Carbene Precursors Research Articles

Rhodium‐Catalyzed Asymmetric Cyclopropanation of Indoles with N‐Triftosylhydrazones

AbstractHerein we report a general rhodium‐catalyzed asymmetric intermolecular dearomative cyclopropanation of indoles using trifluoromethyl N‐triftosylhydrazones as carbene precursors. The reaction enables the rapid construction of diverse cyclopropane‐fused indolines bearing a trifluoromethylated quaternary stereocenter with high enantioselectivity (up to 99 % ee). This mild method exhibits broad substrate scope, tolerating various functional groups, and can even be utilized for the late‐stage diversification of complex bioactive molecules. DFT calculations suggest that the formation of a key zwitterionic intermediate is responsible for the chiral induction. Overall, this approach opens up new possibilities for asymmetric cyclopropanation of challenging aromatic heterocyclic compounds.

Remote Catalytic C(sp3)-H Alkylation via Relayed Carbenoid Transfer upon Olefin Chain Walking.

Transition metal carbenes have emerged as versatile intermediates for various types of alkylations. While reactions of metal carbene species with alkenes have been extensively studied, most examples focus on cyclopropanation and allylic C-H insertion. Herein, we present the first example of a catalytic strategy for the carbene-involved regioselective remote C-H alkylation of internal olefins by synergistically combining two iridium-mediated reactivities of olefin chain walking and carbenoid migratory insertion. The present method, utilizing sulfoxonium ylides as a bench-stable robust carbene precursor, was found to be effective for a series of olefins tethered with alkyl chains, heteroatom substituents, and complex biorelevant moieties. Combined experimental and computational studies revealed that reversible iridium hydride-mediated olefin chain walking proceeds to lead to a terminal alkyl-Ir intermediate, which then forms a carbenoid species for the final migratory insertion, resulting in regioselective terminal-alkylated products.

Unsupported Nanoporous Copper Catalyzed Insertion of Carbenes from α‐Diazo Compounds into Hydrosilanes

The insertion of diazo carbene into Si−H bonds with unsupported nanoporous copper (CuNPore) catalyst has been developed. α‐Aryl diazoesters, diazophosphonates, and unstable aryl diazoalkyls can be used as carbene precursors to exquisitely insert into the Si−H bond of silanes. A variety of α‐silylesters, silylphosphonate, and functionalized arylsilane were obtained in 35−82% yields. The reusability feature of the CuNPore catalyst for this insertion reaction demonstrated its high heterogeneous catalytic activity and practicality.Further, mechanistic studies revealed that the insertion of carbene from diazo compounds into the Si−H bond may include a three‐center concerted transition state on CuNPore.

Visible-light-mediated cyclopropanation reactions of 3-diazooxindoles with olefins

Visible-light-mediated metal-free cyclopropanation reaction of diazo compounds with different olefins or arenes have been fully developed in recent years. However, electron-deficient olefins still could not be well tolerated in these reactions. Here, by using 3-diazooxindole as the carbene precursor, the visible-light-mediated cyclopropanation reaction of diazo compounds with electron-deficient olefins was successfully developed. The electron-rich olefins were also well tolerated in the reactions. A series of spirocyclopropyloxindoles were synthesized in moderate to high yields under mild, metal-free conditions. Mechanism studies reveal that both singlet and triplet carbenes are probably involved in the reaction.

Rhodium-Catalyzed Asymmetric Cyclopropanation of Indoles with N-Triftosylhydrazones.

Here we report a general rhodium-catalyzed asymmetric intermolecular dearomative cyclopropanation of indoles using trifluoromethyl N-triftosylhydrazones as carbene precursors. The reaction enables the rapid construction of diverse cyclopropane fused indolines bearing a trifluoromethylated quaternary stereocenter in high enantioselectivities (up to 99% ee). This mild method exhibits a broad substrate scope, is compatible with various functional groups, and can even be utilized for the late-stage diversification of complex bioactive molecules. DFT calculations suggest that the formation of a key zwitterionic intermediate is responsible for the chiral induction. Overall, this approach opens up new possibilities for asymmetric cyclopropanation of challenging aromatic heterocyclic compounds.

