Diels-Alder Research Articles

Isochroman-3,4-dione and Tandem Aerobic Oxidation of 4-Bromoisochroman-3-one in the Highly Regio- and Diastereoselective Diels-Alder Reaction for the Construction of Bridged Polycyclic Lactones.

Herein we report two processes facilitated by diisopropylethylamine (DIPEA) for the synthesis of novel bridged polycyclic molecule analogues to natural products. The use of 4-bromoisochroman-3-one initiated an autoxidation reaction, followed by a Diels-Alder cycloaddition in the presence of electron-deficient dienophiles. Mechanistic studies revealed isochromane-3,4-dione as a key intermediate, which undergoes in situ dienolization/dearomatization followed by a [4 + 2] cycloaddition. Subsequently, the synthesis and direct application of isochromane-3,4-diones in the Diels-Alder reaction enabled the development of an alternative method with an enhanced efficiency and improved atom economy. In addition to chalcones, other enones and common electron-poor alkenes, bearing ester, nitro and cyano electron-withdrawing groups (including both terminal, cis acyclic and cyclic alkenes), were successfully reacted. The mechanism was also investigated, and a subsequent reductive ring opening was successfully carried out.

Inverse Electron Demand Diels-Alder Reaction of Pyrazines with 2,5-Norbornadiene as Acetylene Precursor

Herein, we report the reaction of pyrazines with 2,5-norbornadiene, an acetylene precursor, as a cascade of Diels-Alder reactions yielding substituted pyridines. In contrast to the known examples of intermolecular Diels-Alder type reaction of pyrazines with acetylene, which usually leads to a mixture of products, in our case the formation of a single isomer was observed. The proposed approach allows the conversion of pyrazines with different types of substitution, except those containing methyl and amino donor groups, to pyridines. In addition, highly functionalized aminonicotic esters were obtained, which can be used for the synthesis of bioactive compounds. An unusual course of the Diels-Alder reaction was found in the case of tetrasubstituted pyrazines, which cleave organic nitriles instead of HCN. Quantum-chemical modeling of possible transition states showed that this Diels-Alder reaction proceeds via cycloaddition of 2,5-norbornadiene to pyrazine with sequential elimination of HCN and cyclopentadene; the reaction pathway including initial formation of acetylene from norbornadiene and subsequent Diels-Alder reaction with the acetylene was rejected as kinetically unfavorable.

Synthesis of Polyoxygenated 4,5-Diarylpyridazines with Antiproliferative and Antitubulin Activity via Inverse Electron-Demand Diels-Alder Reaction of 1,2,4,5- Tetrazine

: The synthesis of a series of multifunctionalized 4,5-diarylpyridazines via inverse electron-demand Diels-Alder reaction between highly oxygenated diarylacetylenes and unsubstituted 1,2,4,5-tetrazine was developed using polyalkoxybenzenes isolated from industrial essential oils as starting material. The reaction proceeded smoothly to afford combretastatin A-4 analogs with pyridazine linker in consistently high yield. In a phenotypic sea urchin embryo assay, diarylpyridazine with 3,4,5-trimethoxyphenyl and 3-amino-4- methoxyphenyl aryl rings was identified as a potent antimitotic microtubule-destabilizing compound.

Wave-transparent and eco-friendly flame-retardant phosphorus-based phthalonitrile/quartz composites by a synchronized self-curing strategy with cyano and alkynyl groups

