Generation Of Carbenes Research Articles

Photocatalytic generation of alkyl carbanions from aryl alkenes

AbstractOrganometallic reagents are routinely used as fundamental building blocks in organic chemistry to rapidly diversify molecular fragments via carbanion intermediates. However, the catalytic generation of carbanion equivalents, particularly from sp3-hybridized alkyl scaffolds, remains an underdeveloped goal in chemical synthesis. Here we disclose an approach for the generation of alkyl carbanions via single-electron reduction of aryl alkenes, enabled by multi-photon photoredox catalysis. We demonstrate that photocatalytically induced alkyl carbanions engage in intermolecular C–C bond-forming reactions with carbonyl electrophiles. Central to this method is the controlled formation of an alkene distonic radical anion intermediate that undergoes nucleophilic addition, followed by a kinetically favoured reductive polar crossover to produce a second carbanion available for further diversification. The versatility of this protocol was illustrated by the development of four distinct intermolecular C–C bond-forming reactions with aromatic alkenes (hydroalkoxylation, hydroamidation, aminoalkylation and carboxyaminoalkylation) to generate a range of valuable and complex scaffolds.

Oxenoid reactivity enabled by targeted photoactivation of periodate.

The chemistry of low-valent intermediates continues to inspire new modes of reactivity across synthetic chemistry. But while the generation and reactivity of both carbenes and nitrenes are well-established, difficulties in accessing oxene, their oxygen-based congener, has severely hampered its application in synthesis. Here, we report a conceptually novel approach to oxene generation through the violet-light photolysis of tetrabutylammonium periodate. By revealing an unexpected geometric change upon periodate photoexcitation that facilitates intersystem crossing, we have exploited the near-barrierless dissociation of triplet periodate into oxene. Under these operationally simple conditions, we have demonstrated the epoxidation of a wide range of substituted olefins, revealing unprecedented functional group compatibility. By overcoming the historic challenges associated with employing oxene as an intermediate in organic chemistry, we believe that this platform will inspire the development of new reactive oxygen-based methodologies across industry and academia.

Oxenoid reactivity enabled by targeted photoactivation of periodate

The chemistry of low‐valent intermediates continues to inspire new modes of reactivity across synthetic chemistry. But while the generation and reactivity of both carbenes and nitrenes are well‐established, difficulties in accessing oxene, their oxygen‐based congener, has severely hampered its application in synthesis. Here, we report a conceptually novel approach to oxene generation through the violet‐light photolysis of tetrabutylammonium periodate. By revealing an unexpected geometric change upon periodate photoexcitation that facilitates intersystem crossing, we have exploited the near‐barrierless dissociation of triplet periodate into oxene. Under these operationally simple conditions, we have demonstrated the epoxidation of a wide range of substituted olefins, revealing unprecedented functional group compatibility. By overcoming the historic challenges associated with employing oxene as an intermediate in organic chemistry, we believe that this platform will inspire the development of new reactive oxygen‐based methodologies across industry and academia.

Mechanism and stereoselectivity in metal and enzyme catalyzed carbene insertion into X-H and C(sp2)-H bonds.

Constructing highly proficient C-X (X = O, N, S, etc.) and C-C bonds by leveraging TMs (transition metals) (Fe, Cu, Pd, Rh, Au, etc.) and enzymes to catalyze carbene insertion into X-H/C(sp2)-H is a highly versatile strategy. This is primarily achieved through the in situ generation of metal carbenes from the interaction of TMs with diazo compounds. Over the last few decades, significant advancements have been made, encompassing a wide array of X-H bond insertions using various TMs. These reactions typically favor a stepwise ionic pathway where the nucleophilic attack on the metal carbene leads to the generation of a metal ylide species. This intermediate marks a critical juncture in the reaction cascade, presenting multiple avenues for proton transfer to yield the X-H inserted product. The mechanism of C(sp2)-H insertion reactions closely resembles those of X-H insertion reactions and thus have been included here. A major development in carbene insertion reactions has been the use of engineered enzymes as catalysts. Since the seminal report of a non-natural "carbene transferase" by Arnold in 2013, "P411", several heme-based enzymes have been reported in the literature to catalyze various abiological carbene insertion reactions into C(sp2)-H, N-H and S-H bonds. These enzymes possess an extraordinary ability to regulate the orientation and conformations of reactive intermediates, facilitating stereoselective carbene transfers. However, the absence of a suitable stereochemical model has impeded the development of asymmetric reactions employing a lone chiral catalyst, including enzymes. There is a pressing need to investigate alternative mechanisms and models to enhance our comprehension of stereoselectivity in these processes, which will be crucial for advancing the fields of asymmetric synthesis and biocatalysis. The current review aims to provide details on the mechanistic aspects of the asymmetric X-H and C(sp2)-H insertion reactions catalyzed by Fe, Cu, Pd, Rh, Au, and enzymes, focusing on the detailed mechanism and stereochemical model. The review is divided into sections focusing on a specific X-H/C(sp2)-H bond type catalyzed by different TMs and enzymes.

