Cascade Reaction Research Articles

Ru-Catalyzed Ortho C-H Alkylation of 4-Aryl-pyrrolo[2,3-d]pyrimidines with Diazo Compounds: An Access to Fluorescent Fused Heteroarenes.

A Ru(II)-catalyzed migratory insertion of carbene into ortho C-H bonds of 4-aryl-pyrrolo[2,3-d]pyrimidines has been developed. This transformation endows the facile fabrication of C-C bonds with high atom economy, good regioselectivity, and wide functional group tolerance, exploiting the directing properties of pyrimidinic nitrogen. In addition, the planar polycyclic pyrrolo-pyrimido-isoindole framework has been accomplished from a cascade reaction of bromination, cyclization, and decarboxylation of synthesized products. Furthermore, the fluorescence properties of C-N annulated compounds have also been determined, which are valuable in the field of fluorescence properties of heterocycles.

Shape-Selective Zeolites for Tandem CO2 Hydrogenation-Carbonylation Reactions.

The valorization of carbon dioxide as a C1 building block in C-C bond forming reactions is a critical link on the road to carbon-circular chemistry. Activation of this inert molecule through reduction with H2 to carbon monoxide in the reverse water-gas shift (RWGS) reaction can be followed by a wide spectrum of consecutive carbonylation reactions, but the RWGS is severely equilibrium limited at the moderate temperatures of carbonylations. Here we successfully reconcile both reactions in one pot, while avoiding incompatibilities through a zeolite-based compartmentalized approach. More specifically, Pt encapsulated in a small-pore LTA zeolite selectively generates carbon monoxide in mild reaction conditions; an ensuing one-pot carbonylation reaction allows to shift the equilibrium through continuous consumption of CO. Moreover, the zeolite encapsulation avoids undesired reactions like hydrogenation of the olefin reactant through a molecular sieving effect. This strategy was first studied in-depth for Rh-catalyzed olefin hydroformylation with CO2/H2, affording aldehydes in good yields with high regioselectivities. The methodology was then extended to a variety of carbonylations using CO2 for the synthesis of bulk and fine chemicals.

Fenton-Inactive Cd Enables Highly Selective O2-Derived Domino Reaction.

Advancing and deploying Fenton-inactive Cd that combines excellent catalytic activity, selectivity, and stability remains a serious challenge, predominantly owing to the difficulty in regulating the intrinsic electronic states and local geometric structures of such fully occupied d10s2 configuration. In this work, a combination of experiments and theoretical calculations reveals that the incorporation of boron (B) enables the tuning of the average oxidation state of Cd0 to Cdδ+, facilitating electron localization and implementing a different electrocatalytic preference compared to conventional d10-electron configurations. The resulting Cd(B) catalyst demonstrates high selectivity (>90% on average) in the O2-to-H2O2 conversion, negligible activity loss over 100h, and a superior H2O2 production rate (15.5mol∙gcat -1h-1 at -100mA). More unexpectedly, the in situ generated H2O2 exhibits a unique advantage over commercial products, selectively oxidizing cinnamaldehyde to benzaldehyde by modulating the practical current.

Synthesis of Amide-Containing Indolo[2,1-a]isoquinoline Derivatives via Palladium-Catalyzed Cascade Reactions.

A convenient palladium-catalyzed cascade cyclization reaction for the construction of amide-containing indolo[2,1-a]isoquinolines from 2-aryl-N-propenyl indoles with aromatic amines and chloroform is described. A variety of amide-containing indolo[2,1-a]isoquinoline compounds have been successfully synthesized in moderate to good yields in which chloroform is employed as the source of CO.

Mechanistic Investigations of Chiral Lithium Binaphtholate Catalysis for Asymmetric Aldol-Tishchenko Reaction of α-Fluoroarylketones.

In this study, we analyzed the asymmetric aldol-Tishchenko reaction of α-fluoroarylketones with aldehydes in the presence of chiral lithium binaphtholate, which was readily prepared from a chiral BINOL derivative and lithium tert-butoxide. This tandem reaction afforded enantiomerically enriched 2-fluoro-1,3-diols with three contiguous stereogenic centers in high yield and with high diastereo- and enantioselectivities. Moreover, mechanistic investigations of the lithium binaphtholate-catalyzed enantioselective aldol-Tishchenko reaction were performed based on the kinetic isotope effect and computational analyses.

Modular Synthesis of α-Quaternary Chiral β-Lactams via Three-Component Asymmetric Kinugasa/Aldol or Kinugasa/Mannich Cascade Reactions.

The β-lactam scaffolds are the prevalent structural units in antibiotics and natural products. Herein, three-component asymmetric Kinugasa/aldol and Kinugasa/Mannich cascade reactions have been developed for constructing α-quaternary chiral β-lactams. This strategy enables sequential assembly of alkynes, nitrones and aldehydes (or imines) and creates three contiguous stereogenic centers, controlled by copper(I) catalysts and chiral bis(oxazolidine) ligands. The developed protocol features high enantioselectivity, good reaction efficiency, and mild operational conditions representing a practical and sustainable synthetic tool for the construction of functionalized chiral β-lactams.

