Oxidative Cyclization Reaction Research Articles

Catalytic Cycloisomerization-Oxidative Cyclization Reaction Sequence of Enyne Diesters Derived from 2-Propargyloxyarylaldehydes.

Enyne diesters derived from 2-propargyloxyarylaldehydes are converted into 2-oxopyranochromenes via In(OTf)3-catalyzed cycloisomerization and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ)-mediated oxidative cyclization reaction sequence in one pot. The process possesses broad substrate scope and good functional group compatibility and generates various 4-(hetero)aryl-substituted 2-oxopyranochromenes in 32-79% yields (over two steps). 2-Oxopyranochromenes undergo selective decarboxylation under Krapcho conditions. When treated with aliphatic secondary amines in DMF, 2-oxopyranochromenes undergo decarboxylative amination at ambient temperature to generate 2-amino-substituted functionalized chromenes in good yields.

Ultrafast Reaction of the Drug Hydralazine with Apurinic/Apyrimidinic Sites in DNA Gives Rise to a Stable Triazolo[3,4-a]phthalazine Adduct.

The clinically used antihypertensive agent hydralazine rapidly generates hydrazone-derived adducts by reaction with apurinic/apyrimidinic (also known as abasic or AP) sites in many different sequences of duplex DNA. The reaction rates are comparable to those of some AP-trapping reagents previously described as "ultrafast." Initially, reversible formation of a hydrazone adduct is followed by an oxidative cyclization reaction that generates a chemically stable triazolo[3,4-a]phthalazine adduct. The net result is that the reaction of hydralazine with AP sites in duplex DNA yields a rapid and irreversible adduct formation. Although the hydrazone and triazolo[3,4-a]phthalazine adducts differ by only two mass units, it was possible to use MALDI-TOF-MS and ESI-QTOF-nanospray-MS to quantitatively characterize mixtures of these adducts by deconvolution of overlapping isotope envelopes. Reactions of hydralazine with the endogenous ketone pyruvate do not prevent the formation of the hydralazine-AP adducts, providing further evidence that these adducts have the potential to form in cellular DNA. AP sites are ubiquitous in cellular DNA, and rapid, irreversible adduct formation by hydralazine could be relevant to the pathogenesis of systemic drug-induced lupus erythematosus experienced by some patients. Finally, hydralazine might be developed as a probe for the detection of AP sites, the study of cellular BER, and marking the location of AP sites in DNA-sequencing analyses.

Iodine(III)-Catalyzed Oxidative Cyclization of Aryl Amines to Construct N-Alkylbenzimidazoles.

An I(III)-catalyzed oxidative cyclization reaction using selectfluor as the oxidant was developed that converts ortho-substituted anilines to benzimidazoles. The mild reaction requires as little as 0.5 mol % of iodobenzene, and its scope is broad: electron-withdrawing or electron-releasing groups on the aniline portion are tolerated, and cyclic or acyclic N-alkylamines are permitted as ortho-substituents. Preliminary mechanistic investigations suggest that benzimidazole formation occurs via cationic reactive intermediates, and an intramolecular kinetic isotope effect of 1.98 ± 0.05 was measured.

The evolutionary origin of naturally occurring intermolecular Diels-Alderases from Morus alba

Biosynthetic enzymes evolutionarily gain novel functions, thereby expanding the structural diversity of natural products to the benefit of host organisms. Diels-Alderases (DAs), functionally unique enzymes catalysing [4 + 2] cycloaddition reactions, have received considerable research interest. However, their evolutionary mechanisms remain obscure. Here, we investigate the evolutionary origins of the intermolecular DAs in the biosynthesis of Moraceae plant-derived Diels-Alder-type secondary metabolites. Our findings suggest that these DAs have evolved from an ancestor functioning as a flavin adenine dinucleotide (FAD)-dependent oxidocyclase (OC), which catalyses the oxidative cyclisation reactions of isoprenoid-substituted phenolic compounds. Through crystal structure determination, computational calculations, and site-directed mutagenesis experiments, we identified several critical substitutions, including S348L, A357L, D389E and H418R that alter the substrate-binding mode and enable the OCs to gain intermolecular DA activity during evolution. This work provides mechanistic insights into the evolutionary rationale of DAs and paves the way for mining and engineering new DAs from other protein families.

Discovery of Latent Cannabichromene Cyclase Activity in Marine Bacterial Flavoenzymes.

