Metal Carbenoid Research Articles

Flow Chemistry of Metal Carbenoid Species towards Selective Organic Synthesis

AbstractThis review deals with C1 carbenoid chemistry, with a focus on lithium carbenoid species generated in flash flow systems. Strict control of the temperature, residence time, and mixing efficiency has led to various transformation reactions involving epoxidation, cyclopropanation, and homologation, among others. The use of other metal species, including trifluoromethylpotassium (CF3K) and magnesium/ zinc carbenoids, in flow systems is also introduced.1 Introduction1.1 Lithium Carbenoids in C1 Chemistry1.2 Flow Chemistry for C1 Lithium Carbenoids2 Flow Reactions Involving Carbenoid Species2.1 Deprotonative Generation of Lithium Carbenoid Species2.2 Generation of Lithium Carbenoid Species via Halogen–Lithium Exchange2.3 Generation of Lithium Carbenoid Species via Reductive Lithiation2.4 Generation of Lithium Carbenoid Species via Alkyllithiation2.5 Generation of Trifluoromethylpotassium Species in Flow2.6 Generation of Other Metal Carbenoid Species3 Conclusion

Synthesizing Silyl Arylsulfonyl hydrazones as Silyldiazomethane Precursors and Their Use in Rhodium‐catalyzed Reactions

A method for synthesizing silyl arylsulfonyl hydrazones as silyldiazomethane precursors has been developed. Although silyldiazomethanes are an important class of diazo compounds, their use in intramolecular cyclization reactions has not been fully explored despite the rich chemistry of diazo compounds, particularly metal carbenoid chemistry. The fundamental challenge underlying the absence of such studies is the lack of a method for synthesizing silyldiazomethanes with functional groups that can react with metal carbenoids. The method reported here provides access to variety of silyl arylsulfonyl hydrazones with functional groups such as ethers, carbamates, and alkynes, which can serve as reaction sites for metal carbenoids. A one‐pot hydrazone formation using unstable formylsilane formed in situ is key to a successful synthesis. The use of 2,4,6‐trimethylbenzenesulfonohydrazide contributed toward achieving broad generality in hydrazone formation. The synthetic potential of this method was demonstrated through the generation of silyldiazomethane and its transformation to several silacycles.

Eco-friendly anaerobic oxidation of aryl diazo esters with heterocyclic N-oxide under ball milling: synthesis of 1,2-dicarbonyl systems

Herein we report anaerobic oxidation of metal carbenoids generated from aryl diazo esters under ball milling with heterocyclic N-oxide in the presence of catalytic copper(i) to afford 1,2-dicarbonyls in excellent yield.

A Combination of Computational and Experimental Studies to Correlate Electronic Structure and Reactivity of Donor–Acceptor Singlet Carbenes

AbstractMost of the reactivities of donor–acceptor (D–A) singlet carbenes are similar to metal carbenoids. However, the lone pair at the carbenoid carbon, coordinated with metal, is free in D–A carbene thereby making it nucleophilic as well. Herein, DFT-optimized structural features of D–A carbene has been investigated and is compared with rhodium carbenoid. It was observed that, when a D–A carbene reacts with cyclic-1,3-diones in different ethereal solvents, it is the lone pair at the sp2 orbital of the carbene that abstracts the proton from the enol form (of the cyclic-1,3-diones) to form a benzylic carbocation and an enolate. Subsequently, the carbocation undergoes nucleophilic attack by O of the ether solvents and then by the enolate to afford the desired ether-linked products. Accordingly, herein the reaction in THF, which otherwise had failed to work as a substrate in reported amino etherification reactions, worked well. DFT-calculated orbital energy levels and reaction profile support this reverse reactivity of singlet carbenes. Furthermore, HOMO–LUMO calculations indicated that electron-rich arenes in D–A carbene stabilizes the LUMO and destabilizes the HOMO which increases yield. Additionally, a library of 37 enol ether and 39 ether-linked compounds of potential medicinal relevance have been synthesized with good to excellent yields using numerous cyclic-1,3-diones.

