Polar Cycloaddition Research Articles

Enantioselective formal (3 + 3) cycloaddition of bicyclobutanes with nitrones enabled by asymmetric Lewis acid catalysis

The absence of catalytic asymmetric methods for synthesizing chiral (hetero)bicyclo[n.1.1]alkanes has hindered their application in new drug discovery. Here we demonstrate the achievability of an asymmetric polar cycloaddition of bicyclo[1.1.0]butane using a chiral Lewis acid catalyst and a bidentate chelating bicyclo[1.1.0]butane substrate, as exemplified by the current enantioselective formal (3 + 3) cycloaddition of bicyclo[1.1.0]butanes with nitrones. In addition to the diverse bicyclo[1.1.0]butanes incorporating an acyl imidazole group or an acyl pyrazole moiety, a wide array of nitrones are compatible with this Lewis acid catalysis, successfully assembling two congested quaternary carbon centers and a chiral aza-trisubstituted carbon center in the pharmaceutically important hetero-bicyclo[3.1.1]heptane product with up to 99% yield and >99% ee.

Photocatalytic Multisite Functionalization of Unactivated Terminal Alkenes by Merging Polar Cycloaddition and Radical Ring-Opening Process.

Although highly appealing for rapid access of molecular complexity, multi-functionalization of alkenes that allows incorporation of more than two functional groups remains a prominent challenge. Herein, we report a novel strategy that merges dipolar cycloaddition with photoredox promoted radical ring-opening remote C(sp3)-H functionalization, thus enabling a smooth 1,2,5-trifunctionalization of unactivated alkenes. A highly regioselective [3+2] cycloaddition anchors a reaction trigger onto alkene substrates. The subsequent halogen atom transfer (XAT) selectively initiates ring-opening process, which is followed by a series of 1,5-hydrogen atom transfer (1,5-HAT) and intermolecular fluorine atom transfer (FAT) events. With this method, site-selective introduction of three different functional groups is accomplished and a broad spectrum of valuable β-hydroxyl-ϵ-fluoro-nitrile products are synthesized from readily available terminal alkenes.

Photocatalytic Multisite Functionalization of Unactivated Terminal Alkenes by Merging Polar Cycloaddition and Radical Ring‐Opening Process

AbstractAlthough highly appealing for rapid access of molecular complexity, multi‐functionalization of alkenes that allows incorporation of more than two functional groups remains a prominent challenge. Herein, we report a novel strategy that merges dipolar cycloaddition with photoredox promoted radical ring‐opening remote C(sp3)−H functionalization, thus enabling a smooth 1,2,5‐trifunctionalization of unactivated alkenes. A highly regioselective [3+2] cycloaddition anchors a reaction trigger onto alkene substrates. The subsequent halogen atom transfer (XAT) selectively initiates ring‐opening process, which is followed by a series of 1,5‐hydrogen atom transfer (1,5‐HAT) and intermolecular fluorine atom transfer (FAT) events. With this method, site‐selective introduction of three different functional groups is accomplished and a broad spectrum of valuable β‐hydroxyl‐ϵ‐fluoro‐nitrile products are synthesized from readily available terminal alkenes.

Divergent Synthesis of Sulfur-Containing Bridged Cyclobutanes by Lewis Acid Catalyzed Formal Cycloadditions of Pyridinium 1,4-Zwitterionic Thiolates and Bicyclobutanes.

Bridged cyclobutanes and sulfur heterocycles are currently under intense investigation as building blocks for pharmaceutical drug design. Two formal cycloaddition modes involving bicyclobutanes (BCBs) and pyridinium 1,4-zwitterionic thiolate derivatives were described to rapidly expand the chemical space of sulfur-containing bridged cyclobutanes. By using Ni(ClO4)2 as the catalyst, an uncommon higher-order (5+3) cycloaddition of BCBs with quinolinium 1,4-zwitterionic thiolate was achieved with broad substrate scope under mild reaction conditions. Furthermore, the first Lewis acid-catalyzed asymmetric polar (5+3) cycloaddition of BCB with pyridazinium 1,4-zwitterionic thiolate was accomplished. In contrast, pyridinium 1,4-zwitterionic thiolates undergo an Sc(OTf)3-catalyzed formal (3+3) reaction with BCBs to generate thia-norpinene products, which represent the initial instance of synthesizing 2-thiabicyclo[3.1.1]heptanes (thia-BCHeps) from BCBs. Moreover, we have successfully used this (3+3) protocol to rapidly prepare thia-BCHeps-substituted analogues of the bioactive molecule Pitofenone. Density functional theory (DFT) computations imply that kinetic factors govern the (5+3) cycloaddition reaction between BCB and quinolinium 1,4-zwitterionic thiolate, whereas the (3+3) reaction involving pyridinium 1,4-zwitterionic thiolates is under thermodynamic control.

