Insertion Reactions Research Articles

Synthesis of An Unsymmetrical Dialumane and Kinetic Analysis of Its Alkene Insertion.

An unsymmetrical dialumane was synthesized by the reaction of a nucleophilic alumanyl anion with a bromoalumane and it was structurally characterized to show the existence of the Et2O-coordination to the Al atom. The reactivity of the obtained Al-Al bond toward ethylene and styrene was examined, and the resulting insertion products underwent subsequent reactions. The reaction of the dialumane with styrene was decelerated by an addition of Et2O, suggesting that an Et2O dissociation occurred before the alkene insertion, which can be distinguished from an associative mechanism involving a five-coordinated Al intermediate.

Computational Insights into the Effect of Ligands and Transition-Metal Centers on the Mechanism and Regioselectivity of Hydrosilylation of Alkenes.

Development of sustainable synthetic methods for the hydrosilylation of alkenes, catalyzed by 3d transition metals, offers a promising alternative to traditional noble metal catalysts. This study presents a computational mechanistic investigation into the hydrosilylation of alkenes, focusing on the role of ligands and metal centers in modulating the reaction's mechanism and regioselectivity. The ligand's electronic and steric properties were found to modulate the regioselectivity for cobalt catalysts, with phosphine ligand (xantphos) promoting higher linear selectivity compared to nitrogen-based ligand (mesPDI). The energy decomposition analysis reveals that the xantphos ligand favors linear products due to stronger electrostatic and orbital interactions despite increased steric repulsion. The metal center also plays a crucial role, with cobalt catalysts favoring the modified Chalk-Harrod mechanism for branched product formation in the presence of PNN ligand (iPrPCNNMe), due to lower activation barriers in alkene insertion. Beneficial electrostatic and orbital interactions predominate, rendering the alkene insertion transition state for cobalt more favorable compared to that for iron. This work provides a comprehensive understanding of how ligand and metal center effects can be harnessed to control regioselectivity in hydrosilylation reactions.

Dealuminated H–Y zeolites generate, stabilize and catalytically insert carbenes from diazocarbonyl compounds

Carbenes are among the most powerful reactants in organic synthesis, with capacity to insert into a variety of otherwise stable bonds, and generate two new bonds in a straightforward manner. However, the intrinsic instability of such carbenes makes them to be catalytically generated, in–situ, from precursors such as diazocarbonyl compounds, and the catalyst, in turn, also controls the subsequent insertion reaction. The catalyst is generally a metal complex in solution, mainly Cu, Ag or Rh, but also others, including protons in rare cases. Here we show that carbenes are generated, stabilized and inserted into C–C, C–H, O–H, N–H, Si–H and O–O bonds after reacting diazocarbonyl compounds with catalytic amounts of metal–free, commercially available dealuminated H–Y zeolites. These results open the way to design carbene–mediated organic reactions on readily available and reusable catalytic solids without involving metals.

Understanding the Directed Evolution of a Natural-like Efficient Artificial Metalloenzyme.

The artificial metalloenzyme containing iridium in place of iron along with four directed evolution mutations C317G, T213G, L69V, and V254L in a natural cytochrome P450 presents an important milestone in merging the extraordinary efficiency of biocatalysts with the versatility of small molecule chemical catalysts in catalyzing a new-to-nature carbene insertion reaction. This is a show-stopper enzyme, as it exhibits a catalytic efficiency similar to that of natural enzymes. Despite this remarkable discovery, there is no mechanistic and structural understanding as to why it displays extraordinary efficiency after the incorporation of the four active site mutations by directed evolution methods, which so far has been intractable to any experimental methods. In this study, we have deciphered how directed evolution mutations gradually alter the protein conformational ensemble to populate a catalytically active conformation to boost a multistep catalysis in a natural-like artificial metalloenzyme using large-scale molecular dynamics simulations, rigorous quantum chemical (QM), and multiscale quantum chemical/molecular mechanics (QM/MM) calculations. It reveals how evolution precisely positions the cofactor-substrate in an unusual but effective orientation within a reshaped active site in the catalytically active conformation stabilized by C-H···π interactions from more ordered mutated L69V and V254L residues to achieve preferential transition state stabilization compared to the ground state. This work essentially tracks down in atomistic detail the shift in the conformational ensemble of the highly active conformation from the less efficient single mutant to the most efficient quadruple mutant and offers valuable insights for designing better enzymes. The active conformation correctly reproduces the experimental barrier height and also accounts for the catalytic effect, which is in good agreement with experimental observations. Moreover, this conformation features an unusual bonding interaction in a metal-carbene species that preferentially stabilizes the rate-determining formation of an iridium porphyrin carbene intermediate to render the observed high catalytic rate acceleration. Our study provides crucial insights into the underlying rationale for directed evolution, reports the major catalytic role of nonelectrostatic interactions in enzyme catalysis different from the electrostatic model, and suggests a crucial principle toward designing enzymes with natural efficiency.

