizing I2 as a catalyst...
Hetero)arenes continue to prove their indispensability in pharmaceuticals, materials science, and synthetic chemistry. As such, the controllable modification of biologically significant (hetero)arenes towards diverse more‐potent complex molecular scaffolds through peripheral and skeletal editing has been considered a challenging goal in synthetic organic chemistry. Despite many excellent reviews on peripheral editing (i. e., C−H functionalization) of (hetero)arenes, their skeletal editings via single atom insertion, deletion, or transmutations have received less attention in the review literature. In this review, we systematically summarize the state‐of‐the‐art skeletal editing reactions of (hetero)arenes using carbenes, with a focus on general mechanistic considerations and their applications in natural product syntheses. The potential opportunities and inherent challenges encountered while developing these strategies are also highlighted.
Skeletal editing involves making specific point‐changes to the core of a molecule through the selective insertion, deletion or exchange of atoms. It thus represents a potentially powerful strategy for the step‐economic modification of complex substrates and is a perfect complement to methods such as C−H functionalization that target the molecular periphery. Given their ubiquity in biologically active compounds, the ability to perform skeletal editing on – and therefore interconvert between – aromatic heterocycles is especially valuable. This review summarizes both recent and key historical examples of skeletal editing as applied to interconversion of aromatic rings; we anticipate that it will serve to highlight not only the innovative and enabling nature of current skeletal editing methods, but also the tremendous opportunities that still exist in the field.
In contrast to ketones and carboxylic esters, amides are classically seen as comparatively unreactive members of the carbonyl family, owing to their unique structural and electronic features. However, recent decades have seen the emergence of research programmes focused on the selective activation of amides under mild conditions. In the past four years, this area has continued to rapidly develop, with new advances coming in at a fast pace. Several novel activation strategies have been demonstrated as effective tools for selective amide activation, enabling transformations that are at once synthetically useful and mechanistically intriguing. This Minireview comprises recent advances in the field, highlighting new trends and breakthroughs in what could be called a new age of amide activation.
The oxidative cleavage of alkenes is an integral process that converts feedstock materials into high-value synthetic intermediates1,2,3. The most viable method to achieve this in one chemical step is with ozone4,5,6,7, which however poses technical and safety challenges owing to the explosive nature of ozonolysis products8,9. Herein, we disclose an alternative approach to achieve oxidative cleavage of alkenes using nitroarenes and purple light irradiation. We demonstrate that photoexcited nitroarenes are effective ozone surrogates that undergo facile radical [3+2] cycloaddition with alkenes. The resulting “N-doped” ozonides are safe to handle and lead to the corresponding carbonyl products under mild hydrolytic conditions. These features have enabled the controlled cleavage of all types of alkenes in the presence of a broad array of commonly used organic functionalities. Furthermore, by harnessing electronic, steric, and mediated polar effects, the structural and functional diversity of nitroarenes has provided a modular platform to obtain site-selectivity in substrates containing more than one alkene.
Electrophilic aminating reagents have seen a renaissance in recent years as effective nitrogen sources for the synthesis of unprotected amino functionalities. Based on their reactivity, several noble and non-noble transition metal catalysed amination reactions have been developed. These include the aziridination and difunctionalisation of alkenes, the amination of arenes as well as the synthesis of aminated sulfur compounds. In particular, the use of hydroxylamine-derived (N-O) reagents, such as PONT (PivONH3OTf), has enabled the introduction of unprotected amino groups on various different feedstock compounds, such as alkenes, arenes and thiols. This strategy obviates undesired protecting-group manipulations and thus improves step efficiency and atom economy. Overall, this feature article gives a recent update on several reactions that have been unlocked by employing versatile hydroxylamine-derived aminating reagents, which facilitate the generation of unprotected primary, secondary and tertiary amino groups.
Main observation and conclusion
Amines are among the most fundamental motifs in chemical synthesis, and the introduction of amine building blocks via selective C—C bond cleavage allows the construction of nitrogen compounds from simple hydrocarbons through direct skeleton modification. Herein, we report a novel method for the preparation of anilines from alkylarenes via Schmidt‐type rearrangement using redox‐active amination reagents, which are easily prepared from hydroxylamine. Primary amines and secondary amines were prepared from corresponding alkylarenes or benzyl alcohols under mild conditions. Good compatibility and valuable applications of the transformation were also displayed.
