Sequential Diels-Alder Research Articles

A Rapid Aza-Bicycle Synthesis from Dendralenes and Imines.

The diene-transmissive 2-fold Diels-Alder sequence between carbon-based dienophiles and [3]dendralenes is becoming an established method for polycarbocycle synthesis. Here, we demonstrate for the first time that imines are competent participants in intermolecular formal [4 + 2] cycloadditions with dendralenes. After a second Diels-Alder process with a carbadienophile, hexahydro- and octahydro-isoquinoline structures are formed. The formal aza-Diels-Alder reaction, which requires Lewis acid promotion, proceeds in high regio- and stereoselectivity under optimized conditions. ωB97XD/Def2-TZVP//M06-2X/6-31+G(d,p) calculations reveal a stepwise ionic mechanism for the formal aza-dienophile cycloadditions and also explain an unexpected Z → E olefin isomerization of a non-reacting C═C bond in the first formal cycloaddition.

Convolution Neural Networks for Motion Detection with Electrospun Reversibly-Cross-linkable Polymers and Encapsulated Ag Nanowires.

This paper presents the design, fabrication, and implementation of a novel composite film, a polybutadiene-based urethane (PBU)/AgNW/PBU sensor (PAPS), demonstrating remarkable mechanical stability and precision in motion detection. The sensor capitalizes on the integration of Ag nanowire (AgNW) electrodes into a neutral plane, embedded within a reversibly cross-linkable PBU polymer. The meticulous arrangement confers pore-free and interfaceless sensor formation, resulting in an enhanced mechanical robustness, reproducibility, and long-term reliability. The PBU polymer is subjected to an electrospinning process, followed by sequential Diels-Alder (DA) and retro-DA reactions to produce a planarized encapsulation layer. This pioneering technology, based on electrospinning, allows for more flawless engineering of the neutral plane as compared to conventional film lamination or layer-by-layer spin-coating processes. This encapsulation, matching the thickness of the preformed PBU film, effectively houses the AgNW electrodes. The PAPS outperforms conventional AgNW/PBU sensors (APS) in terms of mechanical stability and bending insensitivity. When affixed to various body parts, the PAPS generates distinctive signal curves, reflecting the specific body part and degree of motion involved. The PAPS sensor's utility is further magnified by the application of machine learning and deep learning algorithms for signal interpretation. K-means clustering algorithm authenticated the superior reproducibility and consistency of the signals derived from the PAPS over the APS. Deep learning algorithms, including a singular 1D convolutional neural network (1D CNN), long short-term memory (LSTM) network, and dual-layered combinations of 1D CNN + LSTM and LSTM + 1D CNN, were deployed for signal classification. The singular 1D CNN model displayed a classification accuracy exceeding 98%. The PAPS sensor signifies a pivotal development in the field of intelligent motion sensors.

Mechanistic Insights into the Reaction of Amidines with 1,2,3-Triazines and 1,2,3,5-Tetrazines.

1,2,3-Triazines and 1,2,3,5-tetrazines react rapidly, efficiently, and selectively with amidines to form pyrimidines/1,3,5-triazines, exhibiting an orthogonal reactivity with 1,2,4,5-tetrazine-based conjugation chemistry. Whereas the mechanism of the reaction of the isomeric 1,2,4-triazines and 1,2,4,5-tetrazines with alkenes is well understood, the mechanism of the 1,2,3-triazine/1,2,3,5-tetrazine–amidine reaction as well as its intrinsic reactivity remains underexplored. By using 15N-labeling, kinetic investigations, and kinetic isotope effect studies, complemented by extensive computational investigations, we show that this reaction proceeds through an addition/N2 elimination/cyclization pathway, rather than the generally expected concerted or stepwise Diels–Alder/retro Diels–Alder sequence. The rate-limiting step in this transformation is the initial nucleophilic attack of an amidine on azine C4, with a subsequent energetically favored N2 elimination step compared with a disfavored stepwise formation of a Diels–Alder cycloadduct. The proposed reaction mechanism is in agreement with experimental and computational results, which explains the observed reactivity of 1,2,3-triazines and 1,2,3,5-tetrazines with amidines.

Transformation of π-conjugated macrocycles: from furanophanes to napthalenophanes.

Applying sequential Diels-Alder cycloaddition and deoxygenation to small π-conjugated furan macrocycles fully converts them to 1,4-naphthalophanes with either ethylene or acetylene spacers, depending on the reaction conditions. 1,4-Napthalenophane tetraene exhibits a 1,3-alternating conformation in the solid state, inclusion of solvent molecules within the macrocycle, and low reduction potentials.