Palladium‐N‐heterocyclic Carbene Complexes: Synthesis, Characterization and Catalytic Application of C−H Activation for Carboxaldehyde Derivatives

AbstractA series of palladium‐N‐heterocyclic carbene complexes (2 a‐e) were synthesized from corresponding N‐heterocyclic carbene precursors (1 a‐e) in good yields. The structural analysis of all novel compounds was done by spectroscopic methods and elemental analysis was also performed to evaluate the purity of the complexes. Further confirmations of complexes 2 a‐d were provided by X‐ray crystallography technique. Under optimized reaction conditions, the catalytic activity of the palladium‐N‐heterocyclic carbene complexes was reviewed by direct arylation of furan‐2‐carboxaldehyde and 1‐methylpyrrole‐2‐carboxaldehyde with varied aryl halides. This arylation showed productive and selective reaction at the C5‐position of heteroaryl derivatives.

Recent advances in the synthesis of highly substituted imidazolidines.

Imidazolidine is a saturated heterocycle with a cyclic aminal core that can be found in natural products and biologically active molecules. Additionally, these heterocyclic compounds have been utilized as chiral ligands, N-heterocyclic carbene precursors, and catalysts in organic synthesis. This review is an attempt to compile the literature of various synthetic procedures of highly substituted imidazolidines, chiral imidazolidines with high diastereoselectivities and enantioselectivities, bis-imidazolidines, and spiro-imidazolidines, as well as their pharmacological properties during the period from 1949 to 2023.

Recent Progress in Synthetic Applications of Hypervalent Iodine(III) Reagents.

Hypervalent iodine(III) compounds have found wide application in modern organic chemistry as environmentally friendly reagents and catalysts. Hypervalent iodine reagents are commonly used in synthetically important halogenations, oxidations, aminations, heterocyclizations, and various oxidative functionalizations of organic substrates. Iodonium salts are important arylating reagents, while iodonium ylides and imides are excellent carbene and nitrene precursors. Various derivatives of benziodoxoles, such as azidobenziodoxoles, trifluoromethylbenziodoxoles, alkynylbenziodoxoles, and alkenylbenziodoxoles have found wide application as group transfer reagents in the presence of transition metal catalysts, under metal-free conditions, or using photocatalysts under photoirradiation conditions. Development of hypervalent iodine catalytic systems and discovery of highly enantioselective reactions using chiral hypervalent iodine compounds represent a particularly important recent achievement in the field of hypervalent iodine chemistry. Chemical transformations promoted by hypervalent iodine in many cases are unique and cannot be performed by using any other common, non-iodine-based reagent. This review covers literature published mainly in the last 7-8 years, between 2016 and 2024.

Heme‐Enzymatic Biocatalysis for C−C or C−N Bond Formation

AbstractThe C−C or C−N bond formation is critical in the synthesis of pharmaceuticals and other value‐added products; however, traditional metal‐catalysed synthesis has brought about environmental and resource issues. A plethora of engineered heme‐dependent enzymes, such as cytochrome P450, have exhibited enormous potential in biocatalysis for C−C or C−N bond formation. With the development of computational and spectroscopic methods, the mechanisms underlying heme‐catalysed C−C or C−N bond formation have been extensively investigated. In the presence of carbene or nitrene precursor, an active iron porphyrin carbene (IPC) or iron porphyrin nitrene (IPN) is formed, which subsequently reacts with a second substrate to form new C−C or C−N bonds. Apart from the widely studied IPC/IPN‐facilitated catalytic pathway, halide‐initiated radical cyclization pathway and Cpd‐I‐catalysed diradical pathway have also been proposed. These mechanistic insights have enabled rational engineering and de novo design of heme enzymes. This review summarises recent mechanistic advances in heme enzymatic C−C or C−N bond formation and presents successful applications of mechanism‐based enzyme design. It would shed light on the development of tailored biocatalysts for the synthesis of complex but valuable industrial products.