Iron(II)-Catalyzed Synthesis of Nitrated Dihydropyrazole via a Nitrification and C-H Activation/Cyclization Cascade Reaction.

A route for nitrification and C-H activation/cyclization of (E)-N-allyl-N'-benzylidenebenzenesulfonohydrazide and cobalt nitrate via an iron(II)-catalyzed cascade reaction to synthesize nitrated dihydropyrazoles has been developed. The method features convenient operation and good functional group tolerance. In addition, it employs insensitive and inexpensive FeSO4 as the catalyst and provides a direct approach for the preparation of dihydropyrazoles.

Reductive Coupling of N-Heteroarenes and 1,2-Dicarbonyls for Direct Access to γ-Amino Acids, Esters, and Ketones Using a Heterogeneous Single-Atom Iridium Catalyst.

Despite their significant importance, the challenges in direct and diverse synthesis of N-heterocyclic γ-amino acids/esters/ketones hamper exploration of their applications. Herein, by developing a multifunctional heterogeneous iridium single-atom catalyst composed of silica-confined iridium species and a boron-doped ZrO2 support (Ir-SAs@B-ZrO2/SiO2), we describe its utility in establishing a new reductive coupling reaction of N-heteroarenes and 1,2-dicarbonyls for selective and diverse construction of the as-described compounds in a straightforward manner. The striking features, including good substrate and functionality tolerance, high step and atom economy, exceptional catalyst reusability, and diversified product post-transformations, highlight the practicality of the developed chemistry. Mechanistic studies reveal that the synergy between the active Ir sites and acidic support favors a chemoselective reduction of the more inert N-heteroarenes and affords requisite enamine intermediates. In this work, the concept on precise transformation of reductive intermediates will open a door to further develop useful tandem reactions by rational catalyst design.

In Situ Generation of 1‐Acetylpyrene as a Visible‐Light Photocatalyst for the Thia‐Paternò‐Büchi Reaction

AbstractThe thia‐Paternò‐Büchi reaction represents a straightforward approach to build thietane cores. Unfortunately, the significant instability of thiocarbonyls, particularly thioketones and thioaldehydes, has hitherto rendered this photochemical [2+2]‐cycloaddition underexploited. To address this limitation, we report herein a visible‐light photochemical domino reaction including: the in situ generation of thiocarbonyls though a Norrish type II fragmentation of pyrenacyl sulfides, and the aforementioned thia‐Paternò‐Büchi reaction with various non‐volatile electron‐rich alkenes. The highly efficient synthesis of a wide range of unprecedented thietanes from intrinsically highly unstable thiocarbonyls, such as thioaldehydes and aliphatic thioketones, was made possible by the multitasking capability of pyrenacyl sulfides as a source of thiocarbonyl substrates and as precursors of 1‐acetylpyrene, which acts as the photocatalyst for the thia‐Paternò‐Büchi reaction. The photosensitizer properties of the latter have been experimentally established and a triplet‐triplet Dexter energy transfer based mechanism is proposed.

A nucleobase-driven P450 peroxidase system enables regio- and stereo-specific formation of C─C and C─N bonds

P450 peroxidase activities are valued for their ability to catalyze complex chemical transformations using economical H2O2; however, they have been largely underexplored compared to their monooxygenase and peroxygenase activities. In this study, we identified an unconventional P450 enzyme, PtmB, which catalyzes the dimerization of purine nucleobases and tryptophan-containing diketopiperazines (TDKPs), yielding C3-nucleobase pyrroloindolines and nucleobase-TDKP dimers. Unlike typical TDKP P450 enzymes reliant on NAD(P)H cofactors and electron transfer systems, PtmB, and its analogs exhibit remarkable peroxidase activity in synthesizing adenine and other modified 6-aminopurine nucleobase-TDKP dimers. Structural analysis of the PtmB-substrate complex, mutation assays, and computational investigations reveal adenine's dual role as both substrate and acid-base catalyst in activating H2O2 to generate Compound I (Cpd I). This initiates a specific radical cascade reaction, facilitating the formation of precise C─C and C─N bonds. Biochemical assays and molecular dynamics simulations demonstrate that adenine's 6-NH2 hydrogen-bonding networks induce necessary conformational changes for H2O2 activation, thereby driving peroxidase activity. This study unveils an unusual catalytic mechanism for the P450 peroxidase system and underscores the pivotal role of nucleobases in enzyme-mediated reactions, which offers different prospects for developing P450 peroxidases and nucleobase-based biocatalysts.

Divergent Regioselective Synthesis of Functionalized 1,2,3-1H-Triazoles from Nitriles and Arylazides Under Metal-Free and/or Solvent-Free Conditions.