The robust human–machine interaction systems of the aerospace industry necessitate the development of thermal resistant wave-transparent composites, with a pivotal focus on organic resin matrix. However, enhancing the heat resistance of such materials while preserving other critical attributes has been a formidable challenge. In this study, a novel designed strategy of a dual-curing functional phosphorus-based phthalonitrile monomer (P-ALK-PN) has been proposed. The optimized curing temperatures for intra- or intermolecular Diels-Alder reactions of alkynyl groups and polyaddition reaction of cyano groups resulted in a homogeneous and highly crosslinked N-enriched phthalonitrile system. After curing at 450 °C, the resin, namely P-ALK-PN-450 °C, demonstrated exceptional thermal stability (T5% = 644 °C), thermo-oxidative stability (T5% = 554 °C), and char yield at 800 °C (90.7 % in N2 and 67.5 % in air). Their quartz fiber reinforced composites (P-ALK-PN/QFs) were subsequently fabricated by the hot-pressing process. Upon post-curing at 420 °C, P-ALK-PN-420 °C/QF displayed elevated glass transition temperature (550 °C), flexural strength (319 MPa), and relatively low dielectric properties with a dielectric constant (Dk) of approximately 4.2 and a dissipation factor (Df) less than 0.02 across a wide temperature ranging from 25 °C to 600 °C. Especially, it exhibited excellent flame retardancy (only a 6.7 % weight loss at ambient temperatures exceeding 1300 °C for 200 s) as well, stemming from release of eco-friendly inert gases (NH3) and formation of a graphitized protective layer during pyrolysis. These promising results highlight the potential applications of P-ALK-PN resins in aerospace and high-performance engineering fields.

Bioorthogonal Activation of Deep Red Photoredox Catalysis Inducing Pyroptosis.

The revolutionary impact of photoredox catalytic processes has ignited novel avenues for exploration, empowering us to delve into nature in unprecedented ways and to pioneer innovative biotechnologies for therapy and diagnosis. However, integrating artificial photoredox catalysis into living systems presents significant challenges, primarily due to concerns over low targetability, low compatibility with complex biological environments, and the safety risks associated with photocatalyst toxicity. To address these challenges, herein, we present a novel bioorthogonally activatable photoredox catalysis approach. In this approach, potent photocatalyst selection via atom replacement of the rhodamine core yielded the bioorthogonally activatable photocatalyst (PC-Tz). The introduction of 1,2,4,5-tetrazine quenched its photocatalytic properties, which were restored upon an intracellular inverse electron-demand Diels-Alder (iEDDA) reaction with trans-cyclooctene (TCO) localized in mitochondria. This reaction led to remarkable photocatalytic oxidation of nicotinamide adenine dinucleotide (NADH), effectively manipulating the mitochondrial electron transport chain (ETC) under hypoxic conditions in cancer cells. Additionally, photocatalytic pyroptotic cell death was observed through a caspase-3/gasdermin E (GSDME) pathway, achieving notable antitumor efficacy and adenosine triphosphate (ATP) reduction in tumor cells. To the best of our knowledge, this represents the first example of bioorthogonally activatable photoredox catalysis, opening new avenues for chemists to spatiotemporally control activity in specific cell organelles without disrupting other native biological processes.

Unveiling the potential of dual-extrinsic/intrinsic self-healing lignin-based coatings for anticorrosion applications

The development of self-healing ecofriendly coatings for anticorrosion applications provides stronger protection than passive coatings and mitigates the environmental pollution resulting from petroleum-derived coatings. Due to its intrinsic anticorrosion characteristics, lignin is a viable precursor for the formulation of self-healing anticorrosion coatings. However, the structural rigidity of lignin and the lack of self-healing functionalities in pristine lignin-based coatings hinder the comprehensive application of lignin in this field. Accordingly, we introduced Diels-Alder (DA)-based self-healing functions in the lignin-based coatings and meanwhile, the coatings were chemically conjugated with corrosion inhibitors to further improve the anticorrosion performance. A thin layer (16 μm) of the coating increased the Ecorr from −481 mV (for bare steel) to +91 mV and reduced the corrosion rate (CR) >4000 times. The dual self-healing properties of the coating are attributed to the synergistic action of the DA adduct and the conjugated corrosion inhibitor. Practically, in response to the emergence of microcracks in the coating structure, trace amounts of the corrosion inhibitor are released into the microcracks to form a protective layer on the unveiled metal surface. Simultaneously, DA adducts undergo reversible reactions at specific temperatures (80–120 °C) promoting complete restoration of the microcrack.