Divergent Synthesis of Sulfur‐Containing Bridged Cyclobutanes by Lewis Acid Catalyzed Formal Cycloadditions of Pyridinium 1,4‐Zwitterionic Thiolates and Bicyclobutanes

AbstractBridged cyclobutanes and sulfur heterocycles are currently under intense investigation as building blocks for pharmaceutical drug design. Two formal cycloaddition modes involving bicyclobutanes (BCBs) and pyridinium 1,4‐zwitterionic thiolate derivatives were described to rapidly expand the chemical space of sulfur‐containing bridged cyclobutanes. By using Ni(ClO4)2 as the catalyst, an uncommon higher‐order (5+3) cycloaddition of BCBs with quinolinium 1,4‐zwitterionic thiolate was achieved with broad substrate scope under mild reaction conditions. Furthermore, the first Lewis acid‐catalyzed asymmetric polar (5+3) cycloaddition of BCB with pyridazinium 1,4‐zwitterionic thiolate was accomplished. In contrast, pyridinium 1,4‐zwitterionic thiolates undergo an Sc(OTf)3‐catalyzed formal (3+3) reaction with BCBs to generate thia‐norpinene products, which represent the initial instance of synthesizing 2‐thiabicyclo[3.1.1]heptanes (thia‐BCHeps) from BCBs. Moreover, we have successfully used this (3+3) protocol to rapidly prepare thia‐BCHeps‐substituted analogues of the bioactive molecule Pitofenone. Density functional theory (DFT) computations imply that kinetic factors govern the (5+3) cycloaddition reaction between BCB and quinolinium 1,4‐zwitterionic thiolate, whereas the (3+3) reaction involving pyridinium 1,4‐zwitterionic thiolates is under thermodynamic control.

Novel amphiphilic (AB)3‐type star block polymer: Synthesis and micellization study

AbstractAn amphiphilic three‐armed star polymer was synthesized through the polar cycloaddition reaction of a polyethylene glycol‐based macro‐triazide with an Yne‐terminated polycaprolactone in a molar ratio of 1:3 (click chemistry). Thus, each arm is itself a di‐block copolymer branched from the core, which is a 1,3,5‐triazine ring. The attachment of the pre‐synthesized hydrophobic segments to the hydrophilic segments in each arm leads to the creation of a 1,2,3‐triazole ring in the structure. Fourier transform infrared (FTIR) and proton nuclear magnetic resonance (H‐NMR) spectroscopies were used to verify the structures. The micellization process of the prepared amphiphilic polymer was investigated in aqueous medium. For this purpose, the critical micelle concentration (CMC) was specified by the fluorometric method. Using the transmission electron microscopy (TEM) technique, it was observed that spherical self‐assemblies with a mean diameter of <100 nm are formed from the aggregation of the amphiphilic macromolecules. In addition, the hydrodynamic diameter (H) of the polymeric micelles and their size distribution were examined by dynamic light scattering (DLS) technique.

Reaction Paradigms that Leverage Cycloaddition and Ring Strain to Construction Bicyclic Aryl Bioisosteres from Bicyclo[1.1.0]butanes

AbstractWithin a medicinal chemist's toolbox, one of the most effective strategies to improve the overall properties of a biologically active compound is bioisosteric replacement. Ever since the first example of replacing benzene with a bicyclo[1.1.1]pentane (BCP) group was published in the late 1990s,[1] the medicinal chemistry community has continually been expanding the scope of such phenyl bioisosteric replacements. Recent interest from academia has focused on novel synthetic strategies to access C(sp3)‐rich bicyclic hydrocarbons with expanded ring sizes. Herein, we summarize some of these transformations and reveal that most rely on strain releasing cycloadditions with bicyclo[1.1.0]butane (BCB) and bicyclo[2.1.0]pentane (housane). We have organized this review based on the mechanism of such strain release strategies, namely, carbene cycloadditions, energy transfer photocatalyzed cycloadditions, electron transfer catalyzed cycloadditions, and polar cycloadditions.

