Ketene-imine Cycloaddition Reaction Research Articles

Novel Benzotriazole-β-lactam Derivatives as Antimalarial Agents: Design, Synthesis, Biological Evaluation and Molecular Docking Studies.

Many people around the world suffer from malaria, especially in tropical or subtropical regions. While malaria medications have shown success in treating malaria, there is still a problem with resistance to these drugs. Herein, we designed and synthesized some structurally novel benzotriazole-β-lactams using 2-(1H-benzo[d][1,2,3]triazol-1-yl)acetic acid as a key intermediate. To synthesize the target molecules, the ketene-imine cycloaddition reaction was employed. First, The reaction of 1H-benzo[d][1,2,3]triazole with 2-bromoacetic acid in aqueous sodium hydroxide yielded 2-(1H-benzo[d][1,2,3]triazol-1-yl)acetic acid. Then, the treatment of 2-(1H-benzo[d][1,2,3]triazol-1-yl)acetic acid with tosyl chloride, triethyl amine, and Schiff base provided new β-lactams in good to moderate yields.The formation of all cycloadducts was confirmed by elemental analysis, FT-IR, NMR and mass spectral data. Moreover, X-ray crystallography was used to determine the relative stereochemistry of 4a compound. The in vitro antimalarial activity test was conducted for each compound against P. falciparum K1. The IC50 values ranged from 5.56 to 25.65 μM. A cytotoxicity profile of the compounds at 200 μM final concentration revealed suitable selectivity of the compounds for malaria treatment. Furthermore, the docking study was carried out for each compound into the P. falciparum dihydrofolate reductase enzyme (PfDHFR) binding site to analyze their possible binding orientation in the active site.

Synthesis of New Series Bis-3-Chloro-β-Lactam Derivatives from Symmetrical Bis-Schiff Bases as Effective Antimicrobial Agents with Molecular Docking Studies

Endeavoring to find a new type of antimicrobial agents, a new sequence of bis-Schiff bases and bis-3-cholro-β-lactams are synthesized. An astonishing class of strained compounds is part of the symmetrical bis-Schiff bases that has widespread applications and building blocks for the combination of bis-3-cholro-β-lactams antibiotics. Bis-3-cholro-β-lactams are synthesized through (Staudinger) [2+2] ketene-imine cycloaddition reaction. Structures of the produced compounds are deduced by 1H, 13C-NMR, and FT-IR spectroscopies. All produced compounds are shown moderate to good antimicrobial activity compared to human pathogenic bacteria strains (Escherichia coli and Staphylococcus aureus), also compared to Aspergillus Niger and Trichophyton mentagrophytes fungi through the broth microdilution technique. A molecular docking study is used for showing the active sides and binding affinity of the products with the target proteins or receptors of E. coli (PDB ID: 3GI9).

Cis-Diastereoselective Synthesis of Spirooxindolo-β-Lactams by Staudinger Cycloaddition with TsCl as Activating Co-reagent.

A convenient and versatile one-pot method for synthesis of 1,3-bis-aryl spirooxindolo-β-lactams from isatin Schiff bases and substituted phenylacetic acids using ketene–imine cycloaddition reaction with TsCl for a ketene generation has been developed. The reaction procedure does not require absolute solvents and unstable starting reagents. The studied reactions lead to cis-diastereoselective β-lactam formation for all tested phenylacetic acids except 4-MeOC6H4CH2COOH. An increase of trans-diastereomers yields with increasing temperature and solvent polarity was demonstrated.