Recent Advances in Diazophosphonate Chemistry: Reactions and Transformations

AbstractDiazophosphonates function as indispensable synthetic intermediates within the domain of organic chemistry, serving as precursors for a diverse range of molecules, with potential applications as bioactive compounds. α-Diazomethylphosphonates showcase expansive reactivity and elevated levels of enantioselectivity in asymmetric transformations, especially in conjunction with suitable catalyst systems. This review compiles the latest advancements in diazophosphonate chemistry from 2016 to 2024, highlighting their reactivity and transformative potential in organic synthesis. Diazophosphonates, regarded as revolutionary compounds, exhibit unique attributes as carbene precursors, driving diverse chemical reactions such as [3+2] cycloaddition, asymmetric [3+2] cycloaddition, asymmetric [3+3] cycloaddition, and asymmetric substitution reactions. Their adaptability in functional group conversions underscores their pivotal role in various synthetic methodologies. The review highlights the growing interest in diazophosphonate reactions among synthetic chemists, fostering novel synthetic strategies and expanding their application horizons. The multifaceted utility of diazophosphonates as reagents, synthetic intermediates, precursors, and catalysts underscores their significance in modern organic chemistry and pharmaceutical applications, prompting further exploration into this dynamic field.1 Introduction2 [3+2] Cycloaddition Reactions3 Asymmetric [3+2] Cycloaddition Reactions4 Asymmetric [3+3] Cycloaddition Reactions5 Asymmetric Substitution Reactions6 Diazophosphonates as Carbene Precursors7 Diazophosphonates in the Chemistry of Fluorinated Compounds8 Other Reactions9 Future Directions10 Conclusion

Novel nonsymmetrically benzimidazolium salts and their silver(I)-N-heterocyclic carbene complexes: Synthesis, DFT study and Anticancer activities

A series of unsymmetrically substituted N-heterocyclic carbene (NHC) precursors were synthesized from the action of 5,6-dimethylbenzimidazole or benzimidazole with various alkyl halides in DMF at 80 °C for 72 h . These compounds were used to synthesize NHC–silver(I) complexes (3) by reacting these NHC precursors with Ag2O in DMC.The prepared compounds were structurally verified by several spectroscopic techniques including 1H NMR, 13C NMR, FT-IR, LC-MS, and C, H, N analysis. The structures of the NHC precursors and their corresponding silver(I) complexes were also investigated theoretically using density functional theory (DFT) at the BLYP/TZ2P level to optimize geometries and assess electronic properties via Voronoi Deformation Density (VDD) charge analysis. Additionally, the newly synthesized ligands and silver(I) complexes were evaluated for their in vitro anticancer activity against three human cancer cell lines including hepatocellular carcinoma (HePG2), lung adenocarcinoma (A549) and breast adenocarcinoma (MCF7). Most of the newly synthesized silver(I) complexes exhibited better activity than the ligands, and the results have been compared with Cisplatin as a reference drug.

Silver-Catalyzed Single-Carbon Insertion of Indoles with Acetophenone N-Triftosylhydrazones.

Here, we report a silver carbene-enabled single-carbon insertion reaction of indoles via a one-pot, two-step sequence to deliver a dearomative quaternary center quinoline scaffold in a modular fashion. Specifically, we used N-triftosylhydrazones as masked donor-donor carbene precursors that facilitate the insertion of carbon atoms bearing various functional groups to the library of functionalized quinoline. Experimental and DFT evidence support the transient presence of a cyclopropane species and removal of protecting groups.

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.