Synthetic chemistry is built around the formation of carbon-carbon bonds. Conversely, selective methods for C-C bond cleavage is a largely unmet challenge1-6, the solution of which will provide promising applications in synthesis, coal liquefaction, petroleum cracking, polymer degradation and biomass conversion. For example, aromatic rings are ubiquitous skeletal features in inert chemical feed stocks, but are inert to many reaction conditions owing to their aromaticity and low polarity. Over the past century, only a few methods under harsh conditions have achieved direct arene ring modifications involving the cleavage of inert aromatic C-C bonds7,8, and arene ring-cleavage reactions using stoichiometric transition metal complexes or enzymes in bacteria are still limited9-11. We now report a copper-catalysed selective arene ring-opening reaction strategy. Our aerobic oxidative copper catalysis converts anilines, arylboronic acids, aryl azides, aryl halides, aryl triflates, aryl trimethylsiloxanes, aryl hydroxamic acids and aryl diazonium salts into alkenyl nitriles through selective C-C bond cleavage of arene rings. This chemistry was applied to the modification of polycyclic aromatics and the preparation of industrially important hexamethylenediamine and adipic acid derivatives. Several examples of late-stage modification of complex molecules and fused ring compounds further support the potential broad utility of this methodology.
As a readily available feedstock, styrene with about 25 million tons of global annual production serves as an important building block and organic synthon for the synthesis of fine chemicals, polystyrene plastics, and elastomers. Thus, in the past decades, many direct transformations of this costless styrene feedstock were disclosed for the preparation of high-value chemicals, which to date, generally performed on the functionalization of styrenes through the allylic C-H bond, C( sp ² )-H bond, or the C=C double bond cleavage. However, the dealkenylative functionalization of styrenes via the direct C-C single bond cleavage is so far challenging and still unknown. Herein, we report the novel and efficient C-C amination and hydroxylation reactions of styrenes for the synthesis of valuable aryl amines and phenols via the site-selective C(Ar)-C(alkenyl) single bond cleavage. This chemistry unlocks the new transformation and application of the styrene feedstock and provides an efficient protocol for the late-stage modification of substituted styrenes with the site-directed dealkenylative amination and hydroxylation.
Medium-sized rings have much promise in medicinal chemistry, but are difficult to make using direct cyclisation methods. In this minireview, we highlight the value of ring expansion strategies to address this long-standing synthetic challenge. We have drawn on recent progress (post 2013) to highlight the key reaction design features that enable successful ‘normal-to-medium’ ring expansion for the synthesis of these medicinally important molecular frameworks, that are currently under-represented in compound screening collections and marketed drugs in view of their challegning syntheses.
Transition‐metal‐mediated cleavage of C−C single bonds can enable entirely new retrosynthetic disconnections in the total synthesis of natural products. Given that C−C bond cleavage inherently alters the carbon framework of a compound, and that, under transition‐metal catalysis, the generated organometallic or radical intermediate is primed for further complexity‐building reactivity, C−C bond‐cleavage events have the potential to drastically and rapidly remodel skeletal frameworks. The recent acceleration of the use of transition‐metal‐mediated cleavage of C−C single bonds in total synthesis can be ascribed to a communal recognition of this fact. In this Review, we highlight ten selected total syntheses from 2014 to 2019 that illustrate how transition‐metal‐mediated cleavage of C−C single bonds at either the core or the periphery of synthetic intermediates can streamline synthetic efforts.
Aerobic epoxidation of tertiary allylic alcohols remains a significant challenge. Reported here is an efficient and highly chemoselective copper‐catalyzed epoxidation and semipinacol rearrangement reaction of tertiary allylic alcohols with molecular oxygen. The solvent 1,4‐dioxane activates dioxygen, thereby precluding the addition of a sacrificial reductant.
