Carbene Insertion Research Articles

Enantioselective Synthesis of Chiral Amines via Biocatalytic Carbene N-H Insertion.

Optically active amines represent highly valuable building blocks for the synthesis of advanced pharmaceutical intermediates, drug molecules, and biologically active natural products. Hemoproteins have recently emerged as promising biocatalysts for the formation of C-N bonds via carbene transfer, but asymmetric N-H carbene insertion reactions using these or other enzymes have so far been elusive. Here, we report the successful development of a biocatalytic strategy for the asymmetric N-H carbene insertion of aromatic amines with 2-diazopropanoate esters using engineered variants of myoglobin. High activity and stereoinduction in this reaction could be achieved by tuning the chiral environment around the heme cofactor in the metalloprotein in combination with catalyst-matching and tailoring of the diazo reagent. Using this approach, an efficient biocatalytic protocol for the synthesis of a broad range of substituted aryl amines with up to 82% ee was obtained. In addition, a stereocomplementary catalyst useful for accessing the mirror-image form of the N-H insertion products was identified. This work paves the way to asymmetric amine synthesis via biocatalytic carbene transfer, and the present strategy based on the synergistic combination of protein and diazo reagent engineering is expected to prove useful in the context of these as well as other challenging asymmetric carbene transfer reactions.

Site-Selective C–H Benzylation of Alkanes with N-Triftosylhydrazones Leading to Alkyl Aromatics

Summary Alkanes are an abundant and valuable resource for transformation into value-added fine chemicals. However, selective functionalization of specific C(sp3)–H bonds in alkanes for alkyl-alkyl bond formation is a significant challenge because of their intrinsic inertness and the small differences in reactivity among various C(sp3)–H bonds. Here, we report a silver-catalyzed site-selective C(sp3)–H benzylation of simple alkanes using N-triftosylhydrazones as a convenient carbene precursor, which enables the synthesis of high value-added alkylated aromatics. A one-pot two-step protocol starting from aldehydes was also realized, thereby constituting a formal reductive alkylation of aryl aldehydes by alkanes. Experimental investigations and DFT calculations reveal that the role of the [TpBr3Ag]2 catalyst is 3-fold: it modulates the carbene reactivity, inhibits carbene dimerization, and avoids over insertion of the product. All three aspects are crucial for the success of this first site-selective intermolecular insertion of donor carbenes into C(sp3)–H bonds of simple alkanes.

Cu/PCy3‐Catalyzed Formal Carbene Insertion into Electron‐Deficient C−H Bonds

AbstractA carbene insertion into electron‐deficient C−H bonds of 1,3‐diesters, β‐ketoesters, β‐ketonitriles, and malononitriles was realized by using CuCN/PCy3 as the catalyst. The reaction provides a straightforward approach to the synthetically important multi‐substituted succinic acid derivatives. A plausible reaction mechanism with cyclopropanation/ring opening as key steps was proposed based on control experiments.

Iridium‐Catalyzed Carbenoid Insertion of Sulfoxonium Ylides for Synthesis of Quinoxalines and β‐Keto Thioethers in Water

Sulfoxonium ylides as safe carbene precursors are described for iridium‐catalyzed carbene insertions and annulation, providing a facile and green approach to access a variety of quinoxaline derivatives in water. This water‐mediated method also allows the preparation of β‐keto thioethers under mild condition.

Semicontinuous Process for GMP Manufacture of a Carbapenem Intermediate via Carbene Insertion Using an Immobilized Rhodium Catalyst

A two-stage flow process for cGMP manufacture of a commercially important carbapenem intermediate was developed. Stage 1 featured an intramolecular N–H insertion reaction catalyzed by an immobilize...

Homogeneous functionalization of light alkanes

Light alkanes are the most abundantly available carbon-based feedstocks on earth and as major constituents of natural gas and oil-associated gas. Compared with oil, natural gas is considered a greener fuel and promising alternative for energy and chemical production. However, the grand challenge in the chemistry of light alkanes utilization is the development of an efficient method for the selective activation C–H bond. The transportation issue comes from the low boiling point. On the other hand, these unactivated molecules are hard to be activated under mild conditions because of their high bond dissociation energy and low acidity. Moreover, the functionalized products, such as ethylene or methanol, have higher reactivity than light alkanes. Due to these challenges, it is vital that develop efficient processes to achieve value-added convert under economic and green reaction conditions. In this review, we summarized the recent progress in the field of homogeneous functionalizations of light alkanes and was subtitled to four different aspects according to the mechanism, including electrophilic substitution, oxidative addition, carbene insertion, and free radical substitution. However, developing a new, lower temperature, economic, and green direct light alkanes conversion process is still needed to address.