Preparation and characterization of starch-cellulose interpenetrating network hydrogels based on sequential Diels-Alder click reaction and photopolymerization

Herein, starch-cellulose interpenetrating network (IPN) hydrogels were fabricated by sequential Diels-Alder click reaction and photopolymerization in water. Moreover, β-cyclodextrin, a commonly used host molecule in supramolecular chemistry, was also introduced to improve the performance of the IPN hydrogel. Firstly, the starch-based dienes were synthesized by modifying starch with N-maleoyl-β-alanine, and the cellulose-based dienophiles were obtained by the reaction of cellulose and furfurylamide succinate; Secondly, the as-synthesized starch-based dienes, cellulose-based dienophiles, polymerizable β-cyclodextrin, crosslinker, and acrylamide were dissolved in water and obtained a transparent solution. The solution was maintained in a water bath of 50 °C for 3 h, forming the first network via catalyst-free click Diels-Alder reaction, subsequently, the second network was formed by photopolymerization. Their preparation conditions were optimized via one-factor experiments and their properties and structures were characterized. Finally, 5- fluorouracil (5-Fu) was used as a model drug to study the sustained release behavior of the drug-loaded hydrogels. Release profile was found to fit in Ritger-Peppas kinetic model and polymer relaxation and drug diffusion made a valuable contribution to drug release. Taking into account the virtues of easily controllable photopolymerization and catalyst-free Diels-Alder reaction, the strategy described here has a potential application in the preparation of IPN hydrogels.

Allenes in Diels–Alder Cycloadditions

AbstractFor a long time, allenes—and cumulenic systems in general—played a relatively minor role in Diels–Alder cycloadditions. This situation has changed, since allenes are more readily available and as their unique stereochemical features in [4+2]cycloadditions are more widely recognized. This review presents a comprehensive overview of allenes in Diels–Alder processes using selected examples. Allenes in dienes, dienophiles and cycloadducts are covered, inter- and intramolecular Diels–Alder cycloadditions are discussed, and stereochemical features of the addition process are described. Areas of emerging importance are also covered, including allenic components in dehydro-Diels–Alder processes, and dendralenic allenes in Diels–Alder sequences for the rapid generation of target-relevant molecular complexity. Preparatively useful methods for allenic precursor synthesis are also discussed.1 Introduction2 Allenic Dienes2.1 Vinylallenes2.2 Bisallenes2.3 Cross-conjugated Allenes3 Allenic Dienophiles4 Intramolecular Diels–Alder Cycloadditions5 Allenic Cycloadducts6 Conclusions and Outlook

Convergent Synthesis of Triindanone-Fused Spiro[bicyclo[2.2.2]octane-2,3'-indolines] via Domino Reaction of 1,3-Indanedione and 3-Methyleneoxindoles.

A triethylamine-promoted domino reaction of three molecular 1,3-indanediones with various 3-methyleneoxindoles in refluxing ethanol has been developed. Series of novel polycyclic triindanone-fused spiro[bicyclo[2.2.2]octane-2,3'-indoline] derivatives were successfully synthesized in satisfactory yields with high diastereoselectivity. This domino reaction was accomplished with in situ generation of active cyclic dienes by base-promoted cyclotrimerization or cyclotetramerization of 1,3-indanediones and sequential Diels-Alder reaction of active cyclic dienes with dienophilic 3-methyleneoxindoles.

Diene-Transmissive Enantioselective Diels-Alder Reactions and Sequences Involving Substituted Dendralenes.

Readily available and stable substituted [3]dendralenes undergo highly chemo-, regio-, diastereo-, and enantioselective organocatalyzed Diels-Alder reactions with acrolein to form enantiomerically enriched cycloadducts. These monocycloadducts carry semicyclic dienes that undergo a second, substrate-controlled diastereoselective Diels-Alder reaction with a different dienophile to form 2-fold cycloadducts. Overall, annulated, functional group rich, chiral Δ1(9)-octalin building blocks are accessed in one-pot operations that significantly extend the preparative value of diene-transmissive Diels-Alder sequences since they offer products of regio- and stereochemistry complementary to those generated from the parent, unsubstituted [3]dendralene.

Diene-Transmissive Diels-Alder Sequences with Benzynes.