Chemoselective and Triggered Decomposition of Diazo Esters by the [(IMes)Rh2(OAc)4] Complex: En Route to Assisted Tandem Catalysis from Mixtures of Diazo Compounds

AbstractDecomposition of aryl and unsubstituted diazo ester into Rh(II)‐carbenes by the [(IMes)Rh2(OAc)4] complex is shown to be slower than with Rh2(OAc)4. Diazo esters substituted by a second electron‐withdrawing group do not suffer nitrogen extrusion when exposed for several hours to this (NHC)Rh(II) complex at room temperature. This chemoselective decomposition of diazo esters depending on their substituent (Ar, H, EWG) can furthermore be achieved on a mixture of substrates. The catalytic activity of [(IMes)Rh2(OAc)4] towards electron‐poor diazo compounds is also restored by heating to reflux in chloroform, or after decomplexation of the NHC by addition of GaCl3. The [(IMes)Rh2(OAc)4] complex was then used to induce a fully selective reaction cascade from a mixture of two diazo esters. First, a donor/acceptor diazo compound was decomposed selectively at room temperature to give an intermolecular O−H insertion product without any decomposition of the electron poor diazo compound. Addition of GaGl3 then triggered nitrogen extrusion from the diazo malonate to give a 1,5‐C−H insertion product. This transformation, where decomposition of diazo compounds catalyzed by Rh(II) complexes can be externally controlled, represents the first example of assisted tandem catalysis with two metal carbene precursors.

Mechanochemical Synthesis of Corannulene Flanked N-heterocyclic Carbene (NHC) Precursors and Preparation of Their Metal Complexes.

The synthesis of new compounds is an important pillar for the advancement of the field of chemistry and adjacent fields. In this regard, over the last decades huge efforts have been made to not only develop new molecular entities but also more efficient sustainable synthetic methodologies due to the increasing concerns over environmental sustainability. In this context, we have developed synthetic routes to novel corannulene flanked imidazolium bromide NHC precursors both in the solid-state and solution phases. Our work presents a comprehensive comparative study of mechanochemical routes and conventional solution-based methods. Green metrics and energy consumption comparison were performed for both routes revealing ball-milling generation of these compounds to be an environmentally greener technique to produce such precursors compared to conventional solvent-based methods. In addition, we have demonstrated proof-of-concept of the herein reported corannulene flanked NHCs to be robust ligands for transition metals and their ligand substitution reactions.

Transition-Metal-Catalyzed Directed C-H Bond Functionalization with Iodonium Ylides: A Review of the Last 5 Years.

Transition-metal-catalyzed directed C-H functionalization with various carbene precursors has been widely employed for constructing a wide range of complex and diverse active molecules through metal carbene migratory insertion processes. Among various carbene precursors, iodonium ylides serve as a novel and emerging carbene precursor with features including easy accessibility, thermal stability and high activity, which have attracted great attention from organic chemists and have achieved tremendous success in organic transformation. In this review, recent progress on the application of iodonium ylides with multifunctional coupling characteristics in C-H bond activation reactions is summarized, and the potential of iodonium ylides is discussed.

Stereodivergent Synthesis of Pyridyl Cyclopropanes via Enzymatic Activation of Pyridotriazoles.

Hemoproteins have recently emerged as powerful biocatalysts for new-to-nature carbene transfer reactions. Despite this progress, these strategies have remained largely limited to diazo-based carbene precursor reagents. Here, we report the development of a biocatalytic strategy for the stereoselective construction of pyridine-functionalized cyclopropanes via the hemoprotein-mediated activation of pyridotriazoles (PyTz) as stable and readily accessible carbene sources. This method enables the asymmetric cyclopropanation of a variety of olefins, including electron-rich and electrodeficient ones, with high activity, high stereoselectivity, and enantiodivergent selectivity, providing access to mono- and diarylcyclopropanes that incorporate a pyridine moiety and thus two structural motifs of high value in medicinal chemistry. Mechanistic studies reveal a multifaceted role of 7-halogen substitution in the pyridotriazole reagent toward favoring multiple catalytic steps in the transformation. This work provides the first example of asymmetric olefin cyclopropanation with pyridotriazoles, paving the way to the exploitation of these attractive and versatile reagents for enzyme-catalyzed carbene-mediated reactions.

Synthesis and Systematic Investigation of Lepidiline A and Its Gold(I), Silver(I), and Copper(I) Complexes Using In Vitro Cancer Models and Multipotent Stem Cells.