Direct synthesis of α-functionalized amides via heteroatom–hydrogen insertion reactions using amide-sulfoxonium ylides

α-Functionalized Si-, Ge-, B-, Se-, and S-amide moieties are present in many medicinally active molecules, but their synthesis remains challenging. Here, we demonstrate a high-throughput synthesis using amide-sulfoxonium ylides as carbene precursors in a Si–H, Ge–H, B–H, Se–H, and S–H insertion reactions to target a wide range of α-silyl, α-geryl, α-boryl, α-selenyl, and α-sulfur (hetero)amides. The process is featured as simple operation, mild conditions, broad substrate scope, high functional group compatibility, and excellent chemoselectivity. Both experimental and computational studies are conducted to explore the mechanisms underlying the formation of C–Si/Ge/B/Se/S bond. This research highlights the use of highly selective X–H insertion reactions with amide-sulfoxonium ylide-derived carbenes, paving the way for the preparation of diverse functional organosilane, organogermane, organoboron, organoselenium, and organosulfur compounds from accessible and bench-stable precursors.

Ru(II)‐catalyzed ortho C−H Arylation of Heterocyclic Biaryls

AbstractRu(II)‐Pheox complexes are known catalysts for carbene insertion reactions. Herein we teach them a new trick: how to perform ortho C−H arylation processes! Our operationally simple protocol tolerates structurally diverse directing groups and both aryl iodides and diaryliodonium salts as transfer groups.

Molecular Dynamics of the Davies Ambimodal C-H Functionalization/Cope Rearrangement Reaction.

The mechanism of the dirhodium-catalyzed combined C-H functionalization/Cope rearrangement (CH/Cope) reaction discovered by the Davies group has been investigated with density functional theory (DFT) calculations and quasi-classical molecular dynamics (MD) simulations. Computations from the Davies group previously showed that there is a post-transition state bifurcation leading to a direct CH reaction and also to the CH/Cope product. While this work was in preparation, the Tantillo group and the Ess group independently reported quantum mechanical and molecular dynamics studies on the dirhodium-tetracarboxylate-catalyzed diazoester CH/Cope and CH insertion reactions with 1,3-cyclohexadiene and 1,4-cyclohexadiene, respectively. The Tantillo group cited "dynamic mismatching" to explain the origins of the low yield of CH/Cope products in some experiments; the Ess group explained the origins of product selectivity from the perspective of TS vibrational modes and their synchronization that occurs at the entropic intermediates. We report quasi-classical trajectories for the reaction of the carbene with 1-methylcyclohexene that afford both the CH/Cope and C-H insertion products. After passing through the transition state that involves mostly hydrogen transfer, momentum drives the reaction trajectories toward the CH/Cope products.

Cascade [3 + 2]/[4 + 2] Cycloaddition of Enaminones with Vinylene Carbonate for the Synthesis of Functionalized Pyrrolo[2,1-a]isoquinoline Derivatives.