Sulfonamide‐β‐lactam Hybrids Incorporating the Piperazine Moiety as Potential Antiinflammatory Agent with Promising Antibacterial Activity

AbstractSeveral monocyclic β‐lactams have been synthesized via a [2+2] ketene–imine cycloaddition reaction (Staudinger reaction) and evaluated for their biological activities. The structure of synthesized products was confirmed by spectral data and elemental analyses. β‐Lactams 4 b and 4 h exhibited 31 and 27 anti‐inflammatory ratios, respectively, which are as well as the well‐known dexamethasone corticosteroid with a 32 anti‐inflammatory ratio. The two most active compounds 4 b and 4 h showed IC50 values more than 200 μM against the HepG2 cell line, in comparison with doxorubicin (IC50<1 μM), indicated biocompatibility and nontoxic behavior. 4 d, 4 j, 4 k, and 4 l, were active against S. aureus and E. coli and had broad spectrum property. The tested compounds were subjected to in silico prediction of pharmacokinetics properties (ADMET) to assess the potential in vivo effectiveness. The molecular docking study confirmed that the active inhibitors 4 b and 4 h are well fitted in the iNOS active site. This data suggests that 4 b and 4 h could potentially serve as effective iNOS inhibitors, a represent promising lead compounds for treating inflammatory disorders.

Synthesis, docking and evaluation of in vitro anti-inflammatory activity of novel morpholine capped β-lactam derivatives

This study reports the synthesis and biological investigation of three series of novel monocyclic β-lactam derivatives bearing a morpholine ring substituent on the nitrogen. The resulting β-lactam adducts were synthesized via Staudinger's [2 + 2]-ketene-imine cycloaddition reaction. New synthesized products were fully characterized by spectral data and elemental analyses, and then evaluated for anti-inflammatory activity toward human inducible nitric oxide synthase (iNOS) and cytotoxicity toward HepG2 cell line. The compounds 3e, 3h, 3k, 5c, 5f, 6c, 6d and 6f showed higher activity with anti-inflammatory ratio values of 38, 62, 51, 72, 51, 35, 55 and 99, respectively, in comparison to the reference compound dexamethasone having an anti-inflammatory ratio value of 32. Hence, these compounds can be considered as potent iNOS inhibitors. They also exhibited IC50 values of 0.48 ± 0.04 mM, 0.51 ± 0.01 mM, 0.22 ± 0.02 mM, 0.12 ± 0.00 mM, 0.25 ± 0.05 mM, 0.82 ± 0.07 mM, 0.44 ± 0.04 mM and 0.60 ± 0.04 mM, respectively, in comparison with doxorubicin (IC50 < 0.01 mM) against HepG2 cells, biocompatibility and nontoxic behavior. In silico prediction of drug-likeness characteristic indicated that the compounds are compliant with the Lipinski and Veber rules. Molecular docking experiments showed a good correlation between the experimental activity and the calculated binding affinity to human inducible nitric oxide synthase, the enzymatic target for the anti-inflammatory response.

Design, Synthesis and Antimicrobial Study of Novel 1-(1,3-benzothiazol-2- yl)-3-chloro-4H-spiro[azetidine-2,3'-indole]-2',4(1'H)-diones Through Ketene– imine Cycloaddition Reaction

: The present study deals with the synthesis of novel 1-(1,3-benzothiazol-2-yl)-3-chloro-4Hspiro[ azetidine-2,3'-indole]-2',4(1'H)-dione derivatives from the reaction of 3-(1,3-benzothiazol-2- ylimino)-1,3-dihydro-2H-indol-2-one derivatives with chloroacetyl chloride in the presence of triethylamine (TEA). The mechanism involved simple acid or base catalysed reaction through the formation of Schiff base followed by cyclisation via ketene–imine cycloaddition reaction. All synthesized compounds were characterized by FT-IR, 1H-NMR, 13C-NMR, and elemental analysis. The antimicrobial activities of the synthesized derivatives 5a-5g were examined via Micro Broth Dilution method against bacterial strains Bacillius subtilis, Staphylcoccus aureus, E. coli, P. aeruginosa, and fungal strain Candida albicans for determining MIC values. Ampicillin, chloramphenicol, and griseofulvin were used as standard drugs. : The MIC values for antimicrobial activity of synthesized compounds were examined using Micro Broth Dilution method. Compounds 5a, 5b, and 5c were found effective against E. coli (MTCC 442) and P.aeruginosa (MTCC 441) and all compounds showed moderate to excellent activity against Streptococcus aureus (MTCC 96) and Bacillius subtilis (MTCC 441). Regarding the antifungal screening, compounds 5a, 5b, and 5c exhibited excellent activity against Candida albicans MTCC 227. 1-(1,3-benzothiazol-2-yl)-3-chloro-4H-spiro[azetidine-2,3'-indole]-2',4(1'H)-dione derivatives may be used as potential lead molecules as effective antimicrobial agents.

