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The reactivity of [{SiNDipp}AlK]2, which comprises a formally anionic Al(I) centre, has been examined towards a variety of 1,3‐dienic molecules, including 2,3‐dimethylbutadiene, cyclooctatetraene, anthracene and tetracene. In each case, the alumanyl derivative experiences oxidative addition across the Al(I) centre to provide the corresponding potassium aluminacyclopentene, aluminacyclopropene or aluminanorbornadiene products of [4+1] cycloaddition. [ABSTRACT FROM AUTHOR]

Here, we present the synthesis of polysubstituted chalcogenofurans involving an oxidative cycloaddition between 1,3‐diones and chalcogenoalkynes. The method utilizes blue LEDs as a clean energy source, methylene blue as a photocatalyst – an inexpensive and non‐toxic dye – and ammonium persulfate as an oxidant, all conducted at room temperature. This benign protocol enables access to a wide range of chalcogenofurans with good to excellent yields and outstanding regioselectivity. Only one regioisomer was obtained, indicating strong radical stabilization by the chalcogen atom. Various functionalities in both alkynes and 1,3‐diones demonstrated amenability to the developed reaction. A mechanistic understanding, derived from control experiments and the detection of radical intermediates, suggests that a radical forms at the carbon‐2 position of the 1,3‐dione, which subsequently adds to the chalcogenoalkyne, resulting in the formation of an olefinic intermediate. Following this, an intramolecular radical addition occurs, which, upon photoredox cycle closure, leads to the formation of the desired products. [ABSTRACT FROM AUTHOR]

The influence of different (LRu)nII (L=Cp– (n=1, 2); C6H6) moieties η6‐coordinated to corannulene ((CpRu)+, (Benzene)Ru2+ and (CpRu)22+) has been explored by using the Activation Strain Model (ASM) of reactivity together with the Energy Decomposition Analysis (EDA) scheme. The results obtained have been compared with those obtained for the non‐coordinated corannulene counterpart. It has been observed that the presence of the ruthenium moiety favors both kinetically and thermodynamically the [4+2]‐cycloaddition reaction with cyclopentadiene. The factors governing these differences depend on the nature of the [Ru] complex. Whereas the interaction energy is solely responsible for the lower activation energy for the monocationic system (CpRu)+, not only the higher interaction but also the lower strain energy explain the much higher reactivity observed for the dicationic systems ((C6H6)Ru2+ and (CpRu)22+). In this latter case, the Pauli repulsion energy term is the factor controlling the differences in the interaction energies, following the so‐called Pauli repulsion‐lowering concept. Finally, when η6‐coordinating mono‐ or dicationic ruthenium complexes, although the [4+2]‐cycloaddition reaction in the external rim bonds remains the thermodynamically and kinetically more favourable, the cycloaddition becomes also thermodynamically feasible in some internal bonds. [ABSTRACT FROM AUTHOR]

Here, we report a strategy enabling triple switchable chemo‐, regio‐, and stereodivergence in newly developed palladium‐catalyzed cycloadditions of allenes. An asymmetric pseudo‐stereodivergent cycloaddition of allenes bearing a primary leaving group at the α‐position, where a dynamic kinetic asymmetric hydroalkoxylation of racemic unactivated allenes was the enantio‐determining step, is realized, providing four stereoisomers [(Z,R), (Z,S), (E,S), and (E,R)] containing a di‐substituted alkene scaffold and a stereogenic center. By tuning reaction conditions, a mechanistically distinctive cycloaddition is uncovered selectively with the same set of substrates. By switching the position of the leaving group of allenes, a cycloaddition involving an intermolecular O‐attack is disclosed. Diverse mechanisms of the cycloaddition reactions of allenes enable rapid access to structurally and stereochemically diverse 3,4‐dihydro‐2H‐1,4‐benzoxazines in high efficiency and selectivity. [ABSTRACT FROM AUTHOR]

