Kinugasa Reaction Research Articles

Recent Advances in the Direct N–C(sp2) Nitrone Synthesis from Oxime

Nitrones are pivotal in organic chemistry, especially for the synthesis of natural and biologically active compounds via 1,3‐dipolar cycloadditions and Kinugasa reactions. Although numerous methods have been reported for the synthesis of nitrones with an sp3 carbon connected to a nitrogen atom, the development of nitrones with an sp2 carbon linkage, including N‐vinyl, N‐aryl, and N‐alkoxycarbonyl nitrones, remains relatively underexplored. This review summarizes the current research trends and methodologies for the direct synthesis of nitrones, in which an sp2 carbon is directly bonded to a nitrogen atom, beginning with oximes.

A facile, regio and diastereoselective synthesis of functionalized azetidin-2-ones: Cu(I) mediated Kinugasa reaction of functionalized nitrones with acetylenic alcohols

The manuscript presents an efficient method for the synthesis of various cis-azetidin-2-ones with high regio- and diastereoselectivity. This approach utilizes Kinugasa reaction involving diverse functionalized nitrones, including diaryl nitrones and α,β-unsaturated nitrones, in conjunction with acetylenic alcohols. Copper (I) serves as a catalyst to facilitate the transformation.

Copper(I)-Catalyzed Kinugasa Reactions in an Undergraduate Organic Chemistry Laboratory

A β-lactam, the core structure unit of clinically important antibiotics such as penicillin and cephalosporin, is one of the most commonly encountered four-membered heterocycles in organic chemistry and is widely used in medicine and biochemistry. The Kinugasa reaction, a copper(I)-catalyzed cycloaddition of a terminal alkyne with a nitrone, is a straightforward and atom economic approach to 2,3-disubstituted β-lactams. This paper describes a comprehensive chemistry experiment involving the Kinugasa reaction in an advanced undergraduate organic chemistry laboratory course. Undergraduate students perform the Kinugasa reaction on the benchtop and isolate and characterize the β-lactam product. An understanding of this named reaction and the connection of organic chemistry with medicinal chemistry are specially emphasized in the class. Several modern chemistry concepts that are missing from traditional organic courses such as β-lactam chemistry, [3 + 2] cycloaddition, atom economy, and the important role of transition metal catalysis in organic reactions are introduced to students in this course.

Intercepted Kinugasa Reaction with Ir Catalysis: Asymmetric Synthesis of Allylated β-Lactams

Key words copper catalysis - iridium catalysis - Kinugasa reaction

DNA Compatible Oxidization and Amidation of Terminal Alkynes.

Through a modified Kinugasa reaction, a novel method of amidation on terminal oligo alkyne conjugates by copper-promoted oxidation with nitrones has been developed. Unprotected bifunctional carboxylic acid-amine reagents can be transformed directly to the respective amide products under these edited Kinugasa reaction conditions. 3-Cycle DNA-encoded libraries (DELs) can be built in three steps of chemical conversion.

Metal‐free Kinugasa reaction catalyzed by external electric field

AbstractOriented external electric field (OEEF) is in recent interest for its ability to promote reactivity and selectivity in chemical transformations. This article reports facile metal‐free [3 + 2] cycloaddition for the Kinugasa reaction in the presence of OEEF. The free energy of activation is reduced by 4.9 kcal/mol due to a parallel electric field in the orthogonal direction to the reaction axis, Fy = 5.0 V Å−1. As a proof‐of‐principle of this model, a multidrug‐resistant (MDR) antibiotic, carbapenem could be envisioned from the [3 + 2] cycloaddition of a cyclic nitrone and an acetonide substituted acetylene. This reaction shows an interesting ambiaxial electric field‐induced catalysis with a reduced reaction barrier for anti‐parallel fields, −Fx (reaction axis) and −Fz and parallel field along +Fy. This is due to the out‐of‐plane bending of the acetonide unit containing two highly electronegative oxygen atoms. As a result, off‐axial tensorial responses to the electric‐fields on the barriers are observed. Such ambiaxial OEEF driven catalysis is interesting because it expands the utility of electric fields for large enzymes. Disorder and dynamical effects of side chains are envisioned to cause non‐null responses to applied field for parallel or anti‐parallel directions along axes.

Novel N-Substituted 3-Aryl-4-(diethoxyphosphoryl)azetidin-2-ones as Antibiotic Enhancers and Antiviral Agents in Search for a Successful Treatment of Complex Infections.