Diastereoselective Synthesis of Potent Antimalarial Cis-β-lactam Agents.

Fifteen novel β-lactams bearing N-ethyl tert-butyl carbamate group 5a-o and fifteen N-(2- aminoethyl) β-lactams 6a-o were synthesized by [2+2] ketene-imine cycloaddition reaction (Staudinger). The cycloaddition reaction was found to be totally diastereoselective leading exclusively to theformation of cis-β-lactam derivatives. These newly synthesized β-lactams were evaluated for their antimalarial activity against p. falciparum K14 resistant strain and showed good to excellent EC50 values. Of the thirty β-lactams tested, 5 h, 6a and 6c showed IC50 < 20 µM while 5b, 5c, 5e, 5f, 5g, 5i, 5j, 6d, 6g and 6h exhibited IC50 <50 . Compounds 5c, 5h, and 5q-t were examined for their anticancer properties against K562 Leukemia cell line and 5s showed the best activity. Compounds 3a-j, 5a-o, 6a-o, were tested against S. aureus , E. coli, C. albicans and showed no activity below 125 µg/mL.

Ultrasound Assisted Synthesis of 4-(Benzyloxy)-N-(3-chloro-2-(substitutedphenyl)-4-oxoazetidin-1-yl) Benzamide as Challenging Anti-Tubercular Scaffold.

A series of ten novel derivatives of 4-(benzyloxy)-N-(3-chloro-2-(substituted phenyl)-4-oxoazetidin-1-yl) benzamide 6a–j were synthesized in good yield from the key compound 4-(benzyloxy)-N′-(substituted benzylidene) benzo hydrazide, called Schiff ’s bases 5a–j, by Staudinger reaction ([2 + 2] ketene-imine cycloaddition reaction) with chloro acetyl chloride in the presence of catalyst tri ethylamine and solvent dimethyl formamide (DMF), by using ultra-sonication as one of the green chemistry tools. All the synthesised compounds were evaluated for in vitro anti-tubercular activity against Mycobacterium tuberculosis (MTB) and most of them showed promising activity with an IC50 value of less than 1 µg/mL. To establish the safety, all the synthesized compounds were further tested for cytotoxicity against the human cancer cell line HeLa and all 6a–j compounds were found to be non-cytotoxic in nature. The molecular docking study was carried out with essential enzyme InhA (FabI/ENR) of Mycobacterium responsible for cell wall synthesis which suggests that 6a and 6e are the most active derivatives of the series. The theoretical evaluation of cell permeability based on Lipinski’s rule of five has helped to rationalize the biological results and hence the synthesized azetidinone derivatives 6a–j were also analyzed for physicochemical evaluation that is, absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties and the results showed that all the derivatives could comply with essential features required for a potential lead in the anti-tubercular drug discovery process.

A useful ring transformation route to novel thiazepino[7,6-b]indoles from monochloro-β-lactam-fused 1,3-thiazino[6,5-b]indoles, analogues of cyclobrassinin

The Staudinger ketene-imine cycloaddition reactions of cyclobrassinin phytoalexin analogues 2-aryl-4,9-dihydro-1,3-thiazino[6,5-b]indoles with chloroacetyl chloride as a ketene source were investigated under different conditions. Both β-lactam ring formation and the N-chloroacetylation of the indole moiety took place. The indole N-chloroacetyl group can be easily removed by treatment in the presence of silica gel in methanol at reflux temperature. The selective β-lactam formation can be also achieved in certain cases under milder Staudinger conditions. The treatment of azeto[2,1-b]thiazino[6,5-b]indole-1-one derivatives with sodium ethoxide in ethanol provided the novel thiazepino[7,6-b]indole ring systems in a one-step ring transformation. The structures of the new ring systems were determined by means of IR and NMR spectroscopy.