Palladium-catalyzed decarboxylative (4 + 3) cycloadditions of bicyclobutanes with 2-alkylidenetrimethylene carbonates for the synthesis of 2-oxabicyclo[4.1.1]octanes.

While cycloaddition reactions of bicyclobutanes (BCBs) have emerged as a potent method for synthesizing (hetero-)bicyclo[n.1.1]alkanes (usually n ≤ 3), their utilization in the synthesis of bicyclo[4.1.1]octane derivatives (BCOs) is still underdeveloped. Here, a palladium-catalyzed formal (4 + 3) reaction of BCBs with 1,4-O/C dipole precursors for the synthesis of oxa-BCOs is described. Unlike previous catalytic polar (3 + X) cycloadditions of BCBs, which are typically achieved through the activation of BCB substrates, the current reaction represents a novel strategy for realizing the cycloaddition of BCBs through the activation of the "X" cycloaddition partner. Moreover, the obtained functionalized oxa-BCOs products can be readily modified through various synthetic transformations.

Electron Donor-Acceptor Complex Enabled Radical Cyclization of α-Diazodifluoroethyl Sulfonium Salt with Unactivated Alkynes.

An α-diazodifluoroethane sulfonium reagent was developed in this study to undergo [3 + 2] radical cyclization with unactivated alkynes to give the corresponding 3-difluoromethyl pyrazoles under blue light irradiation conditions. The key to the success of this transformation lies in the formation of an electron donor-acceptor (EDA) complex between an electron-deficient α-diazo sulfonium salt and an electron-rich triaryl amine. This study circumvents a major substrate scope limitation in polar cycloaddition reactions of existent diazodifluoroethane reagents.

Unveiling the Chemistry of Higher-Order Cycloaddition Reactions within the Molecular Electron Density Theory

The higher-order cycloaddition (HOCA) reaction of tropone with cyclopentadiene (Cp) has been studied within the Molecular Electron Density Theory. The Electron Localization Function (ELF) analysis of the electronic structure of tropone and Cp characterizes the structural behaviors of the two conjugated unsaturated systems, while the conceptual DFT reactivity indices classify tropone as a strong electrophile and Cp as a strong nucleophile participating in polar cycloaddition reactions of reverse electron density flux. Eight competitive reaction paths have been characterized for this cycloaddition reaction. The most favorable one allowing the formation of the formal out [6 + 4] cycloadduct has an activation enthalpy of 16.2 kcal·mol−1, and the reaction is exothermic by −21.4 kcal·mol−1. This HOCA reaction, which takes place through a non-concerted two-stage one-step mechanism, presents high stereo-, pseudocyclic- and regioselectivities, explaining the exclusive formation of the experimental [6 + 4] cycloadduct. While the most favorable nucleophilic attack of Cp on most electrophilic C2 positions of tropone accounts for regioselectivities, the favorable electrostatic interactions present between the Cp framework and the negatively charged O8 oxygen of tropone account for the stereo- and pseudocyclic selectivities. Despite the symmetry of the two reagents, this HOCA reaction takes place via a highly asynchronous transition state structure as a consequence of the most favorable two-center interactions taking place between the electrophilic C2 center of tropone and the nucleophilic C9 center of Cp.

Conformer-specific polar cycloaddition of dibromobutadiene with trapped propene ions

Diels–Alder cycloadditions are efficient routes for the synthesis of cyclic organic compounds. There has been a long-standing discussion whether these reactions proceed via stepwise or concerted mechanisms. Here, we adopt an experimental approach to explore the mechanism of the model polar cycloaddition of 2,3-dibromo-1,3-butadiene with propene ions by probing its conformational specificities in the entrance channel under single-collision conditions in the gas phase. Combining a conformationally controlled molecular beam with trapped ions, we find that both conformers of the diene, gauche and s-trans, are reactive with capture-limited reaction rates. Aided by quantum-chemical and quantum-capture calculations, this finding is rationalised by a simultaneous competition of concerted and stepwise reaction pathways, revealing an interesting mechanistic borderline case.