Excising an olefin
Plants produce an abundance of structurally complex terpene compounds that are useful precursors to pharmaceuticals and other fine chemicals. However, the carbon frameworks of these compounds constrain the available pathways for diversification. Smaligo et al. now show that successive treatment with ozone, an iron oxidant, and a hydrogen-atom donor can cleanly cleave pendant olefins from terpenes and related compounds (see the Perspective by Caille). Breaking the bond between saturated and double-bonded carbon centers offers a direct route to desirable chiral intermediates from readily available, inexpensive precursors.
Science , this issue p. 681 ; see also p. 635
Metal‐mediated cleavage of aromatic C−C bonds has a range of potential synthetic applications: from direct coal liquefaction to synthesis of natural products. However, in contrast to the activation of aromatic C−H bonds, which has already been widely studied and exploited in diverse set of functionalization reactions, cleavage of aromatic C−C bonds remains Terra incognita. This Minireview summarizes the recent progress in this field and outlines key challenges to be overcome to develop synthetic methods based on this fundamental organometallic transformation.
A novel activation of acetonitrile for the construction of cyclobutenones by [2+2] cyclization was developed. Acetonitrile is utilized for the first time as two‐carbon (C2) cyclization building block. The present protocol successfully inhibits the competitive cycloaddition with the C≡N bond of acetonitrile, but enables the in situ formation of an unsaturated carbon–carbon bond and the subsequent cycloaddition as a C2 unit. This chemistry features simple reaction conditions, high chemoselectivities, wide substrate scope, and offers a new and practical approach to cyclobutenones and cyclobuteneimines.
Anilines are fundamental motifs in various chemical contexts, and are widely used in the industrial production of fine chemicals, polymers, agrochemicals and pharmaceuticals. A recent development for the synthesis of anilines uses the primary amination of C–H bonds in electron-rich arenes. However, there are limitations to this strategy: the amination of electron-deficient arenes remains a challenging task and the amination of electron-rich arenes has a limited control over regioselectivity—the formation of meta-aminated products is especially difficult. Here we report a site-directed C–C bond primary amination of simple and readily available alkylarenes or benzyl alcohols for the direct and efficient preparation of anilines. This chemistry involves a novel C–C bond transformation and offers a versatile protocol for the synthesis of substituted anilines. The use of O2 as an environmentally benign oxidant is demonstrated, and studies on model compounds suggest that this method may also be used for the depolymerization of lignin. © 2018, The Author(s), under exclusive licence to Springer Nature Limited.
Lignin, the heterogeneous aromatic macromolecule found in the cell walls of vascular plants, is an abundant feedstock for the production of biochemicals and biofuels. Many valorization schemes rely on lignin depolymerization, with decades of research focused on accessing monomers through C-O bond cleavage, given the abundance of β-O-4 bonds in lignin and the large number of available C-O bond cleavage strategies. Monomer yields are, however, invariably lower than desired, owing to the presence of recalcitrant C-C bonds whose selective cleavage remains a major challenge in catalysis. In this Review, we highlight lignin C-C cleavage reactions, including those of linkages arising from biosynthesis (β-1, β-5, β-β and 5-5) and industrial processing (5-CH2-5 and α-5). We examine multiple approaches to C-C cleavage, including homogeneous and heterogeneous catalysis, photocatalysis and biocatalysis, to identify promising strategies for further research and provide guidelines for definitive measurements of lignin C-C bond cleavage.
The excitation of carbonyl compounds by light to generate radical intermediates has historically been restricted to ketones and aldehydes; carboxylic acids have been overlooked because of high energy requirements and low quantum efficiency. A successful activation strategy would necessitate a bathochromic shift in the absorbance profile, an increase in triplet diradical lifetime, and ease of further functionalization. We present a single-flask transformation of carboxylic acids to acyl phosphonates that can access synthetically useful triplet diradicals under visible light or near-ultraviolet irradiation. The use of phosphorus circumvents unproductive Norrish type I processes, promoting selectivity that enables hydrogen-atom transfer reactivity. Use of this strategy promotes the efficient scaffold remodeling of carboxylic acids through various annulation, contraction, and expansion manifolds.
This paper primarily focuses on the editing of nitrogen atoms, encompassing the insertion of N, substitution of C with N, and utilization of ¹⁵ N in place of ¹⁴ N for the construction of N-heterocycles.