A novel series of N-substituted cis- and trans-3-aryl-4-(diethoxyphosphoryl)azetidin-2-ones were synthesized by the Kinugasa reaction of N-methyl- or N-benzyl-(diethyoxyphosphoryl)nitrone and selected aryl alkynes. Stereochemistry of diastereoisomeric adducts was established based on vicinal H3–H4 coupling constants in azetidin-2-one ring. All the obtained azetidin-2-ones were evaluated for the antiviral activity against a broad range of DNA and RNA viruses. Azetidin-2-one trans-11f showed moderate inhibitory activity against human coronavirus (229E) with EC50 = 45 µM. The other isomer cis-11f was active against influenza A virus H1N1 subtype (EC50 = 12 µM by visual CPE score; EC50 = 8.3 µM by TMS score; MCC > 100 µM, CC50 = 39.9 µM). Several azetidin-2-ones 10 and 11 were tested for their cytostatic activity toward nine cancerous cell lines and several of them appeared slightly active for Capan-1, Hap1 and HCT-116 cells values of IC50 in the range 14.5–97.9 µM. Compound trans-11f was identified as adjuvant of oxacillin with significant ability to enhance the efficacy of this antibiotic toward the highly resistant S. aureus strain HEMSA 5. Docking and molecular dynamics simulations showed that enantiomer (3R,4S)-11f can be responsible for the promising activity due to the potency in displacing oxacillin at β-lactamase, thus protecting the antibiotic from undesirable biotransformation.

Mechanism of the Kinugasa Reaction Revisited.

The mechanism of the Kinugasa reaction, that is, the copper-catalyzed formation of β-lactams from nitrones and terminal alkynes, is re-evaluated by means of density functional theory calculations and in light of recent experimental findings. Different possible mechanistic scenarios are investigated using phenanthroline as a ligand and triethylamine as a base. The calculations confirm that after an initial two-step cycloaddition promoted by two copper ions, the resulting five-membered ring intermediate can undergo a fast and irreversible cycloreversion to generate an imine and a dicopper-ketenyl intermediate. From there, the reaction can proceed through a nucleophilic attack of a ketenyl copper intermediate on the imine and an intramolecular cyclization, rather than through the previously suggested (2 + 2) Staudinger synthesis.

Recent advancement in copper-catalyzed asymmetric reactions of alkynes

Alkynes are among the most diverse functional groups with a great synthetic profile. In the presence of transition metal catalysts, an alkyne could be transformed into various functionalities such as alkanes, alkenes, carbonyls, allenes, carbocycles, and heterocycles, etc. Copper salts are inexpensive, stable, and extensively used catalysts for alkyne activation that happens either via sigma-bond or pi-bond complex formation. Sigma-bond complexation leads to nucleophilic alkyne species, whereas pi-bond complexation results in electrophilic alkyne species. Different domains of the copper-catalyzed reactions of alkynes have separately been reviewed by several research groups. This review covers the recent reports (2011–2020) on copper-catalyzed asymmetric reactions of alkynes, provides insight into the mode of catalysis, and discusses the evolution of alkyne-based organic transformations such as addition to carbonyls and imines, A3 coupling, allylic alkynylation, hydrofunctionalization, cycloaddition, click chemistry, Kinugasa reaction, and allene formation.

Copper(I)‐Catalyzed Asymmetric Interrupted Kinugasa Reaction: Synthesis of α‐Thiofunctional Chiral β‐Lactams

AbstractA copper(I)‐catalyzed asymmetric, three‐component interrupted Kinugasa reaction has been developed. Diverse chiral sulfur‐containing chiral β‐lactams with two consecutive stereogenic centers were synthesized in one step from readily available starting materials in good yields and with excellent diastereo‐ and enantioselectivity. The key is the interception of in situ formed chiral four membered copper(I) enolate intermediate with sulfur electrophiles.

Copper(I)-Catalyzed Asymmetric Interrupted Kinugasa Reaction: Synthesis of α-Thiofunctional Chiral β-Lactams.

A copper(I)-catalyzed asymmetric, three-component interrupted Kinugasa reaction has been developed. Diverse chiral sulfur-containing chiral β-lactams with two consecutive stereogenic centers were synthesized in one step from readily available starting materials in good yields and with excellent diastereo- and enantioselectivity. The key is the interception of in situ formed chiral four membered copper(I) enolate intermediate with sulfur electrophiles.

CuFe2O4 nanoparticles catalyze the reaction of alkynes and nitrones for the synthesis of 2-azetidinones

The reaction of alkynes and nitrones (Kinugasa reaction) in the presence of magnetically recoverable CuFe2O4 nanoparticles as a highly efficient heterogeneous catalyst under a mild condition for the synthesis of various 2-azetidinones was reported.

Development of TsDPEN based imine-containing ligands for the copper-catalysed asymmetric Kinugasa reaction.

A novel class of chiral N,N,N imine-containing ligands derived from TsDPEN (N-(p-tosyl)-1,2-diphenylethylene-1,2-diamine) has been developed and applied to the copper-catalyzed asymmetric Kinugasa reaction. The copper(ii) salt proved to be an efficient catalyst precursor, and it provides an efficient way to synthesize enantioenriched cis-β-lactam. The pathway is air-tolerant and easily manipulated, and the ligands are easy to synthesize. A working model is proposed in which the stereocontrolling step is the [2 + 2] cycloaddition between ketene and imine to explain the observed stereoselectivities.

Synthesis of β-lactams via diastereoselective, intramolecular Kinugasa reactions.