Here, we report a strategy enabling triple switchable chemo‐, regio‐, and stereodivergence in newly developed palladium‐catalyzed cycloadditions of allenes. An asymmetric pseudo‐stereodivergent cycloaddition of allenes bearing a primary leaving group at the α‐position, where a dynamic kinetic asymmetric hydroalkoxylation of racemic unactivated allenes was the enantio‐determining step, is realized, providing four stereoisomers [(Z,R), (Z,S), (E,S), and (E,R)] containing a di‐substituted alkene scaffold and a stereogenic center. By tuning reaction conditions, a mechanistically distinctive cycloaddition is uncovered selectively with the same set of substrates. By switching the position of the leaving group of allenes, a cycloaddition involving an intermolecular O‐attack is disclosed. Diverse mechanisms of the cycloaddition reactions of allenes enable rapid access to structurally and stereochemically diverse 3,4‐dihydro‐2H‐1,4‐benzoxazines in high efficiency and selectivity. [ABSTRACT FROM AUTHOR]

Visible‐light‐driven dual catalysis was employed to stereoselectively produce densely substituted cyclobutanes from Erlenmeyer‐Plöchl azlactones. The single‐step preparation of non‐natural amino acid dimers containing the cyclobutane moiety was achieved through a synergy between iridium photocatalysis and catalytic nickel(II) triflate as a Lewis acid. The desired 1,2‐(zeta)‐Z,E‐isomers were isolated in good yields and with high regio‐ and diastereoselectivity (in all cases, >19 : 1 d.r.). To the best of our knowledge, this is the first report of direct access to truxinic acid analogues using azlactones. Control experiments, EPR reaction monitoring, and DFT calculations suggest that the presence of a Lewis acid, combined with the use of powerful blue LEDs, plays a crucial role in the reactivity of this reaction. [ABSTRACT FROM AUTHOR]

In recent times, interest in the chemistry of conjugated nitrodienes is still significantly increasing. In particular, the application of these compounds as building blocks to obtain heterocycles is a popular object of research. Therefore, in continuation of our research devoted to the topic of conjugated nitrodienes, experimental and quantum-chemical studies of a cycloaddition reaction between (1E,3E)-1,4-dinitro-1,3-butadiene and N-methyl azomethine ylide have been investigated. The computational results present that the tested reaction is realized through a pdr-type polar mechanism. In turn, the experimental study shows that in a course of this cycloaddition, only one reaction product in the form of 1-methyl-3-(trans-2-nitrovinyl)-Δ3-pyrroline is created. The constitution of this compound has been confirmed via spectroscopic methods. Finally, ADME analysis indicated that the synthesized Δ3-pyrroline exhibits biological potential, and it is a good drug candidate according to Lipinski, Veber and Egan rules. Nevertheless, PASS simulation showed that the compound exhibits weak antimicrobial, inhibitory and antagonist properties. Preliminary in silico research shows that although the obtained Δ3-pyrroline is not a good candidate for a drug, the presence of a nitrovinyl moiety in its structure indicates that the compound is an initial basis for further modifications. [ABSTRACT FROM AUTHOR]

Functionalized 1,2,4,5-tetrasubstituted benzenes are synthetically difficult or laborious to access. The Rh-catalyzed [2+2+2] cycloaddition of a diyne and internal alkyne offers a seemingly straightforward route to these scaffolds; however, this has been largely restricted to alkynes bearing activating (coordinating) functional groups, with very few examples of unactivated alkynes. In this work, we disclose an assessment of Rh-catalyzed [2+2+2] cycloadditions employing unactivated internal alkynes, focusing on the structural diversity and compatibility of both alkyne and diyne components. The limitations of this method are disclosed, with exceptionally bulky alkynes and specific functional groups undergoing side reactions. Furthermore, the practicalities of gram-scale reactions and catalyst recovery/reuse are demonstrated. [ABSTRACT FROM AUTHOR]