Synthesis of some new spirocyclic β-lactam and spirocyclic thiazolidin-4-one derivatives

Selective oxidation of 4-amino-2-methyl-5,10-dioxo-1,5,10,10a-tetrahydrobenzo[g]-quinoline-3-carbonitrile (1) with selenium dioxide provided, 4-amino-2-formyl-5,10-dioxo-1,5,10,10a-tetrahydrobenzo[g]quinoline-3-carbonitrile (2). The one-pot reaction of compound 2 with ethyl cyanoacetate and thiourea in ethanol yielded 4-amino-2-(5-cyano-6-oxo-2-thioxo-1,2,3,6-tetrahydropyrimidin-4-yl)-5,10-dioxo-1,5,10,10a-tetrahydrobenzo[g]-quinoline-3-carbonitrile (3). The cycloaddition reaction of chloroacetic acid with compound 3 yielded 7-(4-amino-3-cyano-5,10-dioxo-1,5,10,10a-tetrahydrobenzo-[g]quinolin-2-yl)-3,5-dioxo-3,5-dihydro-2H-thiazolo[3,2-a]pyrimidine-6-carbonitrile (4). Moreover, Ehrlich-Sachs condensation reaction of compound 4 with the aromatic nitroso compounds 5a-c gave the corresponding new Schiff bases 6a-c. Staudinger's ketene-imine cycloaddition reaction of compounds 6a-c with chloroacetyl chloride afforded the corresponding spiro[chloroazetidinethiazolopyrimidine] derivatives, 7a-c. On the otherhand, cycoladdition reaction of thioglycolic acid with Schiff bases 6a-c yielded the corresponding spiro[thiazolidinethiazolopyrimidine] derivatives, 8a-c. Structures of the new compounds were elucidated by compatible analytical and spectroscopic (IR, 1 H NMR and MS) measurements. Moreover, the reaction mechanisms that account for formation of the synthesized compounds have been discussed.

Synthesis of new nanocopolymer containing β-lactams

Several new monocyclic β-lactam monomers bearing the NO2 group 2a–g were synthesized via a [2 + 2] ketene–imine cycloaddition reaction (Staudinger reaction). Calculation of coupling constant of H-3 and H-4, and the X-ray crystallography of β-lactam 2e confirmed the cis stereochemistry of these β-lactams. Then aminophenyl β-lactams were synthesized by the reduction of NO2 to NH2 group in the presence of Raney Ni and hydrazine hydrate. Treatment of these aminophenyl β-lactams with acryloyl chloride and sodium bicarbonate (NaHCO3), afforded the monomers bearing the NHCOCH=CH2 group. These acrylated β-lactam monomers were dissolved in a warm mixture of butyl acrylate and styrene and then were converted to the corresponding polyacrylate nano β-lactams by emulsion polymerization in water. A unique feature of this methodology is the ability to incorporate water-insoluble compounds directly into the nanoparticle framework. Structures of the synthesized compounds were confirmed by physical and spectral analyses. Dynamic light scattering analysis and transmission electron microscopy of the final emulsions show that the nanoparticles were about 50–70 nm in diameter.

A convenient synthesis of 2-azetidinones via 2-fluoro-1-methylpyridinium p-toluenesulfonate

The application and versatility of 2-fluoro-1-methylpyridinium p-toluenesulfonate as acid activator in the synthesis of several β-lactams under mild reaction conditions by use of ketene–imine cycloaddition reactions has been investigated. The effects of solvents, molar ratio of reagents, and temperature were considered. The method was also used for preparation of β-lactams substituted in position 3 by electron-withdrawing groups. The products are obtained in good to excellent yields. .

