Insertion Reactions Research Articles

Hydroformylation of 1‐butene to N‐pentanal on Co‐based Materials Derived from ZIF‐67: Optimization of Pyrolysis Conditions and DFT Study

AbstractWe prepared the Co‐based materials via the pyrolysis of ZIF‐67 at low temperature (250 °C~350 °C), and obtained the optimum catalyst ZIF‐67‐Sg‐350‐10 with the conversion of 1‐butene, aldehyde selectivity and n/i ratio of 94.9 %, 77.1 % and 2.2, respectively. The conversion of 1‐butene and aldehyde selectivity obviously increased with the increasing pyrolysis temperature and pyrolysis time. It was found that the interaction between the Co cluster and N‐doped carbon composites could improve the hydroformylation activity. Different catalyst models were built to investigate the active centers (Co) in the derived materials. The Co‐N4 surface was the best catalyst model with the lowest hydrogen insertion reaction energy barrier (0.37 eV).

Anti-Selective Synthesis of Substituted β-Homoprolines by Rhodium Alkyl Nitrene C–H Insertion

AbstractA range of β-homoprolines was prepared with high anti-selectivity. An intramolecular C–H insertion reaction involving a rhodium alkyl nitrene is a key step in the ring construction. The carboxylic acid in the products can serve as a springboard for further downstream transformations.

Diphosphine Ligand‐Enabled Nickel‐Catalyzed Chelate‐Assisted Inner‐Selective Migratory Hydroarylation of Alkenes

AbstractThe precise control of the regioselectivity in the transition metal‐catalyzed migratory hydrofunctionalization of alkenes remains a big challenge. With a transient ketimine directing group, the nickel‐catalyzed migratory β‐selective hydroarylation and hydroalkenylation of alkenyl ketones has been realized with aryl boronic acids using alkyl halide as the mild hydride source for the first time. The key to this success is the use of a diphosphine ligand, which is capable of the generation of a Ni(II)‐H species in the presence of alkyl bromide, and enabling the efficient migratory insertion of alkene into Ni(II)‐H species and the sequent rapid chain walking process. The present approach diminishes organosilanes reductant, tolerates a wide array of complex functionalities with excellent regioselective control. Moreover, this catalytic system could also be applied to the migratory hydroarylation of alkenyl azahetereoarenes, thus providing a general approach for the preparation of 1,2‐aryl heteroaryl motifs with wide potential applications in pharmaceutical discovery.

Diphosphine Ligand-Enabled Nickel-Catalyzed Chelate-Assisted Inner-Selective Migratory Hydroarylation of Alkenes.

The precise control of the regioselectivity in the transition metal-catalyzed migratory hydrofunctionalization of alkenes remains a big challenge. With a transient ketimine directing group, the nickel-catalyzed migratory β-selective hydroarylation and hydroalkenylation of alkenyl ketones has been realized with aryl boronic acids using alkyl halide as the mild hydride source for the first time. The key to this success is the use of a diphosphine ligand, which is capable of the generation of a Ni(II)-H species in the presence of alkyl bromide, and enabling the efficient migratory insertion of alkene into Ni(II)-H species and the sequent rapid chain walking process. The present approach diminishes organosilanes reductant, tolerates a wide array of complex functionalities with excellent regioselective control. Moreover, this catalytic system could also be applied to the migratory hydroarylation of alkenyl azahetereoarenes, thus providing a general approach for the preparation of 1,2-aryl heteroaryl motifs with wide potential applications in pharmaceutical discovery.

Direct Access to Quinazolines and Pyrimidines from Unprotected Indoles and Pyrroles through Nitrogen Atom Insertion.

Recent advances in single-atom insertion reactions have opened up new synthetic approaches for molecular diversification. Developing innovative strategies to directly transform biologically relevant molecules, without any prefunctionalization, is key to further expanding the scope and utility of such transformations. Herein, the direct access to quinazolines and pyrimidines from the corresponding unprotected 1H-indoles and 1H-pyrroles is reported, relying on the implementation of lithium bis(trimethylsilyl)amide (LiHMDS) as a novel nitrogen atom source in combination with commercially available hypervalent iodine reagents. Further application of this strategy in late-stage settings demonstrates its potential in lead structure diversification campaigns.