With the advantages of low raw material cost and 100% atom utilization, the synthesis of high value-added chemical product cyclic carbonates by the cycloaddition of CO2 to epoxides has become one of the most prospective approaches to achieve the industrial utilization of CO2. In the reported catalytic systems, the complexity of the catalyst synthesis process, high cost, separation difficulties, and low CO2 capture limit the catalytic efficiency and its large-scale application. In this paper, Ag nanoparticles loaded on polyethyleneimine (PEI)-modified UiO-66-NH2 (Ag/PEI@UiO-66-NH2) are successfully synthesized by in situ immersion reduction. The Ag nanoparticles and the amino groups on the surfaces of PEI@UiO-66-NH2 contribute to the adsorption of CO2 and polarization of C–O bonds in epoxides, thereby boosting the conversion capability for the CO2 cycloaddition reaction. At the amount of propylene oxide of 0.25 mol and the catalyst dosage of 1% of the substrate, the yield and selectivity of propylene carbonate are up to 99%. In addition, the stability and recyclability of Ag/PEI@UiO-66-NH2 catalyst are attained. The Ag/PEI@UiO-66-NH2 catalyst also demonstrates a wide range of activity and distinctive selectivity toward cyclo-carbonates in the cycloaddition of CO2 to epoxides. This work provides a guide to designing a highly efficient catalyst for in situ capture and high-value utilization of CO2 in industrial applications. [ABSTRACT FROM AUTHOR]

Cascade dearomative functionalization is a robust protocol to convert flat arenes into medicinally relevant three‐dimensional architectures with added new functionality. Herein, a dearomative cycloaddition protocol for synthesizing tetrahydroquinoline‐embedded α‐tertiary amine scaffolds has been developed employing quinolinium salts and sulfonyl azides under metal‐free conditions. An underexplored and mechanistically distinct pathway is unveiled, creating quaternary‐center‐bearing amine skeletons by an amine group migration during the transfer hydrogenation and cycloaddition cascade reaction. This approach provided a broad substrate scope of α‐tertiary amine scaffolds from a plethora of C3‐substituted quinolinium and sulfonyl azides. The post‐synthetic modifications have further diversified the α‐tertiary amine core into interesting scaffolds. Preliminary mechanistic studies suggested the involvement of aziridine ring formation for the amine migration to the C‐3 position of quinoline to generate the α‐tertiary amine core. [ABSTRACT FROM AUTHOR]

The molecular mechanism of the reaction between 2-methoxyfuran and ethyl (Z)-3-phenyl-2-nitroprop-2-enoate was investigated using wb97xd/6-311+G(d,p)(PCM) quantum chemical calculations. It was found that the most probable reaction mechanism is fundamentally different from what was previously postulated. In particular, six possible zwitterionic intermediates were detected on the reaction pathway. Their formation is determined by the nature of local nucleophile/electrophile interactions. Additionally, the channel involving the formation of the exo-nitro Diels–Alder cycloadduct was completely ruled out. Finally, the electronic nature of the five- and six-membered nitronates as potential TACs was evaluated. [ABSTRACT FROM AUTHOR]

Kalmanol, the flagship member of the kalmane diterpene family, possesses a complex and highly oxidized 5/5/8/5 tetracyclic skeleton with nine contiguous stereocenters and exhibits significant analgesic effects and cardiotoxic properties. We have achieved the efficient total synthesis of (+)‐kalmanol in 22 steps with 2.3 % yield. The synthesis featured a Rh‐catalyzed [5+2+1] cycloaddition reaction to construct 5/5/8 tricyclic skeleton, and a meticulously designed sequence of stereoselective oxidations of the 5/5/8/5 tetracyclic skeleton. [ABSTRACT FROM AUTHOR]

This perspective discusses bibliography data that has been published since 2018 on the synthesis of oxazolidinones by reacting corresponding aziridines with CO2. The versatility and viability of various procedures have been analyzed by considering the variety of tested substrates as well as experimental conditions and catalytic systems used. Collected data highlights that the reaction can be effectively promoted by several homogeneous and heterogeneous catalytic systems that have been optimized in order to conjugate the process sustainability and productivity with convenient procedural costs. [ABSTRACT FROM AUTHOR]

Kalmanol, the flagship member of the kalmane diterpene family, possesses a complex and highly oxidized 5/5/8/5 tetracyclic skeleton with nine contiguous stereocenters and exhibits significant analgesic effects and cardiotoxic properties. We have achieved the efficient total synthesis of (+)‐kalmanol in 22 steps with 2.3 % yield. The synthesis featured a Rh‐catalyzed [5+2+1] cycloaddition reaction to construct 5/5/8 tricyclic skeleton, and a meticulously designed sequence of stereoselective oxidations of the 5/5/8/5 tetracyclic skeleton. [ABSTRACT FROM AUTHOR]