We developed a protocol for the synthesis of functionalized pyrrolo[2,1-a]isoquinoline derivatives (PIQDs) 3 from enaminones 1 using vinylene carbonate 2. This strategy involved [3 + 2] and [4 + 2] cycloadditions via heating a mixture of substrates 1 with vinylene carbonate 2 and DCE at 60 °C, catalyzed by [Cp*RhCl2]2 and oxidized with Cu(OAc)2 and AgSbF6 promoted by NaOAc. As we increased the reaction temperature to 110 °C under the same conditions, we synthesized PIQDs 4 through sequential C-H activation, alkene insertion, migratory insertion, C-N reductive elimination, β-O elimination, and finally dehydration. As a result, a series of PIQDs 3-4 were generated by forming four bonds (2 C-C and 2 C-N bonds) in a single step. This strategy realizes the synthesis of linear molecules with potential biological activity, specifically natural-like heterocycles (3-4). It expands the application of vinylene carbonate as a C2 synthon in the construction of pyrrole and isoquinoline skeletons for the synthesis of functionalized PIQDs in combinatorial and parallel syntheses via one-pot reactions.

A Comparative Study of CH and mCH Mechanisms in Hydrosilylation Reactions

The cyclic process of Si-H oxidation addition, olefin insertion, and reductive elimination was discussed by density functional theory (DFT) and high-precision quantum chemical calculations. All the calculations were performed at the B3LYP-D3/def2-TZVP level. Two fundamental mechanisms of Chalk-Harrod (CH) and modified Chalk-Harrod (mCH) were explored, in the perspective of computational chemistry. Pt(PH3)2 was used as model for the renowned Speier's catalyst, while HSiR (R=(CH3)3 and CH3(OSi(CH3)3)2 and CH2=CHR’ (R’=H, CH2OH and CH2OCH2CH2OH) were used as the reactant models. Significant findings include the identification of the olefin insertion as the rate-determining step in both mechanisms.The energy barrier of rate-determining step was 27.6 kcal/mol and 41.0 kcal/mol, respectively, according to the CH mechanism and the mCH mechanism, when HSi(CH3)3 and CH2=CH2 were used as the reactant models. But the barrier of rate-determining step become to 27.2 kcal/mol and 28.4 kcal/mol, when HSiCH3(OSi(CH3)3)2 and CH2=CHCH2OCH2CH2OH were used as the reactant models. The difference in energy barriers betweeen the CH and mCH mechanisms become closer as the reactant models increase. The reaction between polyhydrosiloxane and allyl polyether may very potentially follow the mCH mechanism rather than CH mechanism.

Diazo‐Based Construction of Heterocyclic Systems Via a X−H Insertion/Cyclization Cascade

AbstractThe X−H insertion reaction (X=heteroatom) of diazo compounds has emerged as an eminent and reliant approach for the construction of C−X bonds. By merging X−H insertion with the sequential ring‐closing transformations, diverse heterocyclic systems can be obtained in a step‐economical manner. In recent years, the X−H insertion/cyclization cascades and one‐pot transformations attract more research attention, especially in the area of asymmetric synthesis. Concentrating on the assembly of N,O,S‐heterocycles, this Concept elucidates the various combinations of X−H insertion reactions with cyclization via an addition to multiple bonds. The ring‐forming strategies reviewed comprise of Michael‐type and Conia‐ene reactions, aldol condensation, and Mannich reaction.

Enantioselective Synthesis of Aminals Via Nickel-Catalyzed Hydroamination of 2-Azadienes with Indoles and N-Heterocycles.

New methods for the enantioselective synthesis of N-alkylated indoles and their derivatives are of great interest because indoles are pivotal structural elements in biologically active molecules and natural products. They are also versatile intermediates in organic synthesis. Among well-established asymmetric hydroamination methods, the asymmetric hydroamination with indole-based substrates is a formidable challenge. This observation is likely due to the reduced nucleophilicity of the indole nitrogen. Herein, a unique nickel-catalyzed enantio- and branched-selective hydroamination of 2-azadienes with indoles and structurally related N-heterocycles is reported for the generation of enantioenriched N,N-aminals. Salient features of this reaction include good yields, mild reaction conditions, high enantioselectivities, and broad substrate scope (60 examples, up to 96% yield and 99% ee). The significance of this approach with indoles and other N-heterocycles is demonstrated through structural modification of natural products and drug molecules and the preparation of enantioenriched N-alkylated indole core structures. Mechanistic studies reveal that olefin insertion into a Ni-H bond in the hydroamination is the enantio-determining step and oxidative addition of the N-H bond may be the turnover-limiting step.