Comparison of the Efficiency of B-O and B-C Bond Formation Pathways in Borane-Catalyzed Carbene Transfer Reactions Using α-Diazocarbonyl Precursors: A Combined Density Functional Theory and Machine Learning Study.

Lewis acidic boranes, especially tris(pentafluorophenyl)borane [B(C6F5)3], have emerged as metal-free catalysts for carbene transfer reactions of α-diazocarbonyl compounds in a variety of functionalization reactions. The established mechanism for how borane facilitates carbene generation for these compounds in the scientific community is based on the formation of a B-O (C=O) intermediate (path O). Herein, we report an extensive DFT study that challenges the notion of a ubiquitous path O, revealing that B-C(=N=N) bond formation (path C) for certain diazocarbonyl substrates proves to be the preferred pathway. This study elucidates, through the introduction of 22 various substituents on each side of the α-diazocarbonyl backbone, how the electron-donating and -withdrawing properties of substituents influence the competition between these B-O and B-C pathways. To elucidate the impact of the electronic features of diazo substrates on the competition between the O and C pathways in the studied dataset, we employed a machine learning approach based on the Random Forest model. This analysis revealed that substrates with higher electron density on the diazo-attached carbon, lower electron density on the carbonyl carbon, and more stable HOMO orbitals tend to proceed via path C. Furthermore, this study not only demonstrates that borane efficiency in facilitating N2 release is greatly affected by the nature of substituents on both sides of the α-diazocarbonyl functionality but also shows that for some substrates, borane is incapable of catalyzing the release of molecular nitrogen.

Cyclopropanation with Non-Stabilized Carbenes via Ketyl Radicals.

A radical mechanism enables simple and robust access to nonstabilized, alkyl iron carbenes for novel (2 + 1) cycloadditions. This Fe-catalyzed strategy employs simple, aliphatic aldehydes as carbene precursors in a practical, efficient, and stereoselective cyclopropanation. This air- and water-tolerant method permits convenient generation of iron carbenes and coupling to an exceptionally wide range of sterically and electronically diverse alkenes (nucleophilic, electrophilic, and neutral). A transient ketyl radical intermediate is key to accessing and harnessing this rare, alkyl iron carbene reactivity. Mechanistic experiments confirm the (a) intermediacy of ketyl radicals, (b) iron carbene formation by radical capture, and (c) nonconcerted nature of the (2 + 1) cycloaddition.

Visible Light Induced B-H Bond Insertion Reaction with Diazo Compounds.

A protocol induced by visible light for the direct insertion of α-carbonyl carbenes into the B-H bond of amine-borane adducts has been developed under conditions that are free of metal and photocatalyst. This approach provides a straightforward route to various organoboron compounds from diazo compounds and amine-borane adducts with moderate to good yields. Mechanistic investigations reveal that this photoinduced reaction proceeds through concerted carbene insertion into the B-H bond, and the photoinduced generation of free carbene from α-diazo esters may be the rate-determining step.