Fourteen dispiropyrrolidines were synthesized through a [3 + 2] cycloaddition reaction using ultrasound irradiation involving isatin, sarcosine, and derivatives of 5‐benzylidine rhodanine‐3‐acetic acid and characterized using UV–visible, IR, and NMR analysis. The inhibitory potential of these compounds against the HeLa cell line was assessed using the MTT assay. Compounds 4i and 4j displayed promising activity, showing IC50 values of 71.41 µM and 70.54 µM, respectively. The exhibited inhibitory effects compared to Sorafenib, a reference drug with an IC50 of 10.78 µM. In pursuit of a better understanding of molecular interactions, a molecular docking study was performed employing AutoDock Vina, focusing on the HPV protein. Among the synthesized compounds, the most potent molecules 4i and 4j showed a binding affinity of −7.4 and −7.3 Kcal/mol, respectively. [ABSTRACT FROM AUTHOR]

Context: Quantum chemical modeling (DFT-PBE0/cc-pVTZ) of the [4 + 2]-cycloaddition reaction of 1,3-cyclopentadiene (CPD) to (exo/endo)-dicyclopentadiene (DCPD) was carried out, resulting in 14 products—CPD trimers. According to calculations, exo-addition of CPD to the norbornene (NB) fragment of DCPD and trans-addition of CPD to the cyclopentene (CP) fragment of DCPD are kinetically preferred. Ring strain energies ERS were calculated for all trimers using the homodesmotic reaction approach. The least strained trimers are formed by exo-addition of CPD to the NB fragment of exo-DCPD, while the most strained ones are formed by endo-addition of CPD to the NB fragment of endo-DCPD. ERS values are in good agreement with thermodynamic stability of trimers. Analysis of activation energy using the activation strain model showed steric effects causing deformation of the DCPD molecule upon reaching the transition state to be the leading factor of the magnitude of the cycloaddition reaction activation barrier. Deformation of the DCPD molecule mostly occurs in two dihedral angles—the angle of escape of H atoms from the plane of the double bond involved in cycloaddition and the angle between the NB and CP fragments. The sum of deviations of these angles in the transition states (or products) structures is in good agreement with Gibbs activation energies of cycloaddition reactions of CPD to DCPD. Methods: Quantum chemical calculations were carried out using density functional theory in Gaussian 09 software. Hybrid exchange–correlation PBE0 functional was used with cc-pVTZ basis set. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

The copper‐catalyzed azide alkyne [3+2]‐cycloaddition (CuAAC) reaction of organoboranes represents an attractive area of research within the field of click chemistry, with diverse applications in organic synthesis, medicinal chemistry, or materials science. Despite the potential issues caused by the copper insertion into the carbon‐boron bond, significant progress has been made to harness the reactivity of organoboron compounds in CuAAC. This review provides an overview of the catalytic methods reported for CuAAC with various organoboranes, discussing the stability of the boron group and highlighting recent advancements in this area. [ABSTRACT FROM AUTHOR]

This study presents a theoretical investigation of the [3 + 2] cycloaddition (32CA) reaction between cyclic nitrone a1 and substituted alkene b1. The mechanism, regioselectivity, and stereoselectivity of this 32CA reaction were analyzed using transition state theory and reactivity indices obtained from conceptual density functional theory (DFT) at the B3LYP/6-311G(d) level of theory. The results indicate that this cycloaddition reaction proceeds via an asynchronous one-step mechanism, exhibiting a non-polar nature and significant activation energies. These theoretical results are in agreement with the experimental observations. The study also employs topological analyses such as ESP, RDG-NCI, and ELF to determine active sites; distinguish hydrogen bonds, van der Waals interactions, and steric repulsive interactions; and predict electron localization, respectively. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