Intramolecular Photochemical C−H Insertions of α‐Diazocarbonyl Compounds

AbstractIntramolecular photochemical C−H insertion reactions of α‐diazocarbonyl compounds are powerful synthetic transformations leading to carbon‐carbon bond formation. While there are limitations in the scope of C−H bonds amenable to C−H insertion under photochemical conditions relative to metal catalysed C−H insertions, the benefits of conducting these synthetically powerful transformations in a metal‐free approach offers “green” advantages. Recent advances in technology have revolutionised the potential for use of photochemical transformations in synthesis, including the wavelength control enabled by LEDs and the benefits associated with continuous flow processing which overcome many of the traditional challenges associated with synthetic photochemistry including scale‐up. The potential for telescoping the synthesis of α‐diazocarbonyl compounds and downstream photochemical reactions is clear. This review summarises the development of intramolecular photochemical C−H insertions and highlights the benefits of recent technological advances.

Combining Trifunctionalization of Alkynoic Acids, Arene ortho C-H Functionalization and Amination: An Approach to Unsymmetrical 2,3-Diaryl Substituted Indoles.

Here we report a simultaneous construction of two C-C and two C-N bonds in a unified procedure that incorporates alkynoic acid trifunctionalization, ortho C-H functionalization, and amination cascade. In an ordered process, the regioselective alkyne insertion reaction is favored over the decarboxylation process. The presence of the carboxyl group in alkynoic acid ensures the high regioselectivity in the carbopalladation process, paving the way for a novel method to synthesize unsymmetrically 2,3-diaryl substituted indole scaffolds with excellent regioselectivity. The protocol is demonstrated to be suitable for gram-scale synthesis.

A Strongly Ambiphilic Ferrocene-Based Cyclic (Alkyl)(amino)carbene - Specific Decomposition to an Enamine by a 1,2-Phenyl Shift.

The recently described crystalline cyclic (alkyl)(amino)carbene with a 1,1'-ferrocenylene (fc) backbone fc(CPh2-C-NMes) (A, Mes=mesityl) is highly reactive due to its particularly pronounced ambiphilicity and is thermally not stable in solution due to an intramolecular insertion of the divalent carbon atom into a methyl C-H bond of the Mes substituent. The closely related congener fc(CPh2-C-N-p-C6H4-tBu) (1) cannot undergo such an insertion reaction. Nevertheless, 1 is too short-lived for isolation due to a rapid 1,2-shift of a phenyl group, furnishing the isomeric cyclic enamine fc[C(Ph)=C(Ph)-N-p-C6H4-tBu] (1') in a specific decomposition process unprecedented for CAACs. Trapping of 1 was possible with carbon monoxide, elemental selenium and with [CuBr(SMe2)], respectively affording the aminoketene 1=C=O, the selenoamide 1=Se and the homoleptic CuI complex [Cu(1)2][CuBr2]. 1 is an even stronger ambiphile than A according to NMR spectroscopic data. Similar to A, 1 does not react with H2, because the experimentally observed intramolecular process is kinetically more favourable according to DFT results.

Hybrid Metal Catalysts as Valuable Tools in Organic Synthesis: An Overview of the Recent Advances in Asymmetric C─C Bond Formation Reactions.

Carbon-carbon bond formation represents a key reaction in organic synthesis, resulting in paramount importance for constructing the carbon backbone of organic molecules. However, traditional metal-based catalysis, despite its advantages, often struggles with issues related to efficiency, selectivity, and sustainability. On the other hand, while biocatalysis offers superior selectivity due to an extraordinary recognition process of the substrate, the scope of its applicable reactions remains somewhat limited. In this context, Artificial Metalloenzymes (ArMs) and Metallo Peptides (MPs) offer a promising and not fully explored solution, merging the two fields of transition metal catalysis and biotransformations, by inserting a catalytically active metal cofactor into a customizable protein scaffold or coordinating the metal ion directly to a short and tunable amino acid (Aa) sequence, respectively. As a result, these hybrid catalysts have gained attention as valuable tools for challenging catalytic transformations, providing systems with new-to-nature properties in organic synthesis. This review offers an overview of recent advances in the development of ArMs and MPs, focusing on their application in the asymmetric carbon-carbon bond-forming reactions, such as carbene insertion, Michael additions, Friedel-Crafts and cross-coupling reactions, and cyclopropanation, underscoring the versatility of these systems in synthesizing biologically relevant compounds.