Highly Facile, Regio‐ and Stereoselective Synthesis of Spiropyrrolidine‐5‐aza‐2‐oxindole Derivatives through Multicomponent 1,3‐Dipolar Cycloaddition Reaction and Their In‐Vitro and In‐Silico Biological Studies

AbstractHighly facile one pot synthesis of an assortment of novel spiropyrrolidine 5‐aza‐2‐oxindole derivatives via 1, 3‐di polar cycloaddition reaction has been reported. The underlying concept of Huisgen reaction was applied wherein the azomethine ylides (1,3‐dipoles), generated in‐situ from isatin‐derived compounds and cyclic / acyclic α‐amino acids through the thermal decarboxylation, reacted with exo‐cyclic benzylidine derivatives (dipolarophiles) of 5‐aza‐2‐oxindole afforded plethora of spiropyrrolidine 5‐aza‐2‐oxindoles in excellent yield. High regio‐ and stereo selectivity were accomplished employing this methodology and optimum yield was obtained when reaction carried out under methanol reflux in presence of triethylamine. Furthermore, the compounds were tested for their in‐vitro biological potency as anti‐microbial and anti‐mycobacterial. Antibacterial screening result reveals that out of fifteen compounds four compounds emerged with moderate to reasonable activity against gram negative E. coli and P. aeruginosa. Antifungal screening resulted in identification of two compounds as moderate antifungal agents against A. niger. Antimycobacterial activity results revealed that the four compounds displayed good to moderate in‐vitro activity with MIC=12.5 μg/mL against H37Rv strain as compared to standard pyrazinamide (MIC=3.12 μg/mL). Additionally, molecular docking study was carried out to understand the possible binding modes of the synthesized derivatives within the active site of antibacterial (PDB ID : 3ACX), antifungal (PDB ID : 1IYL) and antimycobacterial (PDB ID : 4TZT) target proteins and were found to display good docking energies. Besides, ADMET properties of the synthesized compounds have shown drug likeness with good oral absorption and moderate BBB permeability.

Reactive atomistic simulations of Diels-Alder-type reactions: conformational and dynamic effects in the polar cycloaddition of 2,3-dibromobutadiene radical ions with maleic anhydride

The kinetics, dynamics and conformational specificities for the ionic Diels-Alder reaction (polar cycloaddition) of maleic anhydride with 2,3-dibromobutadiene radical ions have been studied theoretically using multisurface adiabatic reactive molecular dynamics. A competition of concerted and stepwise reaction pathways was found and both the s-cis and s-trans conformers of the diene are reactive. The analysis of the minimum dynamic path of the reaction indicates that both, rotations and vibrations of the reactant molecules are important for driving the system towards the transition state. The rates were computed as s for the s-cis and s for the s-trans conformer of 2,3-dibromobutadiene at an internal temperature of 300 K. The present results are to be contrasted with the neutral variant of the title system in which only the gauche conformer of the diene was found to undergo a considerably slower, concerted and mostly synchronous reaction driven by the excitation of rotations. The results presented here inform detailed experimental studies of the dynamics of polar cycloadditions under single-collision conditions in the gas phase.

Quantum-chemistry-aided identification, synthesis and experimental validation of model systems for conformationally controlled reaction studies: separation of the conformers of 2,3-dibromobuta-1,3-diene in the gas phase.

The Diels-Alder cycloaddition, in which a diene reacts with a dienophile to form a cyclic compound, counts among the most important tools in organic synthesis. Achieving a precise understanding of its mechanistic details on the quantum level requires new experimental and theoretical methods. Here, we present an experimental approach that separates different diene conformers in a molecular beam as a prerequisite for the investigation of their individual cycloaddition reaction kinetics and dynamics under single-collision conditions in the gas phase. A low- and high-level quantum-chemistry-based screening of more than one hundred dienes identified 2,3-dibromobutadiene (DBB) as an optimal candidate for efficient separation of its gauche and s-trans conformers by electrostatic deflection. A preparation method for DBB was developed which enabled the generation of dense molecular beams of this compound. The theoretical predictions of the molecular properties of DBB were validated by the successful separation of the conformers in the molecular beam. A marked difference in photofragment ion yields of the two conformers upon femtosecond-laser pulse ionization was observed, pointing at a pronounced conformer-specific fragmentation dynamics of ionized DBB. Our work sets the stage for a rigorous examination of mechanistic models of cycloaddition reactions under controlled conditions in the gas phase.