Diene-transmissive Diels-Alder (DTDA) sequences are extraordinarily powerful processes for the generation of fused bicyclic systems. Nonetheless, only stable dienophiles have previously been deployed. Herein we report DTDA sequences with a variety of substituted [3]dendralenes in the first study to deploy arynes as dienophiles. We demonstrate the one-flask generation of complex, aromatic-ring-containing, multicyclic systems of relevance to medicinal chemistry. These synthetic operations provide numerous successful examples of the otherwise challenging and rarely reported intermolecular Diels-Alder reaction of acyclic 1,3-butadienes with arynes, which is made possible due to the exalted reactivity of dendralenic dienes.

Cyclic Alkyne Approach to Heteroatom‐Containing Polycyclic Aromatic Hydrocarbon Scaffolds

AbstractWe report a modular synthetic strategy for accessing heteroatom‐containing polycyclic aromatic hydrocarbons (PAHs). Our approach relies on the controlled generation of transient heterocyclic alkynes and arynes. The strained intermediates undergo in situ trapping with readily accessible oxadiazinones. Four sequential pericyclic reactions occur, namely two Diels–Alder/retro‐Diels–Alder sequences, which can be performed in a stepwise or one‐pot fashion to assemble four new carbon–carbon (C−C) bonds. These studies underscore how the use of heterocyclic strained intermediates can be harnessed for the preparation of new organic materials.

HOAc-Mediated Domino Diels-Alder Reaction for Synthesis of Spiro[cyclohexane-1,3'-indolines] in Ionic Liquid [Bmim]Br.

An efficient and diastereoselective synthetic protocol for the construction of spiro[cyclohexane-1,3′-indolin]-3-en-2′-ones and spiro[cyclohexane-1,2′-inden]-3-ene-1′,3′-diones was provided by HOAc-mediated domino reaction of pinacoles with typical dienophiles, such as 3-methyleneoxindolines and 2-arylideneindane-1,3-diones, in ionic liquid [Bmim]Br. This domino reaction involved the in situ generation of 1,3-dienes from acid-mediated dehydration of various pinacoles and the sequential Diels–Alder reaction.

Modular Synthesis of Rigid Polyacene Dimers for Singlet Fission.

An improved, modular synthesis of rigid, geometrically well-defined, alkyne-substituted tetracene (1) and pentacene (2) dimers is reported. The synthesis is rooted in sequential Diels-Alder reactions of a norbornyl tetraene with triisopropylsilylacetylene-substituted (TIPS-acetylene) quinone dienophiles. The incorporation of solubilizing and stabilizing TIPS-acetylene groups early in the synthesis affords a mild and reliable route, providing access, for the first time, to norbornyl-bridged pentacene dimers. A preliminary exploration of the excited state behavior of these molecules is also described.

Regioselective Transformation of Long π-Conjugated Backbones: From Oligofurans to Oligoarenes.

We demonstrate the transformation of oligofurans through sequential Diels-Alder cycloaddition reactions to provide oligoarenes in two chemical steps, regardless of the oligomer length. By this method, oligonaphthalenes containing up to six units were obtained in high yield through the formation of up to 12 new C-C bonds. The versatility of this method was demonstrated for various polyaromatic hydrocarbons. The regioselectivity of this process enabled the synthesis of a library of substituted triarylenes from a single terfuran precursor by modification of the dienophile strength and the order of addition. Overall, this study demonstrates that long oligofurans are interesting not only as organic electronic materials, but also as starting materials for the formation of various conjugated systems.

Naphthazarin-Polycyclic Conjugated Hydrocarbons and Iptycenes.

The synthesis of a set of naphthazarin-containing polycyclic conjugated hydrocarbons is described herein. Sequential Diels-Alder reactions on a tautomerized naphthazarin core were employed to access the final conjugated systems. Complete conjugation across the backbone can be achieved through complexation with BF2, as observed by 1H NMR analysis and UV/vis spectroscopy. Precise synthetic control over the degree of oxidation of naphthazarin quinone Diels-Alder adduct 10 is additionally demonstrated and enables us to direct its subsequent reactivity. Finally, this work serves to demonstrate the potential for naphthazarin as a building block in the synthesis of novel organic electronic materials.

Intramolecular inverse electron-demand [4+2] cycloadditions of ynamidyl-tethered pyrimidines: Comparative studies in trifluorotoluene and sulfolane

Abstract Three representative 6,7-dihydro-5 H -cyclopenta[ b ]pyridin-4-amines were synthesized using an intramolecular inverse electron demand hetero–Diels–Alder/retro–Diels–Alder sequence between pyrimidines (acting as azadienes) and ynamides (acting as dienophiles). Two solvents of this reaction, sulfolane and trifluorotoluene, were compared at 210 °C and the former consistently led to higher yields. In addition, these studies confirmed the importance of the steric bulk of the C5-position of the pyrimidinyl cycloaddition precursor.