An efficient method to prepare sulfoxonium ylides and their reactivity studies using copper powder and Sc(III) as catalysts: Molecular and electronic structure analysis

Sulfoxonium ylides are the viable alternatives for diazo compounds as carbene precursors. Unlike diazo compounds, these are bench‐stable and crystalline solids. However, the existing methods for the synthesis of sulfoxonium ylides have disadvantages related to the yields, substrate scope, and usage of expensive catalysts. Therefore, it is necessary to develop efficient and competitive protocols for the preparation of sulfoxonium ylides. In this study, we developed an economically affordable protocol for the synthesis of sulfoxonium ylides from diazo compounds using copper powder as a catalyst. This protocol leads to the efficient multigram‐scale synthesis of a wide range of sulfoxonium ylides in good yields. Further, we demonstrated scandium triflate–catalyzed carbene insertion into the N−H bond from sulfoxonium ylide. A variety of anilines and sulfoxonium ylides with various functional groups reacted well and produced the corresponding α‐amino esters in good yields. All the synthesized compounds were characterized using various standard spectroscopic and analytical techniques. We also used computational methods to understand the electronic structure of all the sulfoxonium ylides using geometry optimization, frequency calculation, molecular orbital and natural bond orbital analysis, and energy decomposition analysis. Our computational results revealed that the interaction between carbene and dimethyl sulfoxide is covalent in nature and stable enough to handle in the absence of any catalyst.

Highly Enantioselective O-H Bond Insertion Reaction of α-Alkyl- and α-Alkenyl-α-diazoacetates with Water.

Catalytic asymmetric reactions in which water is a substrate are rare. Enantioselective transition-metal-catalyzed insertion of carbenes into the O-H bond of water can be used to incorporate water into the stereogenic center, but the reported chiral catalysts give good results only when α-aryl-α-diazoesters are used as the carbene precursors. Herein we report the first highly enantioselective O-H bond insertion reactions between water and α-alkyl- and α-alkenyl-α-diazoesters as carbene precursors, with catalysis by a combination of achiral dirhodium complexes and chiral phosphoric acids or chiral phosphoramides. Participation of the phosphoric acids or phosphoramides in the carbene transfer reaction markedly suppressed competing side reactions, such as β-H migration, carbene dimerization, and olefin isomerization, and thus ensured good yields of the desired products. Fine-tuning of the ester moiety facilitated enantiocontrol of the proton transfer reactions of the enol intermediates and resulted in excellent enantioselectivity. This protocol represents an efficient new method for preparation of multifunctionalized chiral α-alkyl and α-alkenyl hydroxyl esters, which readily undergo various transformations and can thus be used for the synthesis of bioactive compounds. Mechanistic studies revealed that the phosphoric acids and phosphoramides promoted highly enantioselective [1,2]- and [1,3]-proton transfer reactions of the enol intermediates. Maximization of molecular orbital overlap in the transition states of the proton transfer reactions was the original driving force to involve the proton shuttle catalysts in this process.

Synthesis, Electrochemical and Spectroscopic Characterization of Selected Quinolinecarbaldehydes and Their Schiff Base Derivatives.

A new approach to the synthesis of selected quinolinecarbaldehydes with carbonyl groups located at C5 and/or in C7 positions is presented in this paper in conjunction with spectroscopic characterization of the products. The classical Reimer-Tiemann, Vilsmeier-Haack and Duff aldehyde synthesis methods were compared due to their importance. Computational studies were carried out to explain the preferred selectivity of the presented formylation transformations. A carbene insertion reaction based on Reimer-Tiemann methodology is presented for making 7-bromo-8-hydroxyquinoline-5-carbaldehyde. Additionally, Duff and Vilsmeier-Haack reactions were used in the double formylation of quinoline derivatives and their analogues benzo[h]quinolin-10-ol, 8-hydroxy-2-methylquinoline-5,7-dicarbaldehyde, 8-(dimethylamino) quinoline-5,7-dicarbaldehyde and 10-hydroxybenzo[h]quinoline-7,9-dicarbaldehyde. Four Schiff base derivatives of 2,6-diisopropylbenzenamine were prepared from selected quinoline-5-carbaldehydes and quinoline-7-carbaldehyde by an efficient synthesis protocol. Their properties have been characterized by a combination of several techniques: MS, HRMS, GC-MS, FTIR, electronic absorption spectroscopy and multinuclear NMR. The electrochemical properties of 8-hydroxy-quinoline-5-carbaldehyde, 6-(dimethylamino)quinoline-5-carbaldehyde and its methylated derivative were investigated, and a strong correlation between the chemical structure and obtained reduction and oxidation potentials was found. The presence of a methyl group facilitates oxidation. In contrast, the reduction potential of methylated compounds was more negative comparing to non-methylated structure. Calculations of frontier molecular orbitals supported the finding. The structures of 8-hydroxy-2-methylquinoline-5,7-dicarbaldehyde and four Schiff bases were determined by single-crystal X-ray diffraction measurements.

