Cascade Reaction Research Articles

Silylium-Ion-Promoted (3 + 2) Annulation of Allenylsilanes with Internal Alkynes Involving a Pentadienyl-to-Allyl Cation Electrocyclization.

A (3 + 2) annulation of allenyl- and, after rapid isomerization, propargylsilanes with internal 1-aryl-1-alkynes to form 4-methylenecyclopentenes is reported. The reaction is initiated by a silylium ion, and the catalytic cycle is subsequently maintained by the self-regeneration of the silylium-ion promoter. Unlike the well-established Danheiser annulation, where the allenylsilane serves as a three-carbon synthon, the present transformation engages the allenylsilane as a two-carbon synthon. Experimental observations and DFT calculations unveil a reaction cascade involving various β-silicon-stabilized carbocations, where a pentadienyl-to-allyl cation electrocyclization is the key step.

Cascade Reactions of Alkynyl Ketones and Amides to Generate Unsaturated Oxacycles and Aromatic Carbocycles.

We describe novel amine-mediated transformation of alkynyl ketones and amides to generate 2-methylene-2H-pyrans, substituted 3-hydroxy-9H-fluoren-9-ones, and amine-incorporated arenes. These cascade processes are initiated by conjugate addition of secondary amine followed by hydrolysis of the enamine/vinylogous amide intermediates. The product distribution is highly sensitive to the steric and electronic effects of the substituents on both the alkyne moieties, the tether structure connecting them, and the nature of the amine. Alkynyl amide participates in the Alder-ene reaction favorably to generate more reactive allene amide that reacts with amine to generate amine-incorporated arene products. These metal-free cascade reactions are a useful synthetic method that can be exploited for the construction of various hetero- and carbocyclic systems.

A facile and green procedure in preparing dibenzo-chromeno-phenazine-diones using an effectual and recyclable Brønsted acidic ionic liquid

First, a Brønsted acid ionic liquid (BAIL) in the role of a double acid-base called 1,3-n-propyl-bipyridinium bisulfonic acid-ditrifluoroacetate (PBPBSDT) was produced, and its skeleton was determined via TGA, mass, 13C NMR, 19F NMR, 1H NMR and FT-IR data. Further, it was successfully applied in the preparation of dibenzo-chromeno-phenazine-dione derivatives (1a-12a, 9–15 min, 90–98%) via one-pot multicomponent domino reaction among 2 mmol 2-hydroxynaphthalene-1,4-dione, 1 mmol benzene-1,2-diamine, and 1 mmol aldehydes under optimal conditions (5 mol% of PBPBSDT, solvent-free, 60 °C). The proper reproducibility of the PBPBSDT homogeneous catalyst (5 times), solvent-free medium, reasonable TON (Turnover Number) and TOF (Turnover Frequency) numbers, the non-metallic framework of the catalyst, and the formation of C-N, C = N, C-C, C = C, C-O bonds in a single operation are the distinct advantages of this protocol.

Room-temperature selective cyclodehydrogenation on Au(111) via radical addition of open-shell resonance structures

Cyclodehydrogenation is an important ring-formation reaction that can directly produce planar-conjugated carbon-based nanomaterials from nonplanar molecules. However, inherently high C–H bond energy necessitates a high temperature during dehydrogenation, and the ubiquity of C − H bonds in molecules and small differences in their bond energies hinder the selectivity of dehydrogenation. Here, we report a room-temperature cyclodehydrogenation reaction on Au(111) via radical addition of open-shell resonance structures and demonstrate that radical addition significantly decreases cyclodehydrogenation temperature and further improves the chemoselectivity of dehydrogenation. Using scanning tunneling microscopy and non-contact atomic force microscopy, we visualize the cascade reaction process involved in cyclodehydrogenation and determine atomic structures and molecular orbitals of the planar acetylene-linked oxa-nanographene products. The nonplanar intermediates observed during progression annealing, combined with density functional theory calculations, suggest that room-temperature cyclodehydrogenation involves the formation of transient radicals, intramolecular radical addition, and hydrogen elimination; and that the high chemoselectivity of cyclodehydrogenation arises from the reversibility and different thermodynamics of radical addition step.