Hybrid silver(I) coumarin-carbene and coumarin-triphenylphosphine complexes: Towards more effective antimicrobial therapies

The rise of antimicrobial resistance and the resulting societal burden has highlighted the need for the development of novel therapeutics. Towards that end, a series of hybrid silver(I) coumarin-carbene and coumarin-triphenylphosphine complexes were synthesised and characterised by spectroscopic analysis including IR, 1H and 13C NMR spectroscopy, elemental analysis, and X-ray crystallography. Isolation of coumarin-carbene hybrid complexes was achieved using two methods, with isolation via firstly the in-situ generation of a free carbene under Schlenk conditions, followed by reaction with a coumarin silver(I) complex resulting in the formation of a hybrid complex with two silver ions forming a strong argentophilic Ag(I)–Ag(I) interaction. In this hybrid complex one silver(I) ion was bound to two coumarin carboxylate ligands with the other ion bound to two carbene ligands. Isolation via an ionic carbene route led to more complex aggregates but both types of complexes had good solubility and photostability as did the triphenylphosphine hybrid complexes. All the hybrid complexes showed therapeutic potential as antimicrobial agents against MRSA with the carbene hybrid complexes exhibiting an increased antimicrobial activity against both E. coli and MRSA when compared to the initial silver(I) complexes.

Redox Approaches to Carbene Generation in Catalytic Cyclopropanation Reactions

AbstractTransition metal‐catalyzed carbene transfer reactions have a century‐old history in organic chemistry and are a primary method for the synthesis of cyclopropanes. Much of the work in this field has focused on the use of diazo compounds and related precursors, which can transfer a carbene fragment to a catalyst with concomitant loss of a stable byproduct. Despite the utility of this approach, there are persistent limitations in the scope of viable carbenes, most notably those lacking stabilizing substituents. By coupling carbene transfer chemistry with two‐electron redox cycles, it is possible to expand the available starting materials that can be used as carbene precursors. In this Minireview, we discuss emerging catalytic reductive cyclopropanation reactions using either gem‐dihaloalkanes or carbonyl compounds. This strategy is inspired by classic stoichiometric transformations, such as the Simmons–Smith cyclopropanation and the Clemmensen reduction, but instead entails the formation of a catalytically generated transition metal carbene or carbenoid. We also present recent efforts to generate carbenes directly from methylene (CR2H2) groups via a formal 1,1‐dehydrogenation. These reactions are currently restricted to substrates containing electron‐withdrawing substituents, which serve to facilitate deprotonation and subsequent oxidation of the anion.

Redox Approaches to Carbene Generation in Catalytic Cyclopropanation Reactions.

Transition metal-catalyzed carbene transfer reactions have a century-old history in organic chemistry and are a primary method for the synthesis of cyclopropanes. Much of the work in this field has focused on the use of diazo compounds and related precursors, which can transfer a carbene fragment to a catalyst with concomitant loss of a stable byproduct. Despite the utility of this approach, there are persistent limitations in the scope of viable carbenes, most notably those lacking stabilizing substituents. By coupling carbene transfer chemistry with two-electron redox cycles, it is possible to expand the available starting materials that can be used as carbene precursors. In this Minireview, we discuss emerging catalytic reductive cyclopropanation reactions using either gem-dihaloalkanes or carbonyl compounds. This strategy is inspired by classic stoichiometric transformations, such as the Simmons-Smith cyclopropanation and the Clemmensen reduction, but instead entails the formation of a catalytically generated transition metal carbene or carbenoid. We also present recent efforts to generate carbenes directly from methylene (CR2H2) groups via a formal 1,1-dehydrogenation. These reactions are currently restricted to substrates containing electron-withdrawing substituents, which serve to facilitate deprotonation and subsequent oxidation of the anion.

Spontaneous α‐C−H Carboxylation of Ketones by Gaseous CO2 at the Air‐water Interface of Aqueous Microdroplets

AbstractWe present a catalyst‐free route for the reduction of carbon dioxide integrated with the formation of a carbon‐carbon bond at the air/water interface of negatively charged aqueous microdroplets, at ambient temperature. The reactions proceed through carbanion generation at the α‐carbon of a ketone followed by nucleophilic addition to CO2. Online mass spectrometry reveals that the product is an α‐ketoacid. Several factors, such as the concentration of the reagents, pressure of CO2 gas, and distance traveled by the droplets, control the kinetics of the reaction. Theoretical calculations suggest that water in the microdroplets facilitates this unusual chemistry. Furthermore, such a microdroplet strategy has been extended to seven different ketones. This work demonstrates a green pathway for the reduction of CO2 to useful carboxylated organic products.

Visible Light-Induced Reactions of Diazo Compounds and Their Precursors.