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.

Photogeneration of β-Borylsilyl Radical via Decarboxylation of N-Hydroxyphthalimide Esters.

Gem-borylsilylalkanes are versatile intermediates in organic synthesis, and the traditional synthesis methods have mainly focused on metal reagents, the insertion reactions of diazo compounds, and hydrosilylation/hydroborylation reactions of unsaturated bonds. Herein, a novel, efficient gem-borylsilylalkanes synthesis via a radical approach is reported. This method introduced a β-gem-borylsilyl NHPI ester as the precursor of the β-borylsilyl radical that, coupling with radical acceptors under photo conditions, and the corresponding gem-borylsilylalkanes bearing unsaturated bonds, facilitate subsequent transformations.

Engineering Neuroglobin for Synthesis of Chiral Organoborons via Carbene B-H Insertion.

Organoborons have recently received much attention, while a biocatalytic platform for the synthesis of chiral organoborons is limited only to Rma cytochrome c. In this study, we exploited the other heme protein, neuroglobin (Ngb), and engineered a quadruple mutant, A15C/H64G/V68F/F28M Ngb, by redesigning the heme active site using the structural information on A15C Ngb and molecular docking studies. The enzyme was shown to be efficient in catalyzing carbene transfer B-H insertion reactions between pyridine/quinoline boranes and benzyl 2-diazopropanoates and their derivatives (29 examples). The designed cavity in the heme distal site favors the binding of large volume substrates such as those containing a quinoline, naphthyl, or biphenyl group. As further determined by the X-ray crystallography of 6c, the chiral products are in the R-configuration, with up to 98:2 e.r. Furthermore, both the whole cell and cell lysate containing the enzyme are reactive toward the B-H insertion reactions. This study presents a convenient biocatalytic platform that may be generally applicable for the synthesis of functional chiral organoborons.

High-throughput experimentation and machine learning-promoted synthesis of α-phosphoryloxy ketones via Ru-catalyzed P(O)O-H insertion reactions of sulfoxonium ylides

High-throughput experimentation and machine learning-promoted synthesis of α-phosphoryloxy ketones via Ru-catalyzed P(O)O-H insertion reactions of sulfoxonium ylides

DNA Replication across α-l-(3'-2')-Threofuranosyl Nucleotides Mediated by Human DNA Polymerase η.

α-l-(3'-2')-Threofuranosyl nucleic acid (TNA) pairs with itself, cross-pairs with DNA and RNA, and shows promise as a tool in synthetic genetics, diagnostics, and oligonucleotide therapeutics. We studied in vitro primer insertion and extension reactions catalyzed by human trans-lesion synthesis (TLS) DNA polymerase η (hPol η) opposite a TNA-modified template strand without and in combination with O4-alkyl thymine lesions. Across TNA-T (tT), hPol η inserted mostly dAMP and dGMP, dTMP and dCMP with lower efficiencies, followed by extension of the primer to a full-length product. hPol η inserted dAMP opposite O4-methyl and -ethyl analogs of tT, albeit with reduced efficiencies relative to tT. Crystal structures of ternary hPol η complexes with template tT and O4-methyl tT at the insertion and extension stages demonstrated that the shorter backbone and different connectivity of TNA compared to DNA (3' → 2' versus 5' → 3', respectively) result in local differences in sugar orientations, adjacent phosphate spacings, and directions of glycosidic bonds. The 3'-OH of the primer's terminal thymine was positioned at 3.4 Å on average from the α-phosphate of the incoming dNTP, consistent with insertion opposite and extension past the TNA residue by hPol η. Conversely, the crystal structure of a ternary hPol η·DNA·tTTP complex revealed that the primer's terminal 3'-OH was too distant from the tTTP α-phosphate, consistent with the inability of the polymerase to incorporate TNA. Overall, our study provides a better understanding of the tolerance of a TLS DNA polymerase vis-à-vis unnatural nucleotides in the template and as the incoming nucleoside triphosphate.