An engineered aldolase enables the biocatalytic synthesis of 2′-functionalized nucleoside analogues

AbstractNucleosides functionalized at the 2′-position play a crucial role in therapeutics, serving as both small-molecule drugs and modifications in therapeutic oligonucleotides. However, the synthesis of these molecules often presents substantial synthetic challenges. Here we present an approach to the synthesis of 2′-functionalized nucleosides based on enzymes from the purine nucleoside salvage pathway. Initially, active-site variants of deoxyribose-5-phosphate aldolase were generated for the highly stereoselective synthesis of d-ribose-5-phosphate analogues with a broad range of functional groups at the 2-position. Thereafter, these 2-modified pentose phosphates were converted into 2′-modified purine analogues by construction of one-pot multienzyme cascade reactions, leading to the synthesis of guanosine (2′-OH) and adenosine (2′-OH, 2′-Me, 2′-F) analogues. This cascade allows for the control of the 2′-functional group alongside 2-stereochemistry. Our findings demonstrate the capability of these biocatalytic cascades to efficiently generate 2′-functionalized nucleosides, starting from simple starting materials.

Co single atoms/nanoparticles over carbon nanotubes for synergistic oxidation of 5-hydroxymethylfurfural to 2,5-furandicarboxylic acid

The preparation of high-value 2,5-furandicarboxylic acid (FDCA) from biomass-based platform compound 5-hydroxymethylfurfural (HMF) is an important synthetic reaction, as the resulting FDCA holds promise to replace terephthalic acid to produce environmentally friendly polyester materials. However, due to the complex tandem nature of the oxidation of HMF to FDCA, which involves several stable intermediates, efficient conversion of HMF and achieving a high FDCA yield remain challenging. Herein, a catalyst of Co SAs/NPs@N-CNTs comprising Co single atoms (Co SAs) alongside Co nanoparticles (Co NPs) supported on carbon nanotubes (CNTs) was synthesized. Co SAs/NPs@N-CNTs exhibited outstanding catalytic activity for the selective oxidation of HMF to FDCA, achieving 100% HMF conversion and 94.2% FDCA yield. This remarkable performance was attributed to the synergistic effect between Co SAs and Co NPs. Poisoning and acid treatment experiments indicated that Co SAs served as the active sites, while Co NPs did not directly act as active sites. Instead, Co NPs merely assisted the Co SAs on the sidelines, facilitating the efficient conversion of HMF into various intermediates and promoting the further conversion of these intermediates into FDCA, thereby achieving high FDCA productivity. This strategy offers new insights for designing efficient catalysts for complex tandem reactions.

An Efficient Bifunctional Core-Shell ZIF-90@ZIF-67 Composite as a Stable Pickering Interfacial Catalyst for the Deacetalization-Knoevenagel Tandem Reaction.

Exploiting advanced solid particles is crucial to the construction of Pickering emulsions catalysis. Recently, metal-organic frameworks (MOFs) have been used as ideal emulsifiers stabilizing Pickering emulsions for interfacial catalysis. Although Pickering emulsions stabilized by core-shell MOFs have significant importance in practical studies, to date there have been very limited reports on this topic. Herein, ZIF-90@ZIF-67, a core-shell material with simultaneous acid-base bifunctionality, was synthesized by seeded epitaxial growth. It was firstly applied as an emulsifier in Pickering emulsions to catalyze the deacetalization-Knoevenagel tandem reaction, which exhibited excellent catalytic properties and achieved extremely high yields. Additionally, ZIF-90@ZIF-67 showed high stability and remained well repeatable after five cycles. This work provides a platform for the design of structurally and functionally diverse MOF-based Pickering emulsions interfacial catalysis.

Convergent Assembly of 1,4-Benzothiazide Spiroindolinones via [4 + 2] Spiroannulation Under Open-Air Conditions.

This report discloses a transition-metal-free [4 + 2] spirocyclization of isatin-derived β-silylcarbinols and 2-aminobenzenethiols, providing a facile approach to 1,4-benzothiazide spiroindolinones in decent yields. Control experiments indicate that 3-methylene oxindoles and disulfides are key intermediates in this tandem reaction. Moreover, the resulting products can be facilely converted into pharmaceutically significant sulfone and sulfoxide scaffolds, which further demonstrates the potential utility of this protocol.