Crystal Engineering of Silica Anode Achieving Intrinsic Zero-Strain.

Si-based anodes have large intrinsic volume expansion, which hinders their practicality and commercialization. To address this challenge, the design principle of intrinsic zero-strain anodes (① large intracrystalline cavities and ② strong bonds) is proposed, and silica with large intracrystalline cavities (SLIC) established by strong Si─O bonds ([SiO4 ] coordinate structures) is obtained and acts as an anode, achieving the intrinsic zero-strain feature first in silicon-based anodes. The phase structure of SLIC is maintained and the [SiO4 ] coordinate structure merely shows slight disorder during cycling. The feature stems from lithiation taking place by the solid-solution insertion reaction rather than the conventional conversion/alloying addition reactions, because the solid-solution insertion reaction for the SLIC has the lowest change in the Gibbs free energy. The SLIC anode demonstrates excellent cycling stability and high initial Coulombic efficiency (≈85%). Moreover, owing to the low working voltage (≈0.28V) and relatively high specific capacity, the SLIC anode presents the highest gravimetric energy density among reported zero-/quasi-zero-strain anodes and high volumetric energy density (around twice as much as graphite). The universality of the designing principle is also validated. This work provides design guidelines for zero-strain anodes in next-generation batteries.

Mechanistic Studies on Oxygen-Insertion into Osmium(III)–Carbon Bond via High-Valent Oxido-Osmium(V) Complex

Abstract An osmium(III)-metalacycle complex consisting of 2-phenylpyridine is converted to the 2-phenoxidopyridine-osmium(III) complex upon treatment with a tertiary amine N-oxide, where a high-valent oxido-osmium(V) complex is proposed as a key reactive intermediate (H. Sugimoto et al. Organometallics, 2021, 40, 102–106). To gain insight into the reaction mechanism, substituent effects of 2-phenylpyridine moiety on the oxygen atom insertion reaction are examined using a series of 2-(4-X-phenyl)pyridines. All the cyclometalated complexes react with the tertiary amine N-oxide to produce the phenoxido-osmium(III) complexes. Kinetic analyses are conducted on the adduct formation process and the oxygen insertion reaction. In the former process, the binding constant of the amine N-oxide to the osmium(III) center is not influenced by electron withdrawing nature of the substituent X, but decrease of the reaction rate is observed in the latter process as electron withdrawing nature of X increases. Furthermore, the electronic effects of the amine N-oxides are examined using p-substituted N,N-dimethylaniline N-oxide (p-Y-C6H4N(O)(Me)2) to find that reaction rates increase as the electron withdrawing nature of Y increases. These results are consistent with the proposed mechanism in which the C–O bond formation involves conversion of the osmium(III)-N-oxide adduct to its oxido-osmium(V) species as the active oxidant.

Base Promoted Synthesis of 4‐Quinolones Fused with Medium‐Sized Rings

AbstractIn the presence of cesium carbonate, ynones bearing an ortho‐amino group reacted with cyclic β‐ketoesters through conjugated addition/carbon‐carbon σ‐bond cleavage/nucleophilic aromatic substitution tandem reaction to obtain 4‐quinolones fused with medium‐sized rings in good yields. This is the first example of synthesis of 4‐quinolones through base‐promoted insertion reactions of carbon‐carbon triple bonds into carbon‐carbon σ‐bonds. Notable features of this program are mild and transition‐metal‐free reaction conditions.

Maltose-Derivatized Fluorescence Turn-On Imaging Probe for Bacteria Detection.