The synthesis of nitrogen-containing molecules through C–N bond formation is critical for the discovery and preparation of medicines, agrochemicals and materials. Traditional synthetic methods using alkenes as ubiquitous substrates leverage the reactivity of the C(sp2)–C(sp2) π bond for C–N bond formation. In contrast, methods that can form C–N bonds through complete cleavage of the double bond are scarce, despite the considerable synthetic potential of such a strategy. Here, we report the direct insertion of a nitrogen atom into unactivated carbon-carbon double bonds to access aza-allenium intermediates which can be converted either into nitriles or amidine products, depending on the initial alkene substitution pattern. This operationally simple and highly functional group tolerant reaction works on a wide range of unactivated alkenes. Our mechanistic proposal is supported by chemical trapping experiments, which concomitantly demonstrate the utility of our method to access valuable N-heterocycles. Overall, this study demonstrates the possibility to access reactive nitrogen-containing intermediates (i.e. aza-alleniums), which have ample potential for downstream diversification, from unactivated alkenes, opening new avenues for the discovery and preparation of important products.
Great efforts have been directed toward alkene π bond amination. In contrast, analogous functionalization of the adjacent C(sp3)-C(sp2) σ bonds is much rarer. Here we report how ozonolysis and copper catalysis under mild reaction conditions enable alkene C(sp3)-C(sp2) σ bond-rupturing cross-coupling reactions for the construction of new C(sp3)-N bonds. We have used this unconventional transformation for late-stage modification of hormones, pharmaceutical reagents, peptides, and nucleosides. Furthermore, we have coupled abundantly available terpenes and terpenoids with nitrogen nucleophiles to access artificial terpenoid alkaloids and complex chiral amines. In addition, we applied a commodity chemical, α-methylstyrene, as a methylation reagent to prepare methylated nucleosides directly from canonical nucleosides in one synthetic step. Our mechanistic investigation implicates an unusual copper ion pair cooperative process.
The Wacker process, which is widely used to convert monosubstituted alkenes into the corresponding methyl ketones, is thought to proceed through a PdII/Pd0 catalytic cycle involving a β-hydride elimination step. This mechanistic scenario is inapplicable to the synthesis of ketones from the 1,1-disubstituted alkenes. Current approaches based on semi-pinacol rearrangement of PdII intermediates are limited to the ring expansion of highly strained methylene cyclobutane derivatives. Herein, we report a solution to this synthetic challenge by designing a PdII/PdIV catalytic cycle incorporating a 1,2-alkyl/PdIV dyotropic rearrangement as a key step. This reaction, compatible with a broad range of functional groups, is applicable to both linear olefins and methylene cycloalkanes, including macrocycles. Regioselectivity favors the migration of the more substituted carbon, and a strong directing effect of the β-carboxyl group was also observed.
Compared with peripheral late-stage transformations mainly focusing on carbon–hydrogen functionalizations, reliable strategies to directly edit the core skeleton of pharmaceutical lead compounds still remain scarce despite the recent flurry of activity in this area. Herein, we report the skeletal editing of indoles through nitrogen atom insertion, accessing the corresponding quinazoline or quinoxaline bioisosteres by trapping of an electrophilic nitrene species generated from ammonium carbamate and hypervalent iodine. This reactivity relies on the strategic use of a silyl group as a labile protecting group that can facilitate subsequent product release. The utility of this highly functional group-compatible methodology in the context of late-stage skeletal editing of several commercial drugs is demonstrated.
Discovery chemists routinely identify purpose-tailored molecules through an iterative structural optimization approach, but the preparation of each successive candidate in a compound series can rarely be conducted in a manner matching their thought process. This is because many of the necessary chemical transformations required to modify compound cores in a straightforward fashion are not applicable in complex contexts. We report a method that addresses one facet of this problem by allowing chemists to hop directly between chemically distinct heteroaromatic scaffolds. Specifically, we show that selective photolysis of quinoline N -oxides with 390-nanometer light followed by acid-promoted rearrangement affords N -acylindoles while showing broad compatibility with medicinally relevant functionality. Applications to late-stage skeletal modification of compounds of pharmaceutical interest and more complex transformations involving serial single-atom changes are demonstrated.