Highly selective and divergent syntheses, which are crucial in both organic synthesis and medicinal chemistry, involve significant advancements in compound accessibility. By modifying α-cyano esters into α-cyano ketones, the synthesis pathway broadens to include a diverse range of 4-CN, 5-amino, and 5-arylamino derivatives of 1,2,3-triazoles, which are achieved notably through the Dimroth rearrangement. This versatility extends further with the potential for a triple cascade reaction, leading to the production of carboximidamide compounds, which are facilitated by the Cornforth rearrangement. Advancements in compound accessibility not only expand the repertoire of synthesized molecules but also open new avenues for potential pharmacological agents. Building on these findings, we have developed an innovative and efficient method for the divergent synthesis of functionalized 1,2,3-triazoles. This method strategically utilizes α-cyanocarbonyls and arylazides by harnessing their reactivity and compatibility to orchestrate a variety of molecular transformations. By optimizing these substrates, our goal is to simplify synthetic routes, improve product yields, and accelerate the discovery and development of new chemical entities with promising biological activities.

Iron-Catalyzed One-Pot Cascade Reactions of Oximes with Inactivated Saturated Ketones: Entry to Highly Substituted Pyridines.

An iron-catalyzed oxidative [3 + 3] annulation of oxime esters with inactivated saturated ketones is described. This cascade strategy allows one-step rapid synthesis of various structurally important pyridines through an oxidative dehydrogenation/annulation/oxidative aromatization sequence via direct α,β-dehydrogenation of simple saturated ketones followed by annulation with oximes. This method shows good functional group tolerance, readily accessible starting materials, a wide substrate scope, high chemoselectivity, and no need for extra stoichiometric oxidant and is also applicable to the late-stage functionalization of natural products.

Cascade Reactions for Enhanced CO2 Capture: Concurrent Optimization of Porosity and N‐Doping

AbstractCarbon capture emerges as a pivotal decarbonization technology for addressing global warming challenges. Porous carbons, despite their cost‐effectiveness and ease of regeneration for CO2 capture, typically exhibit limited capacity owing to insufficient adsorption sites. Here, nitrogen‐doped porous carbons (NPCs) are introduced that overcome the prevalent trade‐offs between specific surface area and N‐doped content in NPCs fabrication through cascade reactions. The optimized NPC, which features hierarchical porosity ranging from ultra‐micropores to macropores, shows a superior CO2 capture capacity of 4.46 mmol g−1, ranking in the top 10% of the reported NPCs. This capacity exceeds that of the NPC fabricated with the conventional method by 58% and surpasses the control porous carbon by 106%. Langmuir adsorption modeling and mathematic correlation analysis revealed that this enhanced capacity is attributed to significantly improved ultra‐micropores volume and nitrogen‐species content. Moreover, this optimized NPC demonstrates exceptional stability, preserving its adsorption performance over 110 adsorption–desorption cycles under simulated flue gas conditions. This research not only highlights the integration of templating and N‐doping within NPCs fabrication but also offers an effective strategy to optimize porosity and nitrogen functionality in carbon materials, advancing beyond conventional methodologies.

Green Synthesis of 2-Mercapto 5,6-Dihydro-4H-1,3-Thiazines via Sequential C–S Couplings

The six-membered N,S-heterocyclic 1,3-thiazines and their derivatives are widely acknowledged as pharmaceutical molecules with a wide range of biological activities. In this study, we developed a unique thiol-involved cascade reaction that enables the efficient construction of the 5,6-dihydro-4H-1,3-thiazine scaffold through consecutive intermolecular thiol-isothiocyanate and intramolecular thiol-halogen click reactions. Structurally diverse 2-mercapto dihydrothiazines including three antitumour candidates of bis-dihydrothiazines were readily obtained in high yields from the readily available thiols and 3-chloroisothiocyanate in the green solvent EtOH/H2O (1:1) using K2CO3 (0.6 equiv.) as the base. Between the two synthesis procedures investigated, the microwave-assisted reaction generally behaved more efficiently than that under routine heating conditions. Furthermore, DFT calculation confirmed the sequential addition–substitution mechanism. This cascade C–S coupling reaction methodology offers several advantages, including rapid completion, high reliability, easy purification, and benign conditions.

Defluorinative Multicomponent Cascade Reaction of Trifluoromethylarenes via Photoexcited Palladium Catalysis

Defluorinative Multicomponent Cascade Reaction of Trifluoromethylarenes via Photoexcited Palladium Catalysis

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.

Regio‐ and Diastereoselective One‐pot Double Cascade Hybrid Formation/[3+3] Spirocyclization for the Synthesis of 3‐Spiropiperidines Under Phase Transfer Conditions.

Herein, we report an efficient approach to synthesizing hybrid 3‐spiropiperidines heterocycles that incorporate both 3‐isochromanone and 3‐isoindolinone units through a one‐pot, double cascade reaction facilitated by an economical K₂CO₃/TBAB catalytic system. By examining the nucleophilicity of the lactone 3‐isochromanone, we developed a cascade reaction pathway that first generates a bi‐nucleophilic hybrid intermediate, which then undergoes [3+3] spirocyclization with α,β‐unsaturated aldehydes. The regioselectivity of the spirocyclization strongly depends on the substitution pattern of lactam ring. The process exhibits high diastereoselectivity, even with the formation of three or four stereocenters, including two contiguous quaternary carbons. These sequential cascade reactions were successfully scaled up, and the subsequent reactivity was readily analyzed, enabling the transformation of existing functional groups into valuable new functionalities.

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.