We report a maltose-derivatized fluorescence turn-on imaging probe, Mal-Cz, to detect E. coli and Staphylococci. The fluorescence turn-on is achieved through an intramolecular C-H insertion reaction of the perfluoroaryl azide-functionalized carbazole to give a fluorescent product. Confocal fluorescence microscopy confirmed the successful uptake of Mal-Cz by E. coli and Staphylococci upon photoactivation. The Mal-Cz probe could selectively detect E. coli and S. epidermidis in the presence of P. aeruginosa and M. smegmatis without interference from these bacteria. Both the photoactivation and bacteria detection can be accomplished using a hand-held UV lamp at 365 nm, with the limit of detection of 103 CFU/mL by the naked eye. Mal-Cz could also be used to detect E. coli and S. epidermidis spiked in milk by the naked eye under a hand-held UV lamp. The uptake of Mal-Cz requires metabolically active bacteria: the uptake was reduced in stationary phase bacteria and was diminished in bacteria that were killed by heating or treating with antibiotics or sodium azide. The uptake decreased with increasing concentration of added free maltose, indicating that Mal-Cz hijacked the maltose uptake pathways. In E. coli, the maltose transport systems, including maltoporin LamB, maltose binding protein MBP, and the maltose ATP binding cassette (ABC) transporter MalFGK2, are all critical for the transport of Mal-Cz. The uptake was diminished in the deletion mutants ΔLamB, ΔMalE, ΔMalF, and ΔMalK.

Theoretical insights into phosphate chains: Density functional theory study and Zinc ion insertion reaction

The present research delves into a theoretical examination of phosphate chains using the density functional theory method with the RB3LYP/6-311G model. The geometry of the studied chains was optimized and their atomic charge densities were evaluated. Various parameters, such as HOMO and LUMO energies, energy difference (ΔE), chemical hardness, chemical potential, softness, and global electrophilicity index were thoroughly investigated. Moreover, vibrational frequencies were explored, highlighting both symmetric and asymmetric vibrations in the chains based on the computed IR and Raman spectra. Subsequently, an investigation into the Zinc ion insertion reaction in the studied phosphate chains was carried out. Several parameters were calculated to determine the electrophilic/nucleophilic character of these two constituents. The outcomes revealed that the phosphate chains display nucleophilic behavior and tend to release electrons, while the Zinc ion exhibits electrophilic tendencies and retains electrons. Notably, electron transfer occurs from the chains to the Zinc ion, with the chains acting as electron donors and the Zinc ion as an electron acceptor. The smaller overall electrophilicity gap between chain III and Zn2+ indicates the weak polar character of this reaction. Furthermore, favorable nucleophilic sites for the attack of the Zinc ion (Zn2+) on chain III were identified using the FUKUI indexes.

Palladium-Catalyzed Regiodivergent C-H Olefination of Imidazo[1,2a]pyridine Carboxamide and Unactivated Alkenes.

Despite remarkable successes in linear and branched vinyl (hetero) arene synthesis, regiodivergent C-H olefination with a single catalytic system has remained underdeveloped. Overcoming this limitation, a Pd/MPAA-catalyzed regiodivergent C-H olefination of imidazo[1,2a] pyridine carboxamides with unactivated terminal alkenes to generate branched and linear olefinated products depending upon the electronic nature of alkenes is reported herein. Moreover, this protocol can be applied for C-H deuteriation of the corresponding heteroarenes with D2 O as deuterium source. Preliminary experimental studies combined with computational investigations (DFT studies) suggest that regiodivergent olefination can be controlled by olefin insertion and β-hydride elimination steps.

Recent advance: Sulfur ylides in organic synthesis

AbstractSulfur ylides are versatile structures that display various characteristics and participate in a myriad of reactions to produce simple, effective, and sometimes stereoselective reactions toward synthesizing sulfur‐containing compounds. Nonetheless, their fulfillment tremendous developments have been made in this field in the past few decades. In this comprehensive review, luminosity is illuminated on the application of sulfur ylides involved in various domino, cascade annulation reactions, and carbene trapping reagents with chameleonic reactivity. In the past numerous decennary, chemists have used sulfur ylides in solvent‐dependent, rhodium catalyzed, dealkylative intercepted, photochemical reaction, halotrifluoromethylation, benzannulation, amidation various name reactions such as Mizoroki–Heck, Suzuki–Miyaura, and Sommelet–Hauser rearrangements. Moreover, other prime applications include metal catalysis, epoxidation of carbonyl compounds, acylmethylation, cyclomerization, oxidation, and insertion reactions. Additionally, some sulfur ylides are extremely useful structures that play a major role in the synthesis of various medicinally active heterocycles structural motifs. This review article discusses all these reactions, their proposed mechanisms, and their application in the current scenario, at length. This tutorial review concludes by providing a future outlook on the investigation into sulfur ylides and various other compounds synthesized using it have great potential to be used in industries, laboratories, pharmaceutical companies, drug production, clinical use, medicinal chemistry, and agrochemical purposes.