An improved synthetic procedure for the intramolecular ketene [2+2] cycloaddition was developed for the preparation of 1‐heteroatom‐substituted bicyclo[2.1.1]hexan‐5‐ones. It was found that the use of the Mukaiyama reagent (2‐chloro‐N‐methyl‐pyridinium iodide) was key to efficiently generate the α‐heteroatom substituted homoallyl ketene intermediate for the cycloaddition reaction. The synthetic utility of the resulting bicyclic ketone was demonstrated through the preparation of a saturated variant of vortioxetine. [ABSTRACT FROM AUTHOR]

We used stable and nontoxic [(dimethylamino)methyl]ferrocene (Fc‐N), (hydroxymethyl)ferrocene (Fc‐O), 1,2‐bis[(dimethylamino)methyl]ferrocene (Fc‐N2), and 1‐[(dimethylamino)methyl]‐2‐(hydroxymethyl)ferrocene (Fc‐NO) as halide‐free, neutral, and bifunctional one‐component catalysts for the synthesis of cyclic carbonates. They do not need halide‐based additives or tethered salts attached to ligands when used for this coupling reaction. Among them, Fc‐N2 exhibited the best catalytic activity under the same reaction conditions. Catalytic activity decreased rapidly in the order Fc‐N2 > Fc‐NO > Fc‐N > Fc‐O, and interestingly, the more amino groups introduced into the Cp groups, the higher the activity. Various terminal and internal epoxides were easily converted into the corresponding cyclic carbonates. Calculations based on the density functional theory were also carried out to elucidate the mechanism of the coupling reaction. [ABSTRACT FROM AUTHOR]

The design of various cycloaddition/annulation processes is one of the most intriguing challenges in the development of donor‐acceptor (D–A) cyclopropane chemistry. In this work, a new class of formal high‐order [6+n]‐cycloaddition and annulation processes of D–A cyclopropanes with cycloheptatriene systems has been designed and reported, to fill a significant gap in the chemistry of D–A cyclopropanes. The reactivity of methylated cycloheptatrienes from Me1 to Me5 as well as unsubstituted cycloheptatriene was studied in detail under GaCl3 activation conditions, which makes it possible to efficiently generate gallium 1,2‐zwitterionic complexes or 1,3‐zwitterionic intermediates starting from D–A cyclopropanes, while other Lewis acids are ineffective and non‐selective. New examples of formal [6+2]‐, [6+3]‐, [6+4]‐, [6+1]‐, and [4+2]‐cycloaddition and annulation reactions with cycloheptatrienes along with more complex processes were discovered. Cycloheptatriene itself can also successfully act as a hydride anion donor, which allows the ionic hydrogenation of D–A cyclopropanes to be performed under mild conditions. As a result, a number of efficient and highly diastereoselective protocols for the synthesis of seven‐membered carbocycles has been developed. [ABSTRACT FROM AUTHOR]

Diethyl mesoxalate, a vicinal tricarbonyl compound, possesses multiple functionalities that facilitate diverse chemical conversions. The central carbonyl group with two ester functionalities exhibits high electrophilicity to accept nucleophilic attacks of various reagents. This unusual electrophilicity enables the reaction with acid amides that are not common nucleophiles in organic syntheses. Condensation with active methylene compounds or amines leads to electron‐deficient alkenes and imines, respectively, which can be transformed into more complex polyfunctionalized compounds by a second nucleophilic addition. Chemical transformations between the central and adjacent ester carbonyls furnish new ring systems that are useful in material and pharmaceutical sciences. The central carbonyl group can also be built into a ring system by reacting with reagents possessing nucleophilic and electrophilic sites. Furthermore, the central carbonyl serves as a dienophile that undergoes cycloaddition to form functionalized heterocyclic compounds in a single step. [ABSTRACT FROM AUTHOR]