Unveiling the Structure-Fluorogenic Property Relationship of Seoul-Fluor-Derived Bioorthogonal Tetrazine Probes.

Tetrazine (Tz)-embedded fluorescent probes, known for their fluorogenicity following bioorthogonal inverse electron-demand Diels-Alder (iEDDA) reactions, are extensively used in bioimaging. Despite significant research on fluorogenic Tz probes, there has been limited systematic exploration of their fluorogenic responses with various dienophiles. In this study, we elucidate the structure-fluorogenic property relationship of bioorthogonal Tz probes. We synthesized a series of Seoul-Fluor-Tz (SFTz) probes designed to exhibit differentiated turn-on fluorescence upon iEDDA reactions with three dienophiles: trans-cyclooctene (TCO), bicyclo[6.1.0]nonyne (BCN), and spiro[2.3]hex-1-ene (Sph). Our findings revealed that the fluorogenic properties of the SFTz probes are highly dependent on the structures of dienophile-Tz adducts. By systematically modifying the electronic properties and employing quantum chemical calculations, we developed a series of SFTz probes with optimal dienophile-dependent fluorescence. These probes enabled simultaneous dual-color imaging of different cellular targets using a single probe, providing a robust approach for advanced bioimaging applications that require precise and efficient multicolor labeling strategies.

Impact of Transition-State Aromaticity on Selective Radical-Radical Coupling of Triarylimidazolyl Radicals.

Radical coupling reactions are generally known to have a low selectivity due to the high reactivity of radicals. In this study, high regio and substrate selectivity was discovered in the dimerization of triarylimidazolyl radicals (TAIR), a versatile photochromic reaction. When two different radicals, 2-(4-cyanophenyl)-4,5-diphenyl-1H-imidazolyl radical (CN-TAIR) and 2-(4-methoxyphenyl)-4,5-diphenyl-1H-imidazolyl radical (OMe-TAIR), were simultaneously generated in situ, a hexaarylbiimidazole, formed by selective coupling at the nitrogen atom at position 1 of CN-TAIR and the carbon atom at position 2 of OMe-TAIR, was isolated with high selectivity as the main product among 24 possible radical dimer hexaarylbiimidazole derivatives. This high regio and substrate selectivity cannot be explained solely by the stability of the product and/or the electrophilicity and nucleophilicity of the radicals but originates from the aromaticity of the transition state in the radical-radical coupling reaction. To date, the selectivity of radical coupling reactions has been thought to be controlled by steric hindrance and radical spin density, but this study revealed a new factor for controlling radical coupling, that is, transition-state aromaticity. Aromaticity has been reported to have an important effect not only in the reactivity and structure of ground-state molecules but also on the electronically excited states and transition states in pericyclic reactions such as the Diels-Alder reaction and the Cope-Claisen rearrangement. This study demonstrated for the first time that radical coupling reactions can also be controlled by transition-state aromaticity.

Three-Component Synthesis of Multiply Functionalized 5,6-Dehydroisoquinuclidines through Dearomatization of Pyridine.

A three-component synthesis of multiply functionalized 5,6-dehydroisoquinuclidines is described. After the formation of an N-alkylpyridinium salt, Grignard addition led to the formation of the corresponding 1,2-dihydropyridine bearing an alkyl, alkene, aryl, or alkynyl group. Subsequent Diels-Alder reaction with a dienophile provided functionalized dehydroisoquinuclidines in high yields (up to 93%) with endo selectivities (73:27 to >99:1). This reaction was applicable to the synthesis of an N-(4-methoxybenzyl)pyridinium salt, where the 4-methoxybenzyl group was switched to a benzyloxycarbonyl group after the formation of the dehydroisoquinuclidine.