Dynamic Kinetic Stereoselective Glycosylation via RhII and Chiral Phosphoric Acid‐Cocatalyzed Carbenoid Insertion to the Anomeric OH Bond for the Synthesis of Glycoconjugates

AbstractChemical synthesis of glycoconjugates is essential for studying the biological functions of carbohydrates. We herein report an efficient approach for the stereoselective synthesis of challenging α‐linked glycoconjugates via a RhII/chiral phosphoric acid (CPA)‐cocatalyzed dynamic kinetic anomeric O‐alkylation of sugar‐derived lactols via carbenoid insertion to the anomeric OH bond. Notably, we observed excellent anomeric selectivity, excellent diastereoselectivity, broad substrate scope, and high efficiency for this glycosylation reaction by exploring various parameters of the cocatalytic system. DFT calculations suggested that the anomeric selectivity was mainly determined by steric interactions between the C2‐carbon of the carbohydrate and the phenyl group of the metal carbenoid, while π/π interactions with the C2−OBn substituent on the carbohydrate substrate play a significant role for diastereoselectivity at the newly generated stereogenic center.

Dynamic Kinetic Stereoselective Glycosylation via RhII and Chiral Phosphoric Acid-Cocatalyzed Carbenoid Insertion to the Anomeric OH Bond for the Synthesis of Glycoconjugates.

Chemical synthesis of glycoconjugates is essential for studying the biological functions of carbohydrates. We herein report an efficient approach for the stereoselective synthesis of challenging α-linked glycoconjugates via a RhII /chiral phosphoric acid (CPA)-cocatalyzed dynamic kinetic anomeric O-alkylation of sugar-derived lactols via carbenoid insertion to the anomeric OH bond. Notably, we observed excellent anomeric selectivity, excellent diastereoselectivity, broad substrate scope, and high efficiency for this glycosylation reaction by exploring various parameters of the cocatalytic system. DFT calculations suggested that the anomeric selectivity was mainly determined by steric interactions between the C2-carbon of the carbohydrate and the phenyl group of the metal carbenoid, while π/π interactions with the C2-OBn substituent on the carbohydrate substrate play a significant role for diastereoselectivity at the newly generated stereogenic center.

Activation of Diazo Compounds by Fluorinated Triarylborane Catalysts

AbstractThe diverse applicability of diazo compounds as versatile reagents has enlarged the chemical toolbox in organic synthesis. Over the past few decades, transition-metal-catalyzed diazo compound activation has ignited the classical synthetic methodology via utilizing highly reactive metal carbenoid species. Many reviews have also appeared in the literature that show the advantages and disadvantages of metal-catalyzed activation of diazo compounds. Recently, tris(pentafluorophenyl)borane-mediated diazo activation reactions has remodeled this research area due to the potential for mild, environmentally friendly, metal-free, nontoxic reaction conditions, and the diverse reactivity patterns of boranes towards diazo compounds. In this review, we discuss the reactivity of the boron–diazo precursor adducts with compounds using catalytic and stoichiometric halogenated triarylboranes and, the mechanism of N2 release from the diazo reagent. This generates the reactive carbene species as a key intermediate which can further be exploited for O–H, N–H, S–H, and C–H insertions, azide insertion, carbonate transfer, C–C and C=C bond forming reactions, [2+2] or [2+4] cascade cyclization reactions, annulation reactions, etc.1 Introduction2 Diazo Activation Using Stoichiometric Boranes3 Diazo Activation Using Catalytic B(C6F5)3 4 B(C6F5)3-Catalyzed Diazo Activation Reactions5 Conclusions

Metal-free synthesis and study of glycine betaine derivatives in water for antimicrobial and anticancer applications

A sustainable synthesis of interesting glycine betaine derivatives from cyclic 3°-amines viz. N-methyl morpholine (NMM), N-methyl piperidine (NMP), and 1,4-diazabicyclo[2.2.2]octane (DABCO) with numerous aryl diazoacetates 1 in water and under blue LED is reported. Generally, 3°-amines and metal carbenoids (from diazoacetates with transition metal catalysts) provide C-H insertion at the α-position of the amines. Computational comparison of the metal carbenoid with the singlet carbene (metal free and generated under blue LED) realized the difference in reactivity. Next, experimental results corroborated the preliminary findings. The products were isolated either by precipitation of the solid or gel-like final products from the aqueous reaction mixture without any chromatographic purification. The reaction mechanism was realized by control experiments. These compounds exhibit selective bactericidal properties against Gram-positive S.aureus, induce lipid droplets (LDs) formation in HePG2 cells and single crystal X-ray diffraction study of their halogenated analogs reveal interesting Hal … Hal contacts.

1,2,3-Triazole and Its Analogues: New Surrogates for Diazo Compounds.