Medicinal chemistry continues to be impacted by new synthetic methods. Particularly sought after, especially at the drug discovery stage, is the ability to enact the desired chemical transformations in a concise and chemospecific fashion. To this end, the field of organic synthesis has become captivated by the idea of ‘molecular editing’—to rapidly build onto, change or prune molecules one atom at a time using transformations that are mild and selective enough to be employed at the late stages of a synthetic sequence. In this Review, the definition and categorization of a particularly promising subclass of molecular editing reactions, termed ‘single-atom skeletal editing’, are proposed. Although skeletal editing applies to both cyclic and acyclic compounds, this Review focuses on heterocycles, both for their centrality in medicinal chemistry and for the definitional clarity afforded by a focus on ring systems. A classification system is presented by highlighting methods (both historically important examples and recent advances) that achieve such transformations, with the goal to spark interest and inspire further development in this growing field.
Shuffling nitrogen with a light push
Manipulation of carbon–nitrogen rings is integral to the synthesis of numerous pharmaceutical and agrochemical compounds. Jurczyk et al . report that photoexcitation of carbonyl-substituted cyclic amines can shift the nitrogen from inside to outside the ring framework. The reaction appears to proceed through a 1,5-hydrogen shift to the electronically excited carbonyl, which sets in motion the subsequent carbon–nitrogen and carbon–carbon bonding rearrangements. Several oxygen and sulfur heterocycles were applicable as well. Addition of a chiral phosphoric acid catalyst rendered the reaction asymmetric. —JSY
Selective C−C bond cleavage under mild conditions can serve as a valuable tool for organic syntheses and macromolecular degradation. However, the conventional chemical methods have largely involved the use of noble transition-metal catalysts as well as the stoichiometric and perhaps environmentally unfriendly oxidants, compromising the overall sustainable nature of C−C transformation chemistry. In this regard, electrochemical C−C bond cleavage has been identified as a sustainable and scalable strategy that employs electricity to replace byproduct-generating chemical reagents. To date, the progress made in this area has mainly relied on Kolbe electrolysis and related processes. Encouragingly, more and more examples of the cleavage of C−C bonds via other maneuvers have recently been developed. This review provides an overview on the most recent and significant developments in electrochemically oxidative selective C−C bond cleavage, with an emphasis on both synthetic outcomes and reaction mechanisms, and it showcases the innate advantages and exciting potentials of electrochemical synthesis. CONTENTS
This article reviews synthetic transformations involving cleavage of a carbon-carbon bond of a four-membered ring, with a particular focus on the examples reported during the period from 2011 to the end of 2019. Most significant is the progress of catalytic reactions involving oxidative addition of carbon-carbon bonds onto transition metals or β-carbon elimination of transition metal alkoxides. When they are looked at from synthetic perspectives, they offer unique and efficient methods to build complex natural products and structures that are difficult to construct by conventional methods. On the other hand, β-scission of radical intermediates has also attracted increasing attention as an alternative elementary step to cleave carbon-carbon bonds. Its site-selectivity is often complementary to that of transition metal-catalyzed reactions. In addition, Lewis acid-mediated and thermally induced ring-opening of cyclobutanone derivatives has garnered renewed attention. On the whole, these examples demonstrate unique synthetic potentials of structurally strained four-membered ring compounds for the construction of organic skeletons.
Thermal C-C bond cleavage reactions allow the construction of structurally diverse molecular skeletons via predictable and efficient bond reorganizations. Visible light photoredox-catalyzed radical-mediated C-C bond cleavage reactions have recently emerged as a powerful alternative method for overcoming the thermodynamic and kinetic barrier of C-C bond cleavage in diverse molecular scaffolds. In recent years, a plethora of elegant and useful reactions have been invented, and the products are sometimes otherwise inaccessible by classic thermal reactions. Considering the great influence and synthetic potential of these reactions, we provide a summary of the state of art visible light-driven radical-mediated C-C bond cleavage/functionalization strategies with a specific emphasis on the working models. We hoped that this review will be useful for medicinal and synthetic organic chemists and will inspire further reaction development in this interesting area.