Enantioselective Synthesis of Chiral Sulfonimidoyl Fluorides Facilitates Stereospecific SuFEx Click Chemistry

Sulfur‐centered electrophilic 'warheads' have emerged as key components for chemical proteomic probes through sulfur‐exchange chemistry (SuFEx) with protein nucleophiles. Among these functional groups, sulfonimidoyl fluorides (SIFs) stand out for their modifiable sites, tunable electrophilicities, and chiral sulfur‐center, presenting exciting possibilities for new covalent chemical probes. However, the synthetic access to chiral SIFs has been a challenge, limiting their exploration and applications. In this study, we describe a convenient route to obtain chiral SIFs from readily available sulfenamides via a series of one‐pot tandem reactions with high enantiomeric excess (ees). The resulting chiral SIFs were further converted into a diverse array of chiral S(VI) derivatives under mild conditions or in buffer solutions. Most significantly, the specificity of the chiral SIFs in protein ligation experiments underscored the critical role of sulfur‐center chirality in the design and screening of more‐selective covalent probes and therapeutics.

Stereodivergent Synthesis of 6,12-Guaianolide C1 Epimers via a Rationally Designed Oxy-Cope/Ene Reaction Cascade.

Nature synthesizes epimeric C1 guaianolide congeners, key components of major natural product classes, through a single structurally flexible macrocyclic germacranolide core. Our rationally designed elemanolide-type scaffold (5) now mimics this natural process, enabling the stereodivergent synthesis of both C1 epimers of 6,12-guaianolide lactone motifs. An oxy-Cope/ene cascade acts as the key step of this process, generating two distinct conformers of an intermediate germacranolide, each leading to a specific C1 epimer. Highly stereoselective redox manipulations follow, culminating in the efficient syntheses of diverse osmitopsin-type guaianolides.

Divergent Synthesis of (CF3)‐Indazolo[3,2‐a]Isoquinolines with Potent Photophysical Property and Anticancer Activity from 3‐Aryl‐1H‐Indazoles and Sulfoxonium Ylides

AbstractTransition‐metal‐catalyzed inert C−H bond functionalization using sulfoxonium ylides as metal carbene surrogates to replace the explosive and labile diazo compounds is synthetically attractive. Presented herein is a divergent synthesis of (CF3)‐indazolo[3,2‐a]isoquinoline derivatives based on C−H bond activation‐initiated cascade reactions of 3‐aryl‐1H‐indazoles with sulfoxonium ylides. The formation of products involves Rh(III)‐catalyzed C(sp2)−H bond metalation, carbene formation, migratory insertion, proto‐demetalation and intramolecular condensation. In general, this newly developed protocol features simple substrates, structurally diverse products, step‐economy and scalability. In addition, evaluation of the photophysical properties and anti‐proliferative activity against three human cancer cell lines of the products thus obtained showed that some of them possess potent anticancer activity with potential self‐tracking capability through fluorescence detection.

Enantioselective Synthesis of Chiral Sulfonimidoyl Fluorides Facilitates Stereospecific SuFEx Click Chemistry.

Sulfur-centered electrophilic 'warheads' have emerged as key components for chemical proteomic probes through sulfur-exchange chemistry (SuFEx) with protein nucleophiles. Among these functional groups, sulfonimidoyl fluorides (SIFs) stand out for their modifiable sites, tunable electrophilicities, and chiral sulfur-center, presenting exciting possibilities for new covalent chemical probes. However, the synthetic access to chiral SIFs has been a challenge, limiting their exploration and applications. In this study, we describe a convenient route to obtain chiral SIFs from readily available sulfenamides via a series of one-pot tandem reactions with high enantiomeric excess (ees). The resulting chiral SIFs were further converted into a diverse array of chiral S(VI) derivatives under mild conditions or in buffer solutions. Most significantly, the specificity of the chiral SIFs in protein ligation experiments underscored the critical role of sulfur-center chirality in the design and screening of more-selective covalent probes and therapeutics.