CuI-Zeolite Catalysis for Biaryl Synthesis via Homocoupling Reactions of Phenols or Aryl Boronic Acids

Due to the importance of biaryls as natural products, drugs, agrochemicals, dyes, or organic electronic materials, a green alternative biaryl synthesis has been developed based on easy-to-prepare and cheap copper(I)-exchanged zeolite catalysts. CuI-USY proved to efficiently catalyze the direct homocoupling of either phenols or aryl boronic acids under simple and practical conditions. The CuI-USY-catalyzed oxidative homocoupling of phenols could conveniently be performed under air either in warm methanol or water with good to high yields. In methanol, a small amount of Cs2CO3 was required, while none was necessary in water. The homocoupling of aryl boronic acids was best performed also in warm methanol, without an additive. These mild conditions showed good functional-group tolerance, leading to a variety of substituted (hetero)biaryls (28 examples). The heterogeneous CuI-USY catalyst could readily be recovered and reused. Interestingly, the homocoupling of vinyl boronic acids was successfully coupled to a Diels–Alder reaction, even in a one-pot process, allowing access to highly functionalized cyclohexenes.

Understanding the Reactivity and Selectivity of Oxazaborolidium Ion-Catalyzed Diels-Alder Reactions Involving Cyclobutenones as Dienophiles.

The poorly understood factors controlling the reactivity and selectivity (both stereo- and enantioselectivity) of catalyzed Diels-Alder reactions involving cyclobutenones as dienophiles have been analyzed in detail by means of Density Functional Theory calculations. To this end, the reactions with cyclopentadiene and furan as dienes and 3-(methoxycarbonyl)cyclobutenone catalyzed by Corey's chiral oxazaborolidium ion (COBI) have been selected and compared to their analogous uncatalyzed transformations. The combined Activation Strain Model of reactivity and Energy Decomposition Analysis methods have been used to quantitatively understand the acceleration and selectivity induced by the catalyst in this reaction.

Pretargeted alpha therapy in MUC16-positive high-grade serous ovarian cancer

BackgroundPeritoneal metastasis with micrometastatic cell clusters is a common feature of advanced ovarian cancer. Targeted alpha therapy (TAT) is an attractive approach for treating micrometastatic diseases as alpha particles release enormous amounts of energy within a short distance. A pretargeting approach — leveraging the inverse-electron-demand Diels-Alder reaction between tetrazines (Tz) and trans-cyclooctene (TCO) — can minimize off-target toxicity related to TAT, often associated with full-length antibodies. We hypothesized that a pretargeting strategy could effectively treat high-grade serous (HGS) ovarian tumors while minimizing toxicity. MethodsWe utilized the humanized antibody, AR9.6, labeled with actinium-225 (225Ac). AR9.6 targets fully glycosylated and hypoglycosylated isoforms of MUC16. For biodistribution and radioimmunotherapy studies, AR9.6-TCO was injected into OVCAR3-bearing mice 72 h before administering [225Ac]Ac-mcp-PEG8-Tz, e.g. using a 1,2,4,5-tetrazine conjugated to the macropa chelator via a polyethylene glycol (PEG) linker. ResultsBiodistribution data revealed that the pretargeting approach achieved substantial tumor uptake. Cerenkov luminescence imaging confirmed successful in vivo pretargeting during TAT studies. Compared to the control groups, TAT with AR9.6-TCO and [225Ac]Ac-mcp-PEG8-Tz significantly suppressed tumor growth and improved overall survival in OVCAR3 tumor-bearing mice. Renal and ovarian pathology compatible with toxicity was observed in mice in addition to transient hematologic toxicity. ConclusionWe confirmed that pretargeting with AR9.6-TCO and [225Ac]Ac-mcp-PEG8-Tz has durable antitumor effects in high MUC16-expressing tumors. These findings demonstrate great potential for using pretargeting in combination with TAT for the treatment of ovarian cancer. ClassificationBiological Sciences; Applied Biological Sciences.

Remote-Contact Catalysis for Target-Diameter Semiconducting Carbon Nanotube Arrays.