1,5‐X Insertions of Free Alkylidene Carbenes: A Theoretical Study

Abstract1,5‐X insertions of alkylidene carbenes are powerful methods to construct five‐membered carbocycles and heterocycles, but the mechanisms of these 1,5‐X insertions of alkylidene carbenes remain unclear (concerted or stepwise?). Here we disclose different mechanisms of 1,5‐X insertions of free alkylidene carbenes based on DFT calculations. Except for the 1,5 S−H insertion, all 1,5‐X insertions proceed through stepwise processes via forming ylide intermediates. However, subsequent 1,2 rearrangements of ylides occur through different mechanisms. The formal 1,5 O−H/N−H insertion except S−H insertion happens through deprotonation rather than insertion reaction, while other pathways including nucleophilic substitution, 2,3‐sigmatropic rearrangement, and homolysis of O−C bond are invoked in various 1,5 O−C insertions. The competition between 1,5‐X insertions and other side reactions (such as 1,2 migration, dealkylation) has been discussed to answer why the target insertion products were not obtained in some cases.

Pathway to Construct α-Acyloxy Esters by B(C6F5)3-Catalyzed O-H Insertion of Carboxylic Acids with Sulfoxonium Ylides.

We report the first example of B(C6F5)3-catalyzed O-H insertion reaction of sulfoxonium ylides and carboxylic acids, achieving efficient construction of diester moieties under metal-free condition. This protocol is characterized by broad substrate tolerance, particularly for various phenylacetic acids, and good compatibility with water/air condition, which is superior to most other methods.

Total Syntheses of Uncommon C30 Terpenoids: Chamaecydin and Isochamaecydin.

(-)-Chamaecydin and (-)-isochamaecydin, two uncommon C30 terpenoids comprising abietane-type diterpenes and thujane-type monoterpenes, were achieved from β-pinene with (-)-sabinene in 18 and 20 steps, respectively. Key steps include a Claisen-Ireland rearrangement to establish the all-carbon quaternary center, a Rh catalyzed C-H bond insertion reaction to install a spiro-five-membered ring and a Lewis acid promoted cyclization of polyenes to construct the two six-membered rings.

Asymmetric N‐Alkylation of 1H‐Indoles via Carbene Insertion Reaction

AbstractAn intermolecular enantioselective N‐alkylation reaction of 1H‐indoles has been developed by cooperative rhodium and chiral phosphoric acid catalyzed N−H bond insertion reaction. N‐Alkyl indoles with newly formed stereocenter adjacent to the indole nitrogen atom are produced in good yields (up to 95 %) with excellent enantioselectivities (up to >99 % ee). Importantly, both α‐aryl and α‐alkyl diazoacetates are tolerated, which is extremely rare in asymmetric X−H (X=N, O, S et al.) and C−H insertion reactions. With this method, only 0.1 mol % of rhodium catalyst and 2.5 mol % of chiral phosphoric acid are required to complete the conversion as well as achieve the high enantioselectivity. Computational studies reveal the cooperative relay of rhodium and chiral phosphoric acid, and the origin of the chemo and stereoselectivity.

Asymmetric N-Alkylation of 1H-Indoles via Carbene Insertion Reaction.

An intermolecular enantioselective N-alkylation reaction of 1H-indoles has been developed by cooperative rhodium and chiral phosphoric acid catalyzed N-H bond insertion reaction. N-Alkyl indoles with newly formed stereocenter adjacent to the indole nitrogen atom are produced in good yields (up to 95 %) with excellent enantioselectivities (up to >99 % ee). Importantly, both α-aryl and α-alkyl diazoacetates are tolerated, which is extremely rare in asymmetric X-H (X=N, O, S et al.) and C-H insertion reactions. With this method, only 0.1 mol % of rhodium catalyst and 2.5 mol % of chiral phosphoric acid are required to complete the conversion as well as achieve the high enantioselectivity. Computational studies reveal the cooperative relay of rhodium and chiral phosphoric acid, and the origin of the chemo and stereoselectivity.