Combining Organocatalysis and Lanthanide Catalysis: A Sequential One‐Pot Quadruple Reaction Sequence/Hetero‐Diels–Alder Asymmetric Synthesis of Functionalized Tricycles

AbstractA stereoselective one‐pot synthesis of functionalized complex tricyclic polyethers has been achieved using the combination of secondary amine and lanthanide catalysis. This one‐pot quadruple reaction/Hetero‐Diels–Alder sequence gave good yields (per step) as well as excellent diastereo‐ and enantioselectivities. Furthermore, the particular combination of lanthanide complexes with organocatalysis is one of the first examples described for sequential catalysis.

Selectivity Control in the Tandem Aromatization of Bio-Based Furanics Catalyzed by Solid Acids and Palladium.

Bio‐based furanics can be aromatized efficiently by sequential Diels–Alder (DA) addition and hydrogenation steps followed by tandem catalytic aromatization. With a combination of zeolite H‐Y and Pd/C, the hydrogenated DA adduct of 2‐methylfuran and maleic anhydride can thus be aromatized in the liquid phase and, to a certain extent, decarboxylated to give high yields of the aromatic products 3‐methylphthalic anhydride and o‐ and m‐toluic acid. Here, it is shown that a variation in the acidity and textural properties of the solid acid as well as bifunctionality offers a handle on selectivity toward aromatic products. The zeolite component was found to dominate selectivity. Indeed, a linear correlation is found between 3‐methylphthalic anhydride yield and the product of (strong acid/total acidity) and mesopore volume of H‐Y, highlighting the need for balanced catalyst acidity and porosity. The efficient coupling of the dehydration and dehydrogenation steps by varying the zeolite‐to‐Pd/C ratio allowed the competitive decarboxylation reaction to be effectively suppressed, which led to an improved 3‐methylphthalic anhydride/total aromatics selectivity ratio of 80 % (89 % total aromatics yield). The incorporation of Pd nanoparticles in close proximity to the acid sites in bifunctional Pd/H‐Y catalysts also afforded a flexible means to control aromatic products selectivity, as further demonstrated in the aromatization of hydrogenated DA adducts from other diene/dienophile combinations.

ChemInform Abstract: Collective Total Syntheses of Atisane‐Type Diterpenes and Atisine‐Type Diterpenoid Alkaloids: (.+‐.)‐Spiramilactone B, (.+‐.)‐Spiraminol, (.+‐.)‐Dihydroajaconine, and (.+‐.)‐Spiramines C and D.

The first total syntheses of the architecturally complex atisane-type diterpenes and biogenetically related atisine-type diterpenoid alkaloids (±)-spiramilactone B, (±)-spiraminol, (±)-dihydroajaconine, and (±)-spiramines C and D are reported. Highlights of the synthesis include a late-stage biomimetic transformation of spiramilactone B, a facile formal lactone migration from the pentacyclic skeleton of spiramilactone E, a highly efficient and diastereoselective 1,7-enyne cycloisomerization to construct the functionalized tetracyclic atisane skeleton, and a tandem retro-Diels–Alder/intramolecular Diels–Alder sequence to achieve the tricyclo[6.2.2.0] ring system.

1503750: Sequential Diels-Alder reactions in a conjugated tetraene system – ESI

1503750: Sequential Diels-Alder reactions in a conjugated tetraene system – ESI

Collective Total Syntheses of Atisane‐Type Diterpenes and Atisine‐Type Diterpenoid Alkaloids: (±)‐Spiramilactone B, (±)‐Spiraminol, (±)‐Dihydroajaconine, and (±)‐Spiramines C and D

AbstractThe first total syntheses of the architecturally complex atisane‐type diterpenes and biogenetically related atisine‐type diterpenoid alkaloids (±)‐spiramilactone B, (±)‐spiraminol, (±)‐dihydroajaconine, and (±)‐spiramines C and D are reported. Highlights of the synthesis include a late‐stage biomimetic transformation of spiramilactone B, a facile formal lactone migration from the pentacyclic skeleton of spiramilactone E, a highly efficient and diastereoselective 1,7‐enyne cycloisomerization to construct the functionalized tetracyclic atisane skeleton, and a tandem retro‐Diels–Alder/intramolecular Diels–Alder sequence to achieve the tricyclo[6.2.2.0] ring system.