Front Cover: The TpxM Core in Csp3–H Bond Functionalization Reactions: Comparing Carbene, Nitrene, and Oxo Insertion Processes (Tpx = Scorpionate Ligand; M = Cu, Ag) (Eur. J. Inorg. Chem. 11‐12/2020)

Front Cover: The Tp^xM Core in C_sp³–H Bond Functionalization Reactions: Comparing Carbene, Nitrene, and Oxo Insertion Processes (Tp^x = Scorpionate Ligand; M = Cu, Ag) (Eur. J. Inorg. Chem. 11‐12/2020)

The TpxM Core in Csp3–H Bond Functionalization Reactions: Comparing Carbene, Nitrene, and Oxo Insertion Processes (Tpx = Scorpionate Ligand; M = Cu, Ag)

AbstractInvited for the cover of this issue is the group of Pedro J. Pérez from Universidad de Huelva, Spain. The cover image shows the three metal intermediates (carbene, nitrene, oxo) relevant to the group 11 metal‐catalyzed functionalization of carbon–hydrogen bonds of alkanes.

Synthesis of 1,2-azaphosphetidine 2-oxides/sulfides (microreview)

All reported approaches toward synthesis of 1,2-azaphosphetidine 2-oxide/sulfide derivatives are summarized. Synthetic methods for 1,2-azaphosphetidine 2-oxides/sulfides are gathered in four categories: ring expansion of aziridines, cyclizations, carbene insertions, and cycloadditions.

The TpxM Core in Csp3–H Bond Functionalization Reactions: Comparing Carbene, Nitrene, and Oxo Insertion Processes (Tpx = Scorpionate Ligand; M = Cu, Ag)

A comparison between three TpxM‐catalyzed (Tpx = scorpionate ligand; M = Cu, Ag) reactions leading to the functionalization of non‐activated, alkane Csp3–H bonds by carbene, nitrene or oxo insertion is presented. Analogies and differences in these transformations are discussed, including main reactive intermediates, selectivity trends and mechanistic interpretations.

C-H Insertion by Alkylidene Carbenes To Form 1,2,3-Triazines and Anionic [3 + 2] Dipolar Cycloadditions To Form Tetrazoles: Crucial Roles of Stereoelectronic and Steric Effects.

The synthesis of 1,2,3-triazines and bicyclic tetrazoles from α-azido ketones is described. The common intermediate generated from lithiated trimethylsilyldiazomethane and α-azido ketones diverges depending on the steric bulk of the substituents. The formation of 1,2,3-triazines via a C-H insertion of alkylidene carbene to form 3-azidocyclopropene, followed by its rearrangement, is supported by density functional theory calculations. Tetrazole formation proceeds via a facile anionic [3 + 2] dipolar cycloaddition between a lithiated diazo moiety and an azido group facilitated by the chelation of a lithium ion.

Rhodium-catalyzed coupling of arenes and fluorinated α-diazo diketones: synthesis of chromones.

Rhodium(iii)-catalyzed C-C coupling of heteroarenes and fluorinated α-diazo diketones has been realized for the facile synthesis of 3-arylchromones. The reaction proceeds via chelation-assisted C-H activation, carbene insertion, and uncatalyzed intramolecular nucleophilic aromatic substitution, with C-F cleavage being accommodated in the nucleophilic aromatic substitution step. Three classes of heteroarenes have been defined with decent functional group tolerance.

Stable abnormal N-heterocyclic carbenes and their applications.