Is Enol Always the Culprit? The Curious Case of High Enantioselectivity in a Chiral Rh(II) Complex Catalyzed Carbene Insertion Reaction.

The mechanism of Rh2 (S-NTTL)4 catalyzed carbene insertion into C(3)-H of indole is investigated using DFT methods. Since the commonly accepted enol mechanism cannot account for enantioinduction, a concerted oxocarbenium pathway was proposed in an earlier work using a model catalyst. However, after considering the full catalytic system, this study finds that akin to other reactions, here, too, the enol pathway is of lower energy, which now naturally raises a conundrum regarding the mode of chiral induction. Herein, a new water promoted mechanistic pathway involving a metal-associated enol intermediate hydrogen bonding and stereochemical model are proposed to solve this puzzle. It is shown how the catalyst bowl-shaped structure along with substrate-catalyst binding is crucial for achieving high levels of enantioselectivity. A stereodetermining water-assisted proton transfer is proposed and confirmed through deuterium-labeling experiments. The water molecules are held together by H-bonding interactions with the carboxylate ligands that is reminiscent of enzyme catalysis. Although several previous studies have aimed at understanding the mechanism of metal catalyzed carbene insertion reactions, the origin of high stereoinduction especially with chiral metal complexes remains unclear, and till date there is no transition state model that can explain the high enantioselectivity with such chiral Rh complexes. The metal-associated enol pathway is currently underrepresented in catalytic cycles and may play a crucial role in catalyst design. Since the enol pathway is commonly adopted in other metal-catalyzed X-H insertion reactions involving a diazoester, the presented results are not specific to the current reaction. Therefore, this study could provide the direction for achieving high levels of enantioselectivity which is otherwise difficult to achieve with a single metal catalyst.

Origin of Enantio- and Chemoselectivity in the Synthesis of Spirocycles via Palladium/Xu-Phos-Catalyzed Cascade Heck/Remote C(sp2)-H Alkylation: A Computational Mechanistic Study.

Density functional theory (DFT) calculations were performed to study the mechanism and factors affecting the enantio-, regio-, and chemoselectivities in the palladium/Xu-Phos-catalyzed cascade Heck/remote C(sp2)-H alkylation reaction. The active catalyst is found to be able to sustain coordination with P and S atoms and can adapt its coordination mode to accommodate the significant steric hindrance between the ligand and substrate, unlike previous findings that showed coordination with P and O atoms. The reaction is established to occur in sequence through the oxidative addition of the aryl iodide to Pd(0), intramolecular alkene insertion, C(sp2)-H bond activation, and C(sp2)-C(sp3) bond reductive elimination. The C(sp2)-C(sp3) bond reductive elimination is identified as the rate-determining step, and the intramolecular alkene insertion as the enantioselectivity-determining step. The high enantioselectivity originates from the stronger electronic interaction between the catalyst and substrate; the exclusive 5-exo-regioselectivity is due to the stronger nucleophilicity of the terminal alkene carbon atom, and the chemoselectivity of C-H activation over carboiodination is driven by thermodynamics.

Rh(II)-Catalyzed Si-H Insertion with Nosyl-hydrazone-Protected Aryl Donor Diazo Compounds.

Dirhodium(II,II) paddlewheel catalysts were evaluated in silyl-hydrogen insertion reactions of aryl diazo compounds generated from o-nosyl hydrazones. The high reactivity of aryl diazo compounds necessitates their in situ generation from sulfonyl-protected hydrazones. Herein, we describe our efforts to evaluate this transformation utilizing Rh(II) catalysts, including those with tethered, axially coordinating ligands. The heteroleptic catalyst, Rh2(OAc)3(2-OX), provided the highest yield of silanes when dioxane was the solvent.