The design of various cycloaddition/annulation processes is one of the most intriguing challenges in the development of donor‐acceptor (D–A) cyclopropane chemistry. In this work, a new class of formal high‐order [6+n]‐cycloaddition and annulation processes of D–A cyclopropanes with cycloheptatriene systems has been designed and reported, to fill a significant gap in the chemistry of D–A cyclopropanes. The reactivity of methylated cycloheptatrienes from Me1 to Me5 as well as unsubstituted cycloheptatriene was studied in detail under GaCl3 activation conditions, which makes it possible to efficiently generate gallium 1,2‐zwitterionic complexes or 1,3‐zwitterionic intermediates starting from D–A cyclopropanes, while other Lewis acids are ineffective and non‐selective. New examples of formal [6+2]‐, [6+3]‐, [6+4]‐, [6+1]‐, and [4+2]‐cycloaddition and annulation reactions with cycloheptatrienes along with more complex processes were discovered. Cycloheptatriene itself can also successfully act as a hydride anion donor, which allows the ionic hydrogenation of D–A cyclopropanes to be performed under mild conditions. As a result, a number of efficient and highly diastereoselective protocols for the synthesis of seven‐membered carbocycles has been developed. [ABSTRACT FROM AUTHOR]

Herein, we disclose a FeBr2-promoted cycloaddition of readily available 1,3-enynes and nitrosoarenes, providing a promising platform for the synthesis of privileged 4-acylquinoline scaffolds. This simple, one-pot process is characterized by high atom-economy, broad substrate-scope, and excellent functional-group tolerance. A possible reaction mechanism was proposed, involving processes such as [4+2] cycloaddition, ring opening, aromatization, and dehydroaromatization. [ABSTRACT FROM AUTHOR]

Piperidines are widely present in small molecule drugs and natural products. Despite many methods have been developed for their synthesis, new approaches to polysubstituted piperidines are highly desirable. This work presents a radical (4+2) cycloaddition reaction for synthesis of piperidines featuring dense substituents at 3,4,5‐positions that are not readily accessible by known methods. Using commercially available diboron(4) compounds and 4‐phenylpyridine as the catalyst precursors, the boronyl radical‐catalyzed cycloaddition between 3‐aroyl azetidines and various alkenes, including previously unreactive 1,2‐di‐, tri‐, and tetrasubstituted alkenes, has delivered the polysubstituted piperidines in generally high yield and diastereoselectivity. The reaction also features high modularity, atom economy, broad substrate scope, metal‐free conditions, simple catalysts and operation. The utilization of the products has been demonstrated by selective transformations. A plausible mechanism, with the ring‐opening of azetidine as the rate‐limiting step, has been proposed based on the experimental and computational results. [ABSTRACT FROM AUTHOR]

Piperidines are widely present in small molecule drugs and natural products. Despite many methods have been developed for their synthesis, new approaches to polysubstituted piperidines are highly desirable. This work presents a radical (4+2) cycloaddition reaction for synthesis of piperidines featuring dense substituents at 3,4,5‐positions that are not readily accessible by known methods. Using commercially available diboron(4) compounds and 4‐phenylpyridine as the catalyst precursors, the boronyl radical‐catalyzed cycloaddition between 3‐aroyl azetidines and various alkenes, including previously unreactive 1,2‐di‐, tri‐, and tetrasubstituted alkenes, has delivered the polysubstituted piperidines in generally high yield and diastereoselectivity. The reaction also features high modularity, atom economy, broad substrate scope, metal‐free conditions, simple catalysts and operation. The utilization of the products has been demonstrated by selective transformations. A plausible mechanism, with the ring‐opening of azetidine as the rate‐limiting step, has been proposed based on the experimental and computational results. [ABSTRACT FROM AUTHOR]

A de novo synthesis of cyclobutene‐fused indoline derivatives via thermally induced intramolecular cyclization was reported. This approach efficiently yields valuable high‐strained cyclobute[b]indolines in moderate to high yields and enables further transformation into other valuable heterocycles, demonstrating its potential in organic synthesis. [ABSTRACT FROM AUTHOR]