Physicochemical properties and antimicrobial efficacy of argon cold atmospheric pressure plasma jet activated liquids – a comparative study

Cold atmospheric pressure plasma jet activated liquids (CAPJALs) have attracted considerable scientific attention due to their peculiar antimicrobial characteristics. In the current context, there is a need to compare the bactericidal activity of CAPJALs and demonstrate the specific parameters necessary to obtain greater effectiveness. This in-vitro research examines the antimicrobial activity of liquids, such as deionized water (DI-W), drinking water (DW), tap water (TW), and normal saline (NS) activated by Ar cold atmospheric pressure plasma jet (CAPJ) against multidrug-resistant (MDR) E. coli and S. aureus. The computed D- value showed that CAPJALs' bacterial inactivation efficacy followed the trend – DI-W ≈ NS > DW > TW for both the isolates. To obtain greater bactericidal effectiveness, an optimum combination of liquid activation time by CAPJ and CAPJAL – bacteria interaction time was noticed. In addition, the rate at which the physicochemical parameters (pH, electrical conductivity (EC), total dissolved solids (TDS), and concentration of reactive species (H2O2, NO3-, and NO2-)) changed within the liquid varied in different ways. It was observed that the identified gas-phase species (Ar I, Ar+, N2, N2+, O I, OH•, OH+, NO+, O2+, N2O3-, NO3-, N2O2-, etc.) would contribute to modification of liquid physicochemical property by generating liquid phase reactive species (NO3-, NO2-, H+, H2O2, ONOOH, Cl2, HOCl, etc.) via reaction cascades. These reactive species in the liquid phase, together with other physicochemical characteristics, were found to play a part in the process of bacterial inactivation. This study into the underlying mechanism of CAPJ – liquid and CAPJAL – bacteria interaction would help to determine its potential use as a disinfectant in healthcare settings. List of microorganismsE. coli: Escherichia coli; S. aureus: Staphylococcus aureus.

Photocatalyst‐Free Visible‐Light Induced Radical Difluoromethylation/Cyclization Cascade Reaction for the Synthesis of Difluoromethylated Oxindoles with Difluoromethyl Phenoxathiinium Salt

AbstractA photocatalyst‐free photoinduced radical difluoromethylation approach for the convenient synthesis of difluoromethylated oxindoles from N‐arylacrylamides with difluoromethyl phenoxathiinium salt (PT‐CF2H+BF4−) was developed, this transformation involves radical difluoromethylation/cyclization cascade process and features photocatalyst‐free, mild reaction conditions, broad substrate scope and good functional groups tolerance. With this method, a wide variety of N‐arylacrylamides were successfully converted to desired difluoromethylated oxindoles in good to excellent yields.

Enhancing Compatibility of Two-Step Tandem Catalytic Nitrate Reduction to Ammonia Over P-Cu/Co(OH)2.

Electrochemical nitrate reduction reaction (NO3RR) is a promising approach to realize ammonia generation and wastewater treatment. However, the transformation from NO3 - to NH3 involves multiple proton-coupled electron transfer processes and by-products (NO2 -, H2, etc.), making high ammonia selectivity a challenge. Herein, a two-phase nanoflower P-Cu/Co(OH)2 electrocatalyst consisting of P-Cu clusters and P-Co(OH)2 nanosheets is designed to match the two-step tandem process (NO3 - to NO2 - and NO2 - to NH3) more compatible, avoiding excessive NO2 - accumulation and optimizing the whole tandem reaction. Focusing on the initial 2e- process, the inhibited *NO2 desorption on Cu sites in P-Cu gives rise to the more appropriate NO2 - released in electrolyte. Subsequently, P-Co(OH)2 exhibits a superior capacity for trapping and transforming the desorbed NO2 - during the latter 6e- process due to the thermodynamic advantage and contributions of active hydrogen. In 1m KOH + 0.1m NO3 -, P-Cu/Co(OH)2 leads to superior NH3 yield rate of 42.63mgh- 1cm- 2 and NH3 Faradaic efficiency of 97.04% at -0.4V versus the reversible hydrogen electrode. Such a well-matched two-step process achieves remarkable NH3 synthesis performance from the perspective of optimizing the tandem catalytic reaction, offering a novel guideline for the design of NO3RR electrocatalysts.