In recent years, visible light-induced reactions of diazo compounds have attracted increasing attention in organic synthesis, leading to improvement of existing reactions, as well as to the discovery of unprecedented transformations. Thus, photochemical or photocatalytic generation of both carbenes and radicals provide milder tools toward these key intermediates for many valuable transformations. However, the vast majority of the transformations represent new reactivity modes of diazo compounds, which are achieved by the photochemical decomposition of diazo compounds and photoredox catalysis. In particular, the use of a redox-active photocatalysts opens the avenue to a plethora of radical reactions. The application of these methods to diazo compounds led to discovery of transformations inaccessible by the classical reactivity associated with carbenes and metal carbenes. In most cases, diazo compounds act as radical sources but can also serve as radical acceptors. Importantly, the described processes operate under mild, practical conditions. This Review describes this subfield of diazo compound chemistry, particularly focusing on recent advancements.

Gold-catalyzed intermolecular amination of allyl azides with ynamides: efficient construction of 3-azabicyclo[3.1.0] scaffold

Gold-catalyzed amination reactions based on azides via α-imino gold carbene intermediates have attracted extensive attention in the past decades because this methodology leads to the facile and efficient construction of synthetically useful N-containing molecules, especially valuable N-heterocycles. However, successful examples of intermolecular generation of α-imino gold carbenes by using azides as amination reagents are rarely explored probably due to the weak nucleophilicity of azides. Herein, we disclose an efficient gold-catalyzed intermolecular aminative cyclopropanation of ynamides with the allyl azides, enabling flexible synthesis of a wide range of valuable 3-azabicyclo[3.1.0]hex-2-ene derivatives in good to excellent yields with excellent diastereoselectivities. Importantly, this protocol represents the first use of allyl azide as an efficient amination reagent in gold-catalyzed alkyne amination reactions.

Regio-, diastereo- and enantioselectivity in the photocatalytic generation of carbanions via hydrogen atom transfer and reductive radical-polar crossover

A sequence involving photocatalytic hydrogen atom transfer (HAT), reductive radical-polar crossover (RRPCO), and protonation/deuteration for stereochemical editing at benzylic positions is described.

Consecutive one-pot alkyne semihydrogenation/alkene dioxygenation reactions by Pt(II)/Cu(II) single-chain nanoparticles in green solvent.

Heterobimetallic Pt(II)/Cu(II) single-chain polymer nanoparticles (SCNPs) were sequentially synthesized from a polymeric precursor featuring both α-diazo-β-ketoester and naked β-ketoester functional groups. Photoactivated carbene generation at λexc = 365 nm from α-diazo-β-ketoester moieities was triggered for bonding Pt(II) ions from dichloro(1,5-cyclooctadiene)Pt(II) to the polymeric precursor, whereas Cu(II) ions were subsequently incorporated via Cu(II)-(β-ketoester)2 complex formation using Cu(II) acetate. Both intrachain Pt(II) bonding and Cu(II) complexation were found to contribute to the folding of the polymeric precursor generating Pt(II)/Cu(II)-SCNPs as evidenced by infrared spectroscopy, size exclusion chromatography and dynamic light scattering. These heterobimetallic SCNPs proved highly efficient as soft nanocatalysts for the consecutive one-pot alkyne semihydrogenation/alkene dioxygenation reactions at room temperature in N-butylpyrrolidone, as a non-toxic alternative solvent to N,N-dimethylformamide.

Cascade Reactions of Aryl-Substituted Terminal Alkynes Involving in Situ-Generated α-Imino Gold Carbenes.

An efficient, highly selective and divergent synthetic method to construct 2-substituted indoles and aryl-annulated carbazoles via the intermolecular generation of α-imino gold carbenes from terminal alkynes or diynes in combination with sulfilimines is disclosed. Importantly, the tandem reaction is proposed to proceed through an intermolecular gold carbene generation/C-H annulation followed by the activation of a second alkyne leading to 6-endo-dig cyclization, which is significantly different from previous dual activation or 1,6-carbene shift approaches for diyne systems. In the case of ortho-alkynylaniline as starting material, an unexpected regioselective formation of the indole moiety via the intermolecular path, instead of intramolecular hydroamination was discovered. This reactivity paved the way for a one-pot synthesis of the 11H-indolo [3,2-c] quinoline scaffold by exploiting the formed amino indole for a subsequent Pictet-Spengler reaction with aldehydes. The photophysical properties of the carbazoles indicated good violet-blue emission with quantum yields up to 40 %.