Production of phytocannabinoids remains an area of active scientific interest due to the growing use of cannabis by the public and the underexplored therapeutic potential of the over 100 minor cannabinoids. While phytocannabinoids are biosynthesized by Cannabis sativa and other select plants and fungi, structural analogs and stereoisomers can only be accessed synthetically or through heterologous expression. To date, the bioproduction of cannabinoids has required eukaryotic hosts like yeast since key, native oxidative cyclization enzymes do not express well in bacterial hosts. Here, we report that two marine bacterial flavoenzymes, Clz9 and Tcz9, perform oxidative cyclization reactions on phytocannabinoid precursors to efficiently generate cannabichromene scaffolds. Furthermore, Clz9 and Tcz9 express robustly in bacteria and display significant tolerance to organic solvent and high substrate loading, thereby enabling fermentative production of cannabichromenic acid in Escherichia coli and indicating their potential for biocatalyst development.

Oxidative cyclization reagents reveal tryptophan cation-π interactions.

Methods for selective covalent modification of amino acids on proteins can enable a diverse array of applications, spanning probes and modulators of protein function to proteomics1-3. Owing to their high nucleophilicity, cysteine and lysine residues are the most common points of attachment for protein bioconjugation chemistry through acid-base reactivity3,4. Here we report a redox-based strategy for bioconjugation of tryptophan, the rarest amino acid, using oxaziridine reagents that mimic oxidative cyclization reactions in indole-based alkaloid biosynthetic pathways to achieve highly efficient and specific tryptophan labelling. We establish the broad use of this method, termed tryptophan chemical ligation by cyclization (Trp-CLiC), for selectively appending payloads to tryptophan residues on peptides and proteins with reaction rates that rival traditional click reactions and enabling global profiling of hyper-reactive tryptophan sites across whole proteomes. Notably, these reagents reveal a systematic map of tryptophan residues thatparticipate in cation-π interactions, including functional sites that can regulate protein-mediated phase-separation processes.

Smartphone-Based Quantitative Measurement of Cu2+: Fluorescent Turn-on Chemosensor via Radical Cation Formation.

We report a unique radical cation formation-based fluorescent chemosensor (E)-N'-(4-(diphenylamino)benzylidene)thiophene-2-carbohydrazide (DBTC) that quantitatively determines Cu2+ based on the RGB model using a smartphone. DBTC exhibited a weak turquoise fluorescence due to fluorescence suppression by amide isomerization. When Cu2+ was added into DBTC, it showed strong light blue fluorescence with a high quantum yield ([Formula: see text] = 0.470). The detection limit of Cu2+ was determined to be 0.40 µM at the concentration range of 0-7.5 µM. In addition, the detection mechanism of DBTC for Cu2+ was demonstrated to be an oxidative cyclization reaction through 1H NMR titration, ESI-MS analysis, and DFT calculation. Remarkably, DBTC could be applied to the quantitative measurement of Cu2+ using a smartphone and RGB analysis. The detection limit was calculated to be 0.05 µM, which is the lowest detection limit among chemosensors that could detect Cu2+ through smartphone-based fluorescence measurements. Additionally, spike and recovery experiments conducted with different concentrations of Cu2+ showed good recovery values. DBTC exhibited its potential as a chemosensor for determining Cu2+ through the application of a smartphone-based platform capable of real-time monitoring.

A ratiometric small-molecule fluorescent probe for the selective detection of hypochlorite by an oxidative cyclization reaction: application to commercial disinfectants and live cells.

A highly selective thiophene-thioimidazole hydrazine-based ratiometric chemodosimeter (TPBN) was designed and synthesized to detect hypochlorite (ClO-). The probe showed yellow fluorescence and exhibited ultra sensitivity towards hypochlorite (detection limit 8.74 nM) through the oxidative intramolecular cyclization process to give a blue fluorescent triazole product (TPBN-P). Additionally, the as-designed sensor displayed a fast response (80 s) to hypochlorite with excellent selectivity over other competing analytes. DFT calculations, ESI-MS, and 1H NMR titration experiments supported the detection mechanism. The probe was a valuable and practical ratiometric sensor for test strips, commercial disinfectants, and water samples. The probe was successfully used in the bio-imaging of hypochlorite in human breast cancer cells due to its noteworthy photophysical characteristics and good cell permeability.

Old dye safranine as an organic photocatalyst for the synthesis of substituted quinazolinones

Safranine-catalyzed oxidative cyclization reaction of substituted 2-aminobenzamides and aldehydes to afford quinazolinone products.