Readily accessible and shelf-stable 1,2,3-triazole and its analogues such as pyridotriazole, triazoloindole, benzotriazole, and thiadiazole exist in equilibrium with their ring-opened isomers, viz., diazo compounds. These ring-opened isomers could be trapped by various metal catalysts (e.g., Rh, Pd, Cu, Co, Ag, etc.) to generate the corresponding metal carbenoids with extrusion of nitrogen. As a consequence, these unique N-heterocycles facilitate access to a realm of N-containing complex structural motifs of biological importance through denitrogenative transformations such as transannulations, insertions, ylide formation, and rearrangements by trapping of the metal carbenoids with a diverse range of coupling partners (e.g., alkenes, alkynes, nitriles, carbo/heterocycles, X-H/C-X bonds, etc.). Hence, suitably substituted triazole derivatives have emerged as efficient surrogates of diazo compounds for the generation of reactive metal carbenoids during the past decades. In this comprehensive review, we aim to discuss in detail the remarkable advancement in their synthesis and synthetic applications.

Metal‐Catalyzed Approaches for the Construction of Azepinones

AbstractThe azepinone scaffolds are an important framework of pharmaceutically interesting compounds and many bioactive natural products. This review mainly focused on the metal‐catalyzed approaches towards the synthesis of azepinones (2001–2021). Mainly it covers cycloisomerization and metal carbenoid insertion. It also involves transformations through cycloaddition reactions, metathesis reactions, microwave reactions and direct C−H/C−C/C−N activation reactions. The applications, substrate scope, limitations and plausible mechanisms of these transformations have also been discussed.

Biocatalytic activation of diazirines for carbene-transfer reactions

Diazirines have been traditionally associated with chemical biology and materials chemistry, but their utility has been limited in organic chemistry. Recently in the <i>Journal of the American Chemical Society</i>, Arnold and co-workers employed diazirines as precursors to hemoprotein-derived metal carbenoid species.

Overcoming O-H Insertion to Para-Selective C-H Functionalization of Free Phenols: Rh(II)/Xantphos Catalyzed Geminal Difunctionalization of Diazo Compounds.

Para-selective C–H functionalization of free phenols by metal carbenoids is rather challenging due to the generally more favorable competing O–H insertion. Herein, with the use of the combination of Rh(II) and a Xantphos ligand as the catalyst, a novel multicomponent reaction of free phenols, diazoesters, and allylic carbonates was successfully developed, affording a wide variety of phenol derivatives, bearing an all-carbon quaternary center and a synthetically useful allylic unit. This reaction is likely to occur through a tandem process of carbene-induced para-selective C–H functionalization, followed by Rh(II)/Xantphos-catalyzed allylation. The distinctive reactivity of para-selective C–H rather than O–H insertion for the carbenoid intermediate, combined with features of excellent functional group compatibility, high atom and step economy, and ease in further diversification of the products, might render this protocol highly attractive in facile functionalization of unprotected phenols.

Lithiation–borylation methodology in the total synthesis of natural products

Robust synthetic methods that show a broad substrate scope are of great utility in the synthesis of complex organic molecules. Within this arena, synthetic methods that employ boronic esters are especially useful because they undergo a wide variety of transformations with very high levels of stereoselectivity. In particular, boronic esters can undergo single or multiple homologations using enantioenriched metal carbenoids. The addition of a suitable enantioenriched lithium or magnesium carbenoid to a boronic ester, with subsequent 1,2-migration, gives a homologated boronic ester with high stereocontrol. This process, termed lithiation–borylation, can be iterative, which allows a carbon chain to be extended one atom at a time with remarkable precision. The iterative homologation has been likened to a molecular assembly line and resembles the way nature assembles natural products, for example, in polyketide synthase machinery. The application of lithiation–borylation chemistry to the synthesis of a broad variety of natural products is discussed in this Review.

The Second-Generation Click-to-Sense Probe for Intraoperative Diagnosis of Breast Cancer Tissues Based on Acrolein Targeting

Abstract Recently, we found that a bulky 2,6-diisopropylphenyl azide is more reactive than a simple phenyl azide toward acrolein. Herein, we conjugated tetramethylrhodamine (TAMRA) to the bulky phenyl azide and utilized it as a second-generation click-to-sense (CTS) probe to analyze cancer by targeting the cellular acrolein. Subsequently, we observed that this second-generation CTS probe could distinguish breast cancer tissues with higher sensitivity than the first-generation CTS probe. Moreover, adding Rh2(OAc)4 to the system promotes the formation of a metal carbenoid intermediate that accelerates the covalent attachment of the probe to an organelle in the cancer cells.

Rh-Catalyzed Coupling of Acrylic/Benzoic Acids with α-Diazocarbonyl Compounds: An Alternative Route for α-Pyrones and Isocoumarins.