Kaskadenreaktionen von aryl‐substituierten terminalen Alkinen unter Beteiligung von in situ erzeugten α‐Imino‐Goldcarbenen

AbstractWir berichten über eine effiziente, hochselektive und divergente Synthesemethode zur Herstellung von 2‐substituierten Indolen und aryl‐anellierten Carbazolen über die intermolekulare Erzeugung von α‐Imino‐Goldcarbenen aus terminalen Alkinen oder Diinen in Kombination mit Sulfiliminen. Wichtig ist, dass die Tandemreaktion durch eine intermolekulare Goldcarbenbildung/C−H‐ Anellierung, gefolgt von der Aktivierung eines zweiten Alkins, die zu einer 6‐endo‐dig‐Zyklisierung führt, abläuft, was sich deutlich von früheren Ansätzen der dualen Aktivierung oder 1,6‐Carbenverschiebung für Diin‐Systeme unterscheidet. Im Falle von ortho‐Alkinylanilin als Ausgangsmaterial wurde eine unerwartete regioselektive Bildung der Indolkomponente über den intermolekularen Weg anstelle einer intramolekularen Hydroaminierung entdeckt. Diese Reaktivität ebnete den Weg für eine Eintopfsynthese des 11H‐Indolo‐[3,2‐c]‐Chinolin‐Gerüsts, indem das gebildete Aminoindol für eine anschließende Pictet–Spengler‐Reaktion mit Aldehyden genutzt wurde. Die photophysikalischen Eigenschaften der Carbazole zeigten eine gute violett‐blaue Emission mit Quantenausbeuten von bis zu 40 %.

Kinetics of N2 Release from Diazo Compounds: A Combined Machine Learning-Density Functional Theory Study.

Diazo compounds are commonly employed as carbene precursors in carbene transfer reactions during a variety of functionalization procedures. Release of N2 gas from diazo compounds may lead to carbene formation, and the ease of this process is highly dependent on the characteristics of the substituents located in the vicinity of the diazo moiety. A quantum mechanical density functional theory assisted by machine learning was used to investigate the relationship between the chemical features of diazo compounds and the activation energy required for N2 elimination. Our results suggest that diazo molecules, possessing a higher positive partial charge on the carbene carbon and more negative charge on the terminal nitrogen, encounter a lower energy barrier. A more positive C charge decreases the π-donor ability of the carbene lone pair to the π* orbital of N2, while the more negative N charge is a result of a weak interaction between N2 lone pair and vacant p orbital of the carbene. The findings of this study can pave the way for molecular engineering for the purpose of carbene generation, which serves as a crucial intermediate for many chemical transformations in synthetic chemistry.

Mechanochemical activation of NHC–CS2 adducts for the generation of N‐heterocyclic carbenes

AbstractStable N‐heterocyclic carbenes (NHCs) have garnered significant attention in synthetic chemistry due to their versatile applications. In this study, we explored a novel mechanochemical method for the generation of free carbenes, which could be a good complement to traditional approaches that require strong bases or reductants. Ball milling of NHC–CS2 adducts at room temperature successfully resulted in the quantitative formation of free carbenes that can be subsequently trapped by sulfur or selenium. Importantly, heating NHC–CS2 adducts in solution phase did not lead to the successful generation of free carbenes, in agreement with the high activation energy required for NHC–CS2 dissociation. These findings underscore the potential of ball milling as a robust and versatile approach for generating NHCs from stable NHC‐small molecule adducts, and opens new avenues for developing mechanochemical strategies for generating valuable NHC‐derived compounds.

Rh-Catalyzed [2,3]-Sigmatropic Rearrangement of Alkynyl Carbenes with Allyl Sulfides to Access Sulfide-Substituted 1,5-Enynes.

This study describes the development of Rh-catalyzed [2,3]-sigmatropic rearrangement of alkynyl carbenes with allyl sulfides. The protocol exhibits equitable functional group tolerance and allows the formation of a variety of synthetically valuable sulfide-substituted 1,5-enyne products. To the best of our knowledge, this is the first example of [2,3]-sigmatropic rearrangement of alkynyl carbenes. DFT analysis supports the involvement of rhodium carbene generation, sulfonium ylides formation, and [2,3]-sigmatropic rearrangement pathway.