Preparation and ring transformation of isomeric β-lactam derivatives of bicyclic 1,3-thiazines

Ketene–imine cycloaddition reactions between cis- and trans-2-aryl-4a,5,6,7,8,8a-hexahydro-4H-3,1-benzothazines and chloroacetyl chloride in the presence of base were investigated. Because of the diastereotopic CN faces of cyclohexane-condensed thiazines, both of the possible Staudinger addition product monochloro-β-lactam stereoisomers were obtained for both the cis and the trans compounds. The novel azetidin-2-ones were transformed into the corresponding 3-ethoxycarbonyl-2-aryl-1,5,5a,6,7,8,9,9a-octahydro-4,1-benzothiazepines with sodium ethoxide in a one-step procedure. Structural and stereochemical analyses of the synthesized compounds were carried out by means of IR and NMR spectroscopy.

The first report of [2+2] ketene–imine cycloaddition reactions (Staudinger) on carbon nanotubes

Several new carbon nanotube-functionalized β-lactams have been synthesized from chiral imines derived from β-d-glucopyranosylamine and a ketene from carbon nanotube-based oxyacetic acid via a [2+2] cycloaddition reaction. The cycloadducts were characterized by thermogravimetric analysis, Raman spectrometry, IR, and N2 adsorption processes.

3-Thiolated 2-azetidinones: synthesis and in vitro antibacterial and antifungal activities

A series of 3-thiolated β-lactams were synthesized by [2+2] ketene–imine cycloaddition reaction from S-substituted mercaptoacetic acids and Schiff bases. Then, some of the 3-methylthio β-lactams were converted to 3-(methylsulfinyl) β-lactams and 3-(methylsulfonyl) β-lactams using m-CPBA under different reaction conditions. All the compounds were characterized by spectral data and elemental analyses and were evaluated for their in vitro antibacterial and antifungal activities against pathogenic strains including Staphylococcus aureus (Methicillin resistant strain). The preliminary screening results indicated that some of these compounds demonstrated moderate to very good antibacterial and antifungal activities.

Mechanistic Aspects of the Ketene—Imine Cycloaddition Reactions

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Mechanistic Aspects of the Ketene-Imine Cycloaddition Reactions

The [2+2]-cycloaddition reaction of imines with ketenes, also known as Staudinger reaction, is one of the most commonly employed synthetic entries to the β-lactam ring. Despite this, the detailed mechanism of this reaction has remained an open debate for many years. However, the application of theoretical methods has allowed a deeper understanding of many intricacies surrounding the Staudinger reaction. The experimental evidence and the theoretical studies carried out on the Staudinger reaction mechanism, using ab initio and Density-functional theory methods, are reviewed. Special emphasis is placed on the competition between the concerted and stepwise reaction pathways and the origin of the stereoselectivity of the reaction.

A Versatile Method for the Synthesis of 3-Alkoxycarbonyl β-Lactam Derivatives

[reaction: see text] Ketene-imine cycloaddition reactions (the Staudinger reaction) of ethoxycarbonyl(phenylthio)ketene with various imines and subsequent desulfurization reactions were employed to synthesize 3-ethoxycarbonyl beta-lactam derivatives. The results indicate that the current approach provides a convenient, mild, and versatile method for synthesizing a variety of 3-alkoxycarbonyl trans-beta-lactam derivatives with good to excellent yields and diastereoselectivities.

Asymmetric synthesis of beta-lactams through the Staudinger reaction and their use as building blocks of natural and nonnatural products.

In the last two decades, the better understanding of the mechanistic aspects of the beta-lactams' biological activity and their inhibition, and the chemical exploitation of beta-lactams as synthetic intermediates in organic chemistry, have experienced a continuous and somewhat complementary advance. A prerequisite for such a development has been the accessibility of enantiopure beta-lactams. The latter are now routinely prepared most often through the ketene-imine cycloaddition reaction, also termed the Staudinger reaction. This review accounts for the recent progress made in the asymmetric synthesis of beta-lactams (with special emphasis in the Staudinger reaction approach), as well as in their use as synthetic intermediates en route to natural products, including alpha- and beta-amino acids and peptides derived therefrom.

Diastereo‐ and Enantioselective Synthesis of Novel β‐Lactam‐Containing 1,4‐Benzodiazepines Through a Ketene—Imine Cycloaddition Reaction.

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