C(sp3)−H functionalization methods have been widely employed in many organic transformations such as cyclization reactions, heterocycle synthesis, cross‐coupling protocols, and photochemical transformations. Among these transformations, cyclization reaction through C(sp3)−H functionalization offers a direct route to convert simple linear substrates to complex products. There are three common modes of utilizing C(sp3)−H bonds in cyclization reactions including single, double, and dual C(sp3)−H functionalization. As the most challenging mode, dual C(sp3)−H functionalization refers to converting two separate C(sp3)−H bonds in one molecule into desired C−Z bonds which can be employed in cyclization reactions. Cyclization reaction via dual functionalization of C(sp3)−H bonds can be classified based on the C−H reactivities. Therefore, these reactions can be categorized into three classes based on the types of C(sp3)−H bonds including activated‐activated, activated‐unactivated, and unactivated‐unactivated C(sp3)−H bonds. Most published reports for cyclization reactions through dual C(sp3)−H functionalization involve activated‐activated C(sp3)−H bonds. However, the number of reported papers on the other two classes has been growing. This review focuses on the dual C(sp3)−H functionalization protocols used for cyclization reactions and categorizes the published papers based on the types of C(sp3)−H bonds. [ABSTRACT FROM AUTHOR]

Comprehensive Summary: The stereochemical synthesis of highly substituted Danishefsky‐type dienes remains unsolved in organic chemistry. We describe a simple and efficient approach for the stereoselective synthesis of Danishefsky‐type trisubstituted dienes from readily available propargylic esters via Pd‐catalyzed dienylation reaction through the key intermediate metallacyclobutene in a regio‐, chemo‐ and stereoselective fashion. This method facilitates a broad range of challenging trisubstituted dienes with a high level of stereocontrol. The synthetic utilities of oxygenated trisubstituted dienes have been demonstrated by the downstream chemistry, which notably undergoes Diels‐Alder reaction with a variety of electron‐deficient dienophiles to furnish multisubstituted cyclohexenes in good yields with excellent stereoselectivity. [ABSTRACT FROM AUTHOR]

Comprehensive Summary: Over the past few decades, N‐sulfonyl hydrazones have been recognized as alternative precursors for hazardous diazo compounds in organic synthesis, allowing for diverse innovative and original chemical transformations that were otherwise difficult to achieve. This critical review summarizes the major advancements in the carbene chemistry of N‐sulfonyl hydrazones. The contents of this review are organized based on research conducted by leading scientists who have made significant contributions to this field. The individual carbene transfer reactions and their mechanisms, as well as the potential applications in the synthesis of natural products and complex bioactive molecules, are thoroughly discussed. [ABSTRACT FROM AUTHOR]

Phthalazine can behave as a diene in Diels–Alder (DA) cycloadditions, typically at the pyridazine ring, however, its application is somewhat limited because these reactions usually require harsh conditions or sophisticated catalysts. As an unconventional example, phthalazine was reported to undergo cycloaddition with the [PCO]− anion without any catalyst. In this computational study, we scrutinise the mechanism of the DA reactions between phthalazine and the so far known [ECX]− (E: P, As; X: O, S, Se) anions as dienophiles. In principle, the attack of an [ECX]− anion may occur at two different sites of phthalazine, either at the benzene or the pyridazine ring, and both of these possible reaction channels were juxtaposed on the basis of energetic aspects. In all of the investigated cases, the analysis of the energy profiles reveals a clear regioselectivity that favours the attack at the pyridazine ring. As a result, so far unprecedented 2‐pnictanaphth‐3‐olate analogues seem achievable as final products. Comparing the characteristics of these pathways allowed us to clarify the source of this regioselectivity: The pyridazine ring of phthalazine exhibits lower aromaticity than the benzene subring; therefore, in the DA step, the former ring shows a higher affinity toward a dienophile than the latter, leading to lower activation barriers. To further map the electronic and structural features of the cycloaddition steps, the local interactions evolving in the transition states were analysed and compared using global and local descriptors. In most aspects, the characteristics of both pathways were found to be rather similar, in contrast to the markedly differing activation barriers on the two routes. [ABSTRACT FROM AUTHOR]

The present review is a comprehensive update of the synthesis of monocyclic β-lactams via cycloaddition reactions. According to the IUPAC definition of cycloaddition, both elementary and stepwise processes (formal cycloadditions) have been considered. The years 2019–2022 are covered by the cited literature. The focus of the review is on synthetic aspects with emphasis on the structural scope, reaction conditions, mechanistic aspects, and selectivity results. Selected significant data related to biological activities and synthetic applications are also highlighted. [ABSTRACT FROM AUTHOR]