Electrostatic catalysis uses an external electric field (EEF) to rearrange the charge distribution to boost reaction rates and selectively produce certain reaction products in small-molecule reactions (e.g., Diels-Alder addition), requiring a 10 MV/cm field aligned with the reaction axis. Such a large and oriented EEF is challenging for large-scale implementation or material growth with multiple reaction axes or steps. Here, we demonstrate that the energy band at the tip of an individual single-walled carbon nanotube (SWCNT) can be spontaneously shifted in a high-permittivity growth environment, with its other end in contact with a low-work-function electrode (e.g., hafnium carbide). By adjusting the Fermi level at a point where there is a substantial disparity in the density of states (DOS) between semiconducting (s-) and metallic (m-) SWCNTs, we achieve effective electrostatic catalysis for 99.92% purity s-SWCNT growth with a narrow diameter distribution (0.95 ± 0.04 nm), targeting the requirement of advanced SWCNT-based electronics for future computing.

Computational Insights into Tunable Reversible Network Materials: Accelerated ReaxFF Kinetics of Furan-Maleimide Diels-Alder Reactions for Self-Healing and Recyclability.

In this study, ReaxFF molecular dynamics simulations were benchmarked and used to study the relative kinetics of the retro Diels-Alder reaction between furan and N-methylmaleimide. This reaction is very important for the creation of polymer networks with self-healing and recyclable properties, since they can be used as reversible linkers in the network. So far, the reversible Diels-Alder reaction has not yet been studied by using reactive molecular dynamics simulations. This work is, thus, the first step in simulating a covalent adaptable network (CAN) using Diels-Alder reactions as reversible linkers. For both endo and exo, the bond breaking in 40 product molecules was simulated using the bond boost method and the endo/exo ratio was evaluated. This ratio was benchmarked against density functional theory (DFT) and experimental results for a changing set of bond boost parameters. Given their importance to understand how the CAN performs, the effect of the addition of a polymer backbone and the effect of temperature were successfully simulated using our newly parametrized reactive force field.

Novel Recycling of Epoxy Thermosets by Blending with Reversible Diels-Alder Epoxy Resin.

The introduction of Diels-Alder (D-A) bonds into epoxy resins is a promising pathway to convert these unrecyclable materials into sustainable materials. However, D-A bonds make epoxy resins extremely brittle materials and hinder their practical usability. Nonetheless, the reversibility of D-A bonds allows the transition of the material to a de-crosslinked network formed by separated oligomers that can melt above 90-100 °C. This means that D-A epoxy resins can be reprocessed after being cured like thermoplastics. In the present work, a thermoset blend is made by adding spent epoxy particles to a D-A epoxy resin to increase its thermal and mechanical properties and to evaluate a possible reuse of conventional thermoset wastes. The application of hot-pressing to a mixture of epoxy particles and powder of cured D-A epoxy creates a material in which the interaction of the particles with the D-A resin increases the thermal resistance of the material and prevents the D-A epoxy from melting at high temperatures. In addition, the flexural strength is increased by 80% and the chemical resistance against organic solvents is also improved.

An Expeditious Synthesis of Near-Infrared-Absorbing Imide-Based Graphene Nanoribbons and Their Photothermal Properties.

Graphene nanoribbons (GNRs) with low band gap and strong near-infrared (NIR) absorption are potential candidates for optoelectronic and biomedical applications. In this context, imide-based GNRs are promising, but there are no rational design principles that yield these robust GNRs with strong NIR absorption. Here, we demonstrate a rational synthesis route to achieve NIR-absorbing imide-based robust GNRs by exploring the bay region of polyperylene (PP). Using the oxidative Diels-Alder reaction, we have successfully introduced mono and diimide functional groups on PP. After cyclodehydrogenation, the resultant GNRs, benzoperylene imide GNR (BPI-GNR) and coronene diimide GNR (CDI-GNR), show oscillatory edge geometry with strong NIR absorption (up to 1000 nm) and optical band gap of ~1.3 eV. Computational studies also indicate that imide substituents play an important role in fine-tuning the optoelectronic properties of GNRs. Moreover, these GNRs are solution-processable and can be made into thin films via spray coating. Owing to the strong NIR absorption and imide substitutions, BPI and CDI-GNRs show good photothermal conversion with excellent cyclic stability.