Photocatalytic oxidative cyclization of aromatic thioamides catalyzed by Cu2O rhombic dodecahedra

Cu2O rhombic dodecahedra can photocatalyze the oxidative cyclization reaction of diverse thioamides to form 3,5-diphenyl-1,2,4-thiadiazoles.

Turning waste into wealth: Efficient and reversible iodine capture by decoration of coordinative allylic moiety to a flexible covalent organic framework and its application for catalysis

Two types of flexible N-acylhydrazone-linked 2D COFs based on the triazine-containing monomer and the allyl or propyl group modified terephthalic dihydrazide monomer were synthesized. The effect of the synthesis temperature on the surface morphology and crystallinity was studied and the results demonstrated that the synthesis temperature could lead to significant changes in the surface morphology of COFs. What’s more, the coordinative allylic moiety decorated COF (TFDH-Allyl-IV) achieved an excellent iodine adsorption capacity of 6.32 g/g and 1228.04 mg/g in vapor and in n-hexane solvent, respectively. The controlled experiments including XPS, Raman spectra, solid-state 13C NMR studies and the DFT calculations demonstrated that the high adsorption capacity was endowed by the incorporation of the distal C = C bonds with iodine, generating a relatively stable I2:olefin complex. What’s more, the iodine-loaded adsorbent (I2@TFDH-Allyl-IV) could be employed as efficient reusable molecular iodine supported catalyst for organic reactions, such as the Friedel-Crafts-type reactions and oxidative cyclization reactions, which extended the potential application scope of these COFs.

Oxidative Cyclization Reactions Catalyzed by Designed Transition-Metal Complexes: A New Strategy for the Synthesis of Flavone, Quinolone, and Benzofuran Derivatives

AbstractAn efficient and convenient synthetic protocol is reported for the synthesis of 2-phenyl-4H-chromen-4-one, 2-phenylquinolin-4(1H)-one, and 11H-benzofuro[3,2-b]chromen-11-one derivatives from 2′-hydroxychalcones, 2′-aminochalcones, and 3-hydroxyflavones, respectively, using transition-metal catalysts and TEMPO as an oxidizing agent. This catalytic heterocyclization approach involves in situ free-radical generation as phenoxyl radicals were detected by EPR spectroscopic study and H2O2 was formed. The present method has numerous advantages, such as high atom-economy, less hazardous synthesis, benign solvent and auxiliaries, easy handling, and broader substrate scope with good to excellent product yields.

Synthesis of 4-Alkylated 1,4-Dihydropyridines: Fe(II)-Mediated Oxidative Cascade Cyclization Reaction of Cyclic Ethers with Enaminones.

Syntheses of highly functionalized 4-alkylated 1,4-dihydropyridines (1,4-DHPs) from cyclic ethers and enaminones via iron(II)-mediated oxidative free radical cascade C(sp3)-H bond functionalization/C(sp3)-O bond cleavage/cyclization reaction have been first developed. This novel synthetic strategy offers an alternative method for the construction of 1,4-DHPs by using esters as the C4 sources, as well as expands the application of ethers in heterocycle synthesis.

PhIO‐Mediated Cascade Reactions of Activated Acetylamides and Cyclic Amidines: Access to Polysubstituted Imidazolidin‐2‐ones

AbstractA facile and efficient synthesis of polysubstituted imidazolidin‐2‐ones has been developed via an oxidative cyclization reaction of activated acetyl amides and cyclic amidines mediated by iodosobenzene (PhIO). A mechanism is proposed for this transformation, which involves sequential intermolecular addition, Hofmann‐type rearrangement and intramolecular cyclization reactions. The novel protocol features readily available starting materials, mild reaction conditions, simple execution, metal‐free oxidative cyclization, and one‐pot procedure.

Cycloadditions and Cyclization Reactions via Post-Synthetic Modification and/or One-Pot Methodologies for the Stabilization of Imine-Based Covalent Organic Frameworks

Interest in covalent organic frameworks as high-value materials has grown steadily since their development in the 2000s. However, the great advantage that allows us to obtain these crystalline materials—the reversibility of the bonds that form the network—supposes a drawback in terms of thermal and chemical stability. Among the different strategies employed for the stabilization of imine-based Covalent Organic Frameworks (COFs), cycloaddition and other related cyclization reactions are especially significant to obtain highly stable networks with extended π-delocalization and new functionalities, expanding even further the potential application of these materials. Therefore, this entry gathered the most recent research strategies for obtaining stable COFs by means of cyclization reactions, including the Povarov reaction and intramolecular oxidative cyclization reactions as well as some other recent innovative approaches.