Synthesis of Oxazolines using Aldol/Cyclization Cascade Reactions Employing 1,1‐Diaminobenzalazine as Organocatalyst

Abstract1,1‐Diaminobenzalazine has been recently reported to catalyze different types of Michael addition reactions; this organic molecule has unique characteristic features for bifunctional organocatalysis. Organocatalysts were shown to be useful in different aldol/cyclization cascade reactions, it is important to establish whether 1,1‐diaminobenzalazine can be employed in the aldol/cyclization cascade reactions. In this work, the synthesis of oxazolines with the help of organocatalyst, 1,1‐diaminobenzalazine, has been reported. This method is relatively more efficient, cost‐effective, and environmentally safe as it avoids the use of metal oxides as co‐catalysts.

One-dimensional rare-earth La-MOFs coordinated with hexamethylenetetramine-Co MOFs derived highly efficient catalyst for cascade reaction of nitroarenes with alcohols☆

A composite metal-organic frameworks (MOFs) structure, designated as Co-hmta@La-salen, was synthesized through coordination interactions between a one-dimensional lanthanum MOFs (La-salen) with high density of uncoordinated imine (–CH=N–) groups and a cobalt-based MOFs (Co-hmta) structure prepared using hydrogen bonding stacking with hexamethylenetetramine (hmta) as the organic ligand. Subsequently, the Co-hmta@La-salen composite was chosen as a template for the pyrolysis process to synthesize a La(OH)3 supported metallic Co catalyst incorporating carbon-nitrogen (Co/La(OH)3-CN-hmta) catalyst. The catalytic results show that Co/La(OH)3-CN-hmta (54% and 46% selectivity for aniline and N-phenylbenzylamine, respectively) displays superior cascade performance compared to classic Co/La(OH)3-CN-nit catalyst (69% and 31% selectivity for aniline and N-phenylbenzylamine, respectively). Moreover, the kinetic test results indicate that N-alkylation is the rate-limiting step of the overall cascade reaction. The Co/La(OH)3-CN-hmta catalyst can be separated from the reaction system using a magnet, and it also exhibits good cyclic stability. All of these suggest that the “MOFs plus MOFs via coordination” templating method can be employed as an efficient strategy for the preparation of supported catalysts.

Self-assembly nanomedicine initiating cancer-immunity cycle with cascade reactions for boosted immunotherapy

Immune checkpoint blockade (ICB) therapy has been extensively integrated into cancer clinical management. However, its overall response rate is limited due to the stagnating cancer-immunity cycle (CIC) caused by the immunosuppressive tumor microenvironment (TME). Here, a multi-pronged nanomedicine, defined as LCCS, was constructed by the self-assembly of lactate oxidase, catalase, chlorin e6, and sorafenib. Through cascade reactions, LCCS effectively reprogrammed the TME and re-initiated the CIC by depleting lactate, alleviating hypoxia, inducing immunogenic cell death, and normalizing tumor vessels. Immunological analyses indicated that treatment with LCCS decreased the infiltration of immunosuppressive cells while increasing the recruitment of immune effector cells in tumors. Leveraging the effective operation of the CIC, LCCS improved the efficacy of ICB therapy to inhibit breast cancer, and effectively induced the elimination of colorectal cancer and long-term immune memory. Therefore, multifunctional nanomedicines targeting CIC hold great potential for applications in cancer immunotherapy.

Exploring Spinel Oxides for CO<sub>2</sub> Hydrogenation in Tandem Reaction with SSZ-13 Catalyst

Exploring Spinel Oxides for CO<sub>2</sub> Hydrogenation in Tandem Reaction with SSZ-13 Catalyst

Recent Advances in Radical Reactions of 1,n‐Enynes with Phosphorus‐Centered Radicals

AbstractOrganophosphorus compounds have been widely used as achiral and chiral ligands in organic synthesis (PPh3, BINAP, dppe, Duphos, Xantphos, PPFA, Chiraphos, SEGPHOS), flame retardants, functional materials (LED, PV), as well as agrochemicals and medicines due to their broad biological activities. As the privileged versatile building blocks, 1,n‐enynes have been successfully applied in the synthesis of various functionalized cyclic compounds based on their two active unsaturated chemical bonds (C═C double and C≡C triple bonds). With the development of highly selective and efficient methods in organic chemistry, various organophosphorus cyclic compounds synthesis through radical cascade strategy has attracted considerable attention in recent years. In here, we have summarized the recent main achievements in the radical cascade reactions of 1,n‐enynes with phosphorus‐centered radicals. Furthermore, we also displayed the detailed reaction mechanisms in this review.