A coupling of acrylic acids/benzoic acids with α-diazocarbonyl compounds has been realized by a combined catalytic system of rhodium catalyst and Zn(OAc)2 additive. The presence of Zn(OAc)2 obviously accelerates the C(sp2)-H activation and destructed the formation of carboxylic ester that is formed via a nucleophilic O-H insertion to metal carbenoid. The procedure featured mild reaction conditions and broad substrate scope, providing a straightforward approach to the synthesis of α-pyrones and isocoumarins without the transformation of carboxylic acids to the corresponding amides.

Palladium-Catalyzed Asymmetric Tandem Denitrogenative Heck/Tsuji–Trost of Benzotriazoles with 1,3-Dienes

The asymmetric denitrogenative cycloaddition has emerged as a powerful tool to build chiral aza-heterocyles. However, only one example of asymmetric denitrogenative cycloaddition of benzotriazole with unsaturated hydrocarbons has been explored so far, because the ring-opening of benzotriazole to generate α-imino metal carbenoid species is a thermodynamically unfavorable process. We herein report an efficient asymmetric denitrogenative cycloaddition of benzotriazoles with cyclic and acyclic 1,3-dienes enabled by Pd and chiral sulfonamide phosphine ligand. A variety of substituted hexahydrocarbazoles and indolines were delivered in good yields with high ee values. Interestingly, a pair of enantiomers could be obtained with the use of Xu1 and PC2 with the same absolute configuration. The synthetic utilities of the optically active hexahydrocarbazoles were also showcased.

Recent Achievements in the Rhodium‐Catalyzed Concise Construction of Medium N‐Heterocycles, Azepines and Azocines

AbstractMedium N‐heterocycles, azepines and azocines, serve as important skeletons that occurred widely in natural products, however, due to the lack of efficient synthetic methodologies, their application potential in biologically active molecules, pharmaceuticals and agrochemicals remained to be explored. In this context, rhodium catalysis in this field featured good reactivity and functional group tolerance, with readily available starting materials, and enabled rapid access to the azepines and azocines. Delightfully, great achievements in the concise construction of these 7 and 8‐membered N‐heterocycles under rhodium catalysis have been made, which mainly included cycloisomerization of unsaturated C−X bonds (which might also combine the ring‐opening strategy on strained rings), metal carbenoid or nitrene insertion involved transformations and direct C−H activation reactions. Considering the great performance of rhodium catalyst in the synthesis of azepines and azocines, herein, we summarized the recent results in this field, and wish to give further insight and inspired more encouraging methodologies and new drug discovery based on these 7 and 8‐membered N‐heterocycles.magnified image

Solvation Effects on the Structure and Stability of Alkali Metal Carbenoids.

s‐Block metal carbenoids are carbene synthons and applied in a myriad of organic transformations. They exhibit a strong structure–activity relationship, but this is only poorly understood due to the challenging high reactivity and sensitivity of these reagents. Here, we report on systematic VT and DOSY NMR studies, XRD analyses as well as DFT calculations on a sulfoximinoyl‐substituted model system to explain the pronounced solvent dependency of the carbenoid stability. While the sodium and potassium chloride carbenoids showed high stabilities independent of the solvent, the lithium carbenoid was stable at room temperature in THF but decomposed at −10 °C in toluene. These divergent stabilities could be explained by the different structures formed in solution. In contrast to simple organolithium reagents, the monomeric THF‐solvate was found to be more stable than the dimer in toluene, since the latter more readily forms direct Li/Cl interactions which facilitate decomposition via α‐elimination.

Unusual multiple insertion of diazo carbonyl compounds into (purin-6-yl)benzene derivative

The consecutive alkylation of 9-isopropyl-6-phenyl-9H-purine with methyl 2-diazo-3,3,3-trifluoropropionate and diethyl diazomalonate proceeds at the phenyl substituent firstly via ortho-C–H activation under chelation-assistance of the purine core, followed by classical electrophilic metal carbenoid insertion to the C−H bond of a malonate moiety.

Rhodium-Catalyzed Intermolecular Cyclopropanation of Benzofurans, Indoles, and Alkenes via Cyclopropene Ring Opening.

The generation of metal carbenoids via ring opening of cyclopropenes by transition metals offers a simple entry into highly reactive intermediates. Herein, we describe a diastereoselective intermolecular rhodium-catalyzed cyclopropanation of heterocycles and alkenes using cyclopropenes as carbene precursors with a low loading of a commercially available rhodium catalyst. The reported method is scalable and could be performed with catalyst loadings as low as 0.2 mol %, with no impact to the reaction yield or selectivity.