The imidazole alkaloid lepidiline A from the root of Lepidium meyenii has a moderate to low in vitro anticancer effect. Our aim was to extend cytotoxicity investigations against a panel of cancer cells, including multidrug-resistant cancer cells, and multipotent stem cells. Lepidiline A is a N-heterocyclic carbene precursor, therefore a suitable ligand source for metal complexes. Thus, we synthesized lepidiline A and its copper(I), gold(I), and silver(I) complexes and tested them against ovarian, gastrointestinal, breast, and uterine cancer cells and bone marrow-derived and adipose-derived mesenchymal stem cells. Lepidiline A and its copper complex demonstrated moderate cytotoxicity, while silver and gold complexes exhibited significantly enhanced and consistent cytotoxicity against both cancer and stem cell lines. ABCB1 in the multidrug-resistant uterine sarcoma line conferred significant resistance against lepidiline A and the copper-lepidiline A complex, but not against the silver and gold complexes. Our results indicate that only the copper complex induced a significant and universal increase in the production of reactive oxygen species within cells. In summary, binding of metal ions to lepidiline A results in enhanced cytotoxicity with the nature of the metal ion playing a critical role in determining its properties.

D4-Symmetric Dirhodium Tetrakis(binaphthylphosphate) Catalysts for Enantioselective Functionalization of Unactivated C-H Bonds.

Dirhodium tetrakis(2,2'-binaphthylphosphate) catalysts were successfully developed for asymmetric C-H functionalization with trichloroethyl aryldiazoacetates as the carbene precursors. The 2,2'-binaphthylphosphate (BNP) ligands were modified by introduction of aryl and/or chloro functionality at the 4,4',6,6' positions. As the BNP ligands are C2-symmetric, the resulting dirhodium tetrakis(2,2'-binaphthylphosphate) complexes were expected to be D4-symmetric, but X-ray crystallographic and computational studies revealed this is not always the case because of internal T-shaped CH-π and aryl-aryl interactions between the ligands. The optimum catalyst is Rh2(S-megaBNP)4, with 3,5-di(tert-butyl)phenyl substituents at the 4,4' positions and chloro substituents at the 6,6' positions. This catalyst adopts a D4-symmetric arrangement and is ideally suited for site-selective C-H functionalization at unactivated tertiary sites with high levels of enantioselectivity, outperforming the best dirhodium tetracarboxylate catalyst developed for this reaction. The standard reactions were conducted with a catalyst loading of 1 mol % but lower catalyst loadings can be used if desired, as illustrated in the C-H functionalization of cyclohexane in 91% ee with 0.0025 mol % catalyst loading (29,400 turnover numbers). These studies further illustrate the effectiveness of donor/acceptor carbenes in site-selective intermolecular C-H functionalization and expand the toolbox of catalysts available for catalyst-controlled C-H functionalization.

Enantioselective Construction of Quaternary Stereocenters via A Chiral Spiro Phosphoric Acid-Assisted Formal Gold Carbene gem-Dialkylation Reaction.

Enantioselective construction of all-carbon quaternary stereocenters has attracted much attention over the past few decades. A variety of catalytic asymmetric methods have been disclosed based on the use of presynthesized complex reagents that impart congested steric hindrance to the reaction center, which generally produce the chiral molecules through forming one C-C bond. The use of readily available reagents that could build two C-C bonds on the same carbonic center with the concomitant assembly of quaternary stereocenters remains challenging. Herein, we disclose a catalytic asymmetric alkyne multifunctionalization reaction using a gold complex and a chiral spiro phosphoric acid (SPA) for synergistic catalysis. In this method, the readily accessible internal alkynes served as the key gold carbene precursors, followed by carbene gem-dialkylation through Mannich-type addition of enolate species or stepwise formal cycloaddition with methylenimines that are derived from 1,3,5-triazinanes in the presence of SPA. The reaction provides practical access to poly-functionalized chiral linear and cyclic ketones that bear two adjacent quaternary stereocenters in generally good yields and excellent enantioselectivities, leading to an essential complement to the asymmetric construction of quaternary stereocenters using readily available materials with high bond formation efficiency.