How does the global electron density transfer diminish activation energies in polar cycloaddition reactions? A Molecular Electron Density Theory study

The key role of the Global Electron Density Transfer (GEDT) in polar cycloaddition reactions is analysed within the Molecular Electron Density Theory (MEDT) using Density Functional Theory (DFT) calculations at the MPWB1K/6-311G(d) computational level. A comparative MEDT study of the non-polar Diels-Alder reaction between cyclopentadiene (Cp) and ethylene and the polar Diels-Alder reaction between Cp and tetracyanoethylene makes it possible to establish that the GEDT taking place in the direction of the transition state structures favours the bonding changes required for the formation of the new CC single bonds along polar cycloaddition reactions. Analysis of the reactivity indices defined within the conceptual DFT at the ground state of the reagents makes it possible to predict the reactivity of organic molecules in polar reactions.

Synthesis and Characterization of Novel1,3,4,9a-Tetrahydrobenzo[e][1,3]oxazepin-5(5aH)-one Derivativesvia Cycloaddition Reactions ofSchiff Bases

A series of novel1,3,4,9a-tetrahydrobenzo[e][1,3]oxazepin-5(5aH)-one derivatives were synthesized by the reaction of Schiff bases with bicyclo]2.2.2[oct.7-ene-2,3,5,6-tetracarboxylic anhydridein anhydrous acetonitrile under dry and reflux conditionswith high yields via polar cycloaddition. Schiff bases were synthesized by the reaction of aromatic aldehydes, ketones or preparedchalcones with primary aromatic amines. The products were identified by their melting point,FT-IR, UV-Vis-spectra, 1H-NMR and13C-NMR spectra.

A Theoretical Study of 2-nitrofuran vs 3-nitrofuran as Dienophilic Electrophile in Polar Cycloaddition Reaction: Comparison of the Reactivity and Reaction Mechanism

Fil: Cainelli, Mauro. Universidad Nacional del Litoral. Instituto de Quimica Aplicada del Litoral. Consejo Nacional de Investigaciones Cientificas y Tecnicas. Centro Cientifico Tecnologico Conicet - Santa Fe. Instituto de Quimica Aplicada del Litoral.; Argentina

ChemInform Abstract: Butyrolactone Synthesis via Polar Radical Crossover Cycloaddition Reactions: Diastereoselective Syntheses of Methylenolactocin and Protolichesterinic Acid.

A direct catalytic synthesis of γ-butyrolactones from simple alkene and unsaturated acid starting materials is reported. The catalytic system consists of the Fukuzumi acridinium photooxidant and substoichiometric quantities of a redox-active cocatalyst. Oxidizable alkenes such as styrenes and trisubstituted aliphatic alkenes are cyclized with unsaturated acids via polar radical crossover cycloaddition (PRCC) reactions. This method has been applied to the diastereoselective total synthesis of methylenolactocin and protolichesterinic acid.

Polar Diels–Alder reactions using electrophilic nitrobenzothiophenes. A combined experimental and DFT study

The reactions between 2- and 3-nitrobenzothiophenes with three dienes of different nucleophilicity, 1-methoxy-3-trimethylsilyloxy-1,3-butadiene, 1-trimethylsilyloxy-1,3-butadiene and isoprene developed in anhydrous benzene and alternative under microwave irradiation with molecular solvents or in free solvent conditions, respectively, for produce dibenzothiophenes permit to conclude that both nitroheterocycles act as electrophile with the cited dienes. In the cases of the dienes 1-methoxy-3-trimethylsilyloxy-1,3-butadiene and 1-trimethylsilyloxy-1,3-butadiene which posses major nucleophilicity the observed product is the normal cycloaddition one. However when the diene is isoprene the product with both electrophiles follow the hetero Diels–Alder way. These reactions are considered polar cycloaddition reactions and the yields are reasonables. Moreover the polar Diels–Alder reactions of nitrobenzothiophenes with electron rich dienes 1-trimethylsilyloxy-1,3-butadiene have been theoretically studied using DFT methods.

ChemInform Abstract: Intramolecular Polar [4+ + 2] Cycloadditions of Aryl‐1‐aza‐2‐azoniaallene Salts: Unprecedented Reactivity Leading to Polycyclic Protonated Azomethine Imines.

ChemInform Abstract: Intramolecular Polar [4⁺ + 2] Cycloadditions of Aryl‐1‐aza‐2‐azoniaallene Salts: Unprecedented Reactivity Leading to Polycyclic Protonated Azomethine Imines.