Cleavage of C-C bonds by transition metal complexes is a fascinating organometallic transformation that underpins a range of industrial processes and offers exciting opportunities for development new synthetic methods through reconstruction of hydrocarbon framework. Various examples of single C-C bond cleavage have been extensively covered in recent literature, but equally rich chemistry of metal-mediated scission of unsaturated C-C bonds has not been comprehensively surveyed so far. This review aims to fill this gap and highlights stoichiometric and catalytic reactions involving metal-induced full cleavage of unsaturated C-C bonds in alkenes, alkynes and aromatic systems.
Sourcing nitrogen from nitromethane
Nitromethane is produced in bulk quantities for use as a solvent. Its applications as a reagent have focused mainly on the acidity of the methyl protons en route to modifying the carbon center. Liu et al. now report an alternative protocol that activates the nitrogen center to produce an aminating agent. An in situ reductive reaction with triflic anhydride, formic acid, and acetic acid yields an acetylated hydroxylamine, characterized by mass spectrometry. This nitrogen donor conveniently transforms a variety of ketones and aldehydes into amides.
Science , this issue p. 281
In contrast to the recent breakthrough in electrochemical C-H aminations, the electrochemically oxidative C-N bond formation through a C-C bond cleavage is rarely studied. This work describes a novel electrochemical C-C amination of alkylarenes for the efficient synthesis of versatile anilines, as well as carbonyl compounds. With the cheap and durable graphite plates as electrodes, and in a simple undivided cell, this protocol is much more economical with the consumption of electricity.
A novel structural reorganization of cycloketoxime esters beyond the traditional Beckmann rearrangement process has been established to build cyano‐containing ketones in the presence of photocatalysis. This novel transformation is remarkable with selective C‐C bond cleavage and an oxidation processes enabled by DMSO used as the solvent, oxidant, and oxygen source avoiding acid, base and toxic cyanide salts as the cyano source. Further applications in late‐stage modification of complex and chiral molecules have also been reported.
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A silver cleaver splits cyclic amines
Carbon-carbon single bonds are fairly unreactive when they are not strained in a tight ring. Roque et al. now report that a silver salt can cleave C–C bonds in unstrained cyclic amines such as pyrrolidines and piperidines. Paired with an electrophilic fluorine source in aqueous solution, the silver first oxidizes the α carbon adjacent to the nitrogen. Ring-opening fluorination of the β carbon then proceeds by an apparent radical mechanism. The reaction offers a versatile means of introducing fluorine to structural motifs common in pharmaceutical research.
Science , this issue p. 171
The selective oxidation of organic molecules is a fundamentally important component of modern synthetic chemistry. In the past decades, direct oxidative C–H and C–C bond functionalization has proved to be one of the most efficient and straightforward methods to synthesize complex products from simple and readily available starting materials. Among these oxidative processes, the use of molecular oxygen as a green and sustainable oxidant has attracted considerable attention because of its highly atom-economical, abundant, and environmentally friendly characteristics. The development of new protocols using molecular oxygen as an ideal oxidant is highly desirable in oxidation chemistry. More importantly, the oxygenation reaction of simple molecules using molecular oxygen as the oxygen source offers one of the most ideal processes for the construction of O-containing compounds. Aerobic oxidation and oxygenation by enzymes, such as monooxygenase, tyrosinase, and dopamine β-monooxygenase, have been observed in some biological C–H bond hydroxylation processes. Encouraged by these biological transformations, transition-metal- or organocatalyst-catalyzed oxygenation through dioxygen activation has attracted academic and industrial prospects.
Metal-catalysed functionalization of a carbon–hydrogen bond can occur selectively even in the presence of ostensibly more reactive functional groups. Such conversions have changed our perceptions of organic chemistry because we can now consider a C–H bond as a functional group, the reactions of which are among the most attractive and powerful means to rapidly add complexity. Another versatile tool in organic synthesis is the metal-catalysed selective cleavage of C–C bonds. Applying both expedient methods in a tandem process would give us an ideal approach to synthesizing complex molecular architectures. The challenge lies in ensuring that the reactions do not interfere with each other; the simultaneous control of both C–H and C–C bond activations is the subject of this Review. The reactions that meet this challenge and enable a selective merger of C–H and C–C bond activations in a one-pot process are discussed. Their realization could afford sophisticated molecular fragments that are otherwise difficult to access.