An Efficient Route towards Quinazolinone Derivatives via I2/DMSO-Promoted Oxidative Decarboxylation of α-Amino Acids and Subsequent Oxidative Annulation Reaction

AbstractAn efficient and straightforward strategy to synthesize a wide range of quinazolinone derivatives from commercially inexpensive 2-aminobenzamides and various amino acids via molecular iodine promoted oxidative decarboxylation of α-amino acids, followed by oxidative cyclization reaction, is revealed. Operational simplicity, consistent yield, functional group tolerance and sustainability are the other noteworthy features of the reaction. A large number of quinazolinone derivatives were conveniently prepared employing the current strategy. The synthesis of other related heteroarenes, such as benzoxazole and benzothiazole derivatives, following the same reaction conditions broadens the scope of the method.

Synthesis and Biological Activities Evaluation of Novel Spiroheterocycles Containing 1,3,4-Oxadiazoline Moiety

A novel series of spiro 3-acetyl-1,3,4-oxadiazolines were synthesized via oxidative cyclization reaction of different 2-furoyl and 2-thenoyl hydrazones with acetic anhydride. The structures of obtained compounds were confirmed by IR, MS, 1H NMR, 13C NMR and Elemental analysis methods and are in full agreement with their molecular structure. The newly synthesized spiro 1,3,4-oxadiazolines were screened for in vitro for their biological activity against a variety of bacterial strains (Euterococci, Escherichia coli, Staphylococcus aureus, Klebsiella spp, Proteus spp), and fungi (Aspergillus niger, Candida albicans), employing the nutrient agar disc diffusion method. The obtained results showed that these compounds have good inhibition against the tested pathogens.

Synthesis of N‐Sulfonyl Amidines and 1,3,4‐Oxadiazoles through Electrochemical Activation of DMF

AbstractElectrochemical routes for the synthesis of N‐sulfonyl amidines and 1,3,4‐oxadiazoles are reported through the activation of DMF molecule. Successful implementation of electro‐redox on dehydrative coupling and oxidative cyclization reactions eliminates the necessity of stoichiometric chemical oxidants and minimizes the generation of reagent waste. Both protocols exhibited broad functional group tolerance, permitting a widespread substrate scope with 47–94% isolated yield. Several control experiments and cyclic voltammetry studies were performed and mechanistic details of these transformations are thoroughly outlined.magnified image

Study of the Antioxidant Activity of Synthetic 3-hydroxyflavone Derivatives by DPPH and Hydrogen Peroxide Methods

Flavonoids have good efficacy as antioxidants due to their ability to scavenge free radicals within cells. In our previous study, synthetic flavonoid derivatives (A2-A13) were prepared in vitro through condensation, oxidative cyclization, alkylation and esterification reactions. The antioxidant activity of the alkyl and esterified derivatives of the flavonoid compound (A2) 3-hydroxy-2-(4-[dimethylamino]phenyl) benzo-4-pyrone was studied by two methods: 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical inhibition method and inhibition of hydrogen peroxide (H2O2) and compared to the activity of standard antioxidant compounds, ascorbic acid and quercetin. The flavonoids (prepared samples) A2, A5, and A7 showed high activity approaching that of ascorbic acid and quercetin as well-known antioxidants. As for the compounds (A3, A6, A8, A9, A10, A11, A12, A13), which contain an -OH enol group, a benzyl group, and a chlorine group and the acetate group, its effectiveness has decreased significantly.

Copper catalysed oxidative cascade deamination/cyclization of vinyl azide and benzylamine for the synthesis of 2,4,6-triarylpyridines.

A highly efficient one-pot method for the synthesis of 2,4,6-triaryl pyridines has been developed via cascade deamination and annulation. Copper triflate and molecular iodine easily promoted the oxidative cyclization reaction of vinyl azide and benzylamine to access a wide variety of substituted pyridine substrates under an oxygen atmosphere. The presence of benzyl amine enables the cyclization process by providing the aryl functionality and the nitrogen source. Moreover, a broad range of substrates with good functional group tolerance, avoidance of external oxidants, excellent product yields, operational simplicity and mild conditions are the notable advantages of the present protocol.