Fullerene-Hybridized Fused-Ring Electron Acceptor with High Dielectric Constant and Isotropic Charge Transport for Organic Solar Cells.

A novel isotropic fullerene-hybridized fused-ring electron acceptor, designated C60-Y, has been synthesized via a mild [4+2] Diels-Alder cycloaddition reaction with fullerene C60 to enhance the performance of organic solar cells (OSCs). Comparative analysis shows that C60-Y significantly outperforms the control acceptor Me-Y, with a notable increase in the relative dielectric constant from 2.79 to 3.95. This improvement enhances exciton dissociation and reduces non-radiative energy losses. Additionally, the isotropic molecular packing of C60-Y, similar to fullerene, facilitates efficient interface formation with donor polymers and improves charge mobility. As a result, incorporating C60-Y as an electron acceptor increases the power conversion efficiency (PCE) of binary OSCs to 15.02 %, surpassing the 13.31 % achieved with Me-Y. Moreover, when integrated into a ternary blend system, an impressive PCE of 19.22 % is achieved, top-performing among reported ternary OSCs utilizing fullerene derivatives as the third component. These results suggest that fullerene-hybridized acceptors like C60-Y hold great potential for advancing high-efficiency OSCs by enhancing exciton dissociation, reducing energy losses, and improving charge mobility.

Construction of Naphtho[2,1-d]oxazoles and 1,4-Epoxyisoquinolines via Regioselectivity-Switchable Diels-Alder Reaction of 4-Alkenyloxazoles with Arynes.

A Regioselectivity-switchable Diels-Alder reaction of arynes and 4-alkenyloxazoles was explored. By regulating the reaction temperature and the polarity of the solvent, the reaction activity of aryne was controlled to selectively react with different favorable reaction sites of 4-alkenyloxazoles, providing naphtho[2,1-d]oxazoles and 1,4-epoxyisoquinolines. Density functional theory (DFT) calculations demonstrated that the Diels-Alder reaction on acyclic dienes site needs more energy than the reaction on cyclic dienes to overcome the potential reaction barrier.

Using Near-Infrared Irradiation for Heating Mechanochemical Reactions in Organic-Dye-Doped Epoxy Milling Jars.

Albeit mechanochemistry is a novel promising technology that give access to reactivity under solvent-free conditions, heating such reactions is sometimes compulsory to obtain satisfactory results in terms of conversion, selectivity and/or yield. In this work, we developed a novel approach using a dye that absorbs NIR photons and release the energy as heat. Hence, de novo milling jars in epoxy resin doped with the dye were thus produced to obtain reactors that would produce heat upon irradiation at 850 nm. Temperature profiles were recorded, depending on the irradiance, dye charge in the resin, and milling frequency, showing an excellent control of the temperature. The usefulness of the heating jar was then demonstrated in mechanochemical reactions that are known to require heat to yield the desired product, namely Diels-Alder reactions with high activation energies and the newly developed rearrangement of a sydnone into corresponding 1,3,4-oxadiazolin-2-one.

Diels–Alder Adducts of <i>N</i>-Substituted 2-Pyridones with Maleinimides. Synthesis and Antiviral Activity

Adducts of N-substituted 2-pyridones [pyridine-2(1H)-ones] and N-substituted maleic acid imides were synthesized under thermal conditions of the Diels–Alder reaction with yields from 68 to 97%. Cytotoxicity and antiviral activity of the obtained compounds were studied using a model of adenovirus infection [human adenovirus type 5 (AdV5)] in MA-104 cell culture. It was shown that the synthesized adducts have low toxicity and medium antiviral activity. Only 9-hexyl-2-phenyl-3a,4,7,7a-tetrahydro-1H-4,7-(epiminomethano)isoindole-1,3,8-trione has the most pronounced viral inhibitory properties with a selectivity index of 7.