Intramolecular Kinugasa reactions on in situ generated carbohydrate-derived alkynylnitrones are described. The effects of the length of chains, their mutual configuration, influence of experimental conditions on product distribution and feasibility of the β-lactam ring construction were studied. Intramolecular reactions proceed with high stereoselectivity to provide in each case one product only. The cycloadducts from tartaric acid were converted into the corresponding non-racemic 4-acetoxy azetidinones in good yields.

Synthesis of Exclusively 4-Substituted β-Lactams through the Kinugasa Reaction Utilizing Calcium Carbide.

A new Kinugasa reaction protocol has been elaborated for the one-pot synthesis of 4-substituted β-lactams utilizing calcium carbide and nitrone derivatives. Calcium carbide is thereby activated by TBAF·3H2O in the presence of CuCl/NMI. The ease of synthesis and use of inexpensive chemicals provides rapid access of practical quantities of β-lactams exclusively substituted at position 4.

A Revised Mechanism for the Kinugasa Reaction.

Detailed kinetic analysis for the Cu(I)-catalyzed Kinugasa reaction forming β-lactams has revealed an anomalous overall zero-order reaction profile, due to opposing positive and negative orders in nitrone and alkyne, respectively. Furthermore, the reaction displays a second-order dependence on the catalyst, confirming the critical involvement of a postulated bis-Cu complex. Finally, reaction progress analysis of multiple byproducts has allowed a new mechanism, involving a common ketene intermediate to be delineated. Our results demonstrate that β-lactam synthesis through the Kinugasa reaction proceeds via a cascade involving (3 + 2) cycloaddition, (3 + 2) cycloreversion, and finally (2 + 2) cycloaddition. Our new mechanistic understanding has resulted in optimized reaction conditions to dramatically improve the yield of the target β-lactams and provides the first consistent mechanistic model to account for the formation of all common byproducts of the Kinugasa reaction.

Synthesis of Monobactams via the Diastereoselective Kinugasa Reaction

The Kinugasa reaction between phthalimidoacetylene and cyclic nitrones derived from l-phenylglycine or l-serine and glyoxylic acid­, catalyzed by copper(I) chloride in the presence of triethylamine, is reported. The acetylene molecule approaches the nitrone exclusively anti to the bulky substituent next to the nitrogen atom to provide the cis-substituted β-lactam ring preferentially. The six-membered oxazinone ring can be easily opened, the phthaloyl residue can be transformed into a Boc protecting group, and substituents at the C-4 carbon atom and the nitrogen atom of the β-lactam ring can be easily removed or transformed into groups suitable for further synthesis of a variety of monobactam structures. Selected synthesized compounds were evaluated for their biological activity, showing interesting properties.

Asymmetric Synthesis of β-Lactams through Copper-Catalyzed Alkyne-Nitrone Coupling with a Prolinol-Phosphine Chiral Ligand.

Prolinol-phosphine chiral ligands enabled highly enantioselective copper-catalyzed intermolecular alkyne-nitrone coupling (Kinugasa reaction) to produce 1,3,4-trisubstituted chiral β-lactams. A high level of enantiocontrol was achieved not only with aryl- or alkenylacetylenes but also with alkylacetylenes, which were important but unfavorable substrates in the previously reported protocols. Two-point hydrogen bonding between the chiral ligand and the nitrone oxyanion consisting of O-H⋅⋅⋅O and C(sp3 )-H⋅⋅⋅O hydrogen bonds is proposed.

Preparation and characterization of cyclohexandiamine/Fe3O4/ZnO core/shell nanomagnetic composite as a novel reusable catalyst and its application for the diastereoselective synthesis of β‐lactams via the asymmetric Kinugasa reaction

A novel magnetic composite catalyst has been prepared by immobilizing a chiral diamine on core/shell Fe3O4/ZnO. This new catalyst was characterized using X‐ray diffraction, energy‐dispersive X‐ray analysis, Fourier transform infrared spectroscopy, scanning electron microscopy, thermogravimetric analysis and vibrating sample magnetometry. The performance of the catalyst was investigated in the asymmetric Kinugasa reaction and confirmed to be efficient in the synthesis of β‐lactam derivatives under mild conditions.

Theoretical exploration of mechanism of carbapenam formation in catalytic Kinugasa reaction

Molecular mechanism of catalytic Kinugasa reaction of a cyclic nitrone and acetylene, derived from d-glyceraldehyde acetonide, using acetonitrile as a ligand and solvent is studied with density functional theory methods. Possible pathways of Cu(L) catalyzed 1,3-diploar cycloaddition/rearrangement cascade reaction are investigated. For a cycloaddition process, two possible mechanisms have been characterized: the first one corresponds to a one-step cycloaddition with a high activation barrier. The second one corresponds to the mono- or di-copper catalyzed stepwise process that in terms of calculated energy barriers, di-copper path is the most favorable. The reaction proceeds by rearrangement with two competitive mechanisms, formation of bicyclic oxaziridinium intermediate or ketene intermediate. Our calculations show that formation of ketene intermediate is the lowest energy pathway for the rearrangement process.