Although N-heterocyclic carbenes (NHCs) have been known as ligands for organometallic complexes since the 1960s, these carbenes did not attract considerable attention until Arduengo et al. reported the isolation of a metal-free imidazol-2-ylidene in 1991. In 2001 Crabtree et al. reported a few complexes featuring an NHC isomer, namely an imidazol-5-ylidene, also termed abnormal NHC (aNHCs). In 2009, it was shown that providing to protect the C-2 position of an imidazolium salt, the deprotonation occurred at the C-5 position, affording imidazol-5-ylidenes that could be isolated. Over the last ten years, stable aNHCs have been used for designing a range of catalysts employing Pd(ii), Cu(i), Ni(ii), Fe(0), Zn(ii), Ag(i), and Au(i/iii) metal based precursors. These catalysts were utilized for different organic transformations such as the Suzuki-Miyaura cross-coupling reaction, C-H bond activation, dehydrogenative coupling, Huisgen 1,3-dipolar cycloaddition (click reaction), hydroheteroarylation, hydrosilylation reaction and migratory insertion of carbenes. Main-group metal complexes were also synthesized, including K(i), Al(iii), Zn(ii), Sn(ii), Ge(ii), and Si(ii/iv). Among them, K(i), Al(iii), and Zn(ii) complexes were used for the polymerization of caprolactone and rac-lactide at room temperature. In addition, based on the superior nucleophilicity of aNHCs, relative to that of their nNHCs isomers, they were used for small molecules activation, such as carbon dioxide (CO2), nitrous oxide (N2O), tetrahydrofuran (THF), tetrahydrothiophene and 9-borabicyclo[3.3.1]nonane (9BBN). aNHCs have also been shown to be efficient metal-free catalysts for ring opening polymerization of different cyclic esters at room temperature; they are among the most active metal-free catalysts for ε-caprolactone polymerization. Recently, aNHCs successfully accomplished the metal-free catalytic formylation of amides using CO2 and the catalytic reduction of carbon dioxide, including atmospheric CO2, into methanol, under ambient conditions. Although other transition metal complexes featuring aNHCs as ligand have been prepared and used in catalysis, this review article summarize the results obtained with the isolated aNHCs.

Diazoalkane decay kinetics from UVA-active protein labelling molecules: Trifluoromethyl phenyl diazirines

Trifluoromethyl phenyl diazirine (TPD) molecules are relatively stable carbene precursors, that readily form carbon covalent bonds with proteins. The stability of the diazoalkane intermediates is unknown, as are the factors which control carbene/diazoalkane ratios. This leads to incomplete carbene insertion onto desired compounds. Herein, stability and decay kinetics of diazoalkanes are evaluated from TPDs with various electron drawing groups, including 3-Phenyl-3-(trifluoromethyl)-3H-diazirine (TPD-H), p-benzyl alcohol (TPD-CH2OH), p-4-benzoic acid (TPD-COOH), and p-benzyl bromide (TPD-CH2Br). The spectroscopic analysis before and after UVA activation is performed both in dilute chloroform and neat by 19F NMR and ATR-FTIR, respectively. The increase of diazoalkane concentration after UVA exposure was in the order of: TPD-H > TPD-CH2Br > TPD-CH2OH > TPD-COOH. Indirect carbene/diazoalkane ratios ranged from 6: 1 to 3:1. Diazoalkane was relatively stable over the evaluation period of 30 min (post-UVA activation) in all compounds except TPD-CH2Br, which exhibits an 11 min half-life.

Catalytic O–H bond insertion reactions using surface modified sewage sludge as a catalyst

More economically and greener surface modified sewage sludge for carbene insertion of diazo compounds into O–H bond of phenols with good yields and high functional group tolerance.

Cooperative Catalysis with Transition Metal and Organic Molecule:Highly Enantioselective Carbene Insertion into N-H Bond of Aliphatic Amines

Cooperative Catalysis with Transition Metal and Organic Molecule:Highly Enantioselective Carbene Insertion into N-H Bond of Aliphatic Amines

Copper-catalyzed carbene insertion and ester migration for the synthesis of polysubstituted pyrroles.

Copper-catalyzed carbene insertion/ester migration/cyclization of enaminones and α-diazo compounds occurred efficiently to afford 2-ester polysubstituted pyrroles under mild conditions in moderate-to-good yields. Substituent functionality was well tolerated and 13C-labelled experiments demonstrated 1,2-ester migration during the reaction.