Comprehensive Summary: Chiral phosphine‐catalyzed asymmetric (4+2) annulation of the amide‐based Morita–Baylis–Hillman (MBH) carbonates with β,γ‐unsaturated butenolides has been developed to give enantiomer‐enriched bicyclic δ‐lactam γ‐butyrolactone compounds. The amide‐based MBH carbonates were first used as acceptor and aza‐C4 synthon in phosphine catalysis. Under mild reaction conditions, a variety of amide‐based MBH carbonates and unsaturated butenolides were well tolerated to provide chiral bicyclic δ‐lactam γ‐butyrolactone derivatives in high yields with excellent enantioselectivities as well as diastereoselectivities. A plausible reaction mechanism was also proposed based on control experiments and DFT calculations. [ABSTRACT FROM AUTHOR]

Comprehensive Summary: Electron‐rich alkynes, such as ynol and thioynol ethers, have proven to be versatile and appealing partners in catalytic cycloaddition reactions, and thus have raised considerable attentions owing to the practical application in the modular assembly of valuable carbo‐ and heterocycles. The past decades have witnessed inspiring advances in this emerging field, and an increasing number of related discoveries have been exploited. Divided into two main sections on the basis of substrate type, in each section this comprehensive review will initially summarize their synthetic preparations and subsequently examine their reactivity in every sort of catalytic cycloaddition with emphasis on the methodology development, aimed at providing an access to this burgeoning area and encouraging further innovations in the near future. Key Scientists: For the cycloaddition of ynol ethers, in 2004, Kozmin et al. firstly developed a silver‐catalyzed [2 + 2] cycloaddition of siloxy alkynes with electron‐poor olefins. In 2012, Hiyama et al. realized a palladium‐catalyzed formal [4 + 2] annulation of alkynyl aryl ethers with internal alkynes. In the same year, Sun et al. discovered an efficient [6 + 2] cyclization between siloxy alkynes and 2‐(oxetan‐3‐yl)benzaldehydes by applying HNTf2 as catalyst. In 2017, Wender et al. first utilized vinylcyclopropanes (VCPs) as coupling partners in the [5 + 2] annulation of ynol ethers. In 2018 and 2020, Ye et al. reported zinc‐catalyzed formal [3 + 2] and [4 + 3] cycloaddition, respectively. For the cycloaddition of thioynol ethers, in 2004, Hilt et al. realized a [4 + 2] cycloaddition by employing the alkynyl sulfides and acyclic 1,3‐dienes. In 2006, a ruthenium‐catalyzed [2 + 2] cycloaddition of thioynol ethers with bicyclic alkenes was accomplished by Tam. In 2014, Sun et al. reported an elegant iridium‐catalyzed click reaction of thioalkynes with azides. [ABSTRACT FROM AUTHOR]

Tethering of two biologically active molecules in a single unit is considered as a captivating solution for the extension of existing antibiotics. β-Lactams which display a vast array of biological properties due to various ring substitutions continue to attract the attention of synthetic chemists. The incorporation of the 'isoxazole' nucleus in its appendage is known to enhance the properties of β-lactam compounds. Its inclusion in the compounds offers decreased toxicity, increased efficacy, and improved pharmacokinetics spectrum. In the reported work, we highlight the efficient use of 1,3-dipolar cycloaddition reaction to synthesize novel isoxazole/dihydroisoxazole ring-linked β-lactam hybrids using 3-propargyloxy-β-lactams/3-allyl-β-lactams as synthons. The methodology devised has been found to be highly regioselective and generalized for the selected substrates to provide a variety of novel hybrid compounds under elementary reaction conditions. The synthesized compounds have been well characterized by various spectroscopic techniques and optimized reaction conditions for both types of hybrid compounds have been studied. [ABSTRACT FROM AUTHOR]

Fused bicyclic cyclopropanes were converted by Lewis acid‐catalysis with thioureas to furo‐, pyrano, and pyrrololactams with yields of up to 99 % and high diastereoselectivity. The formation of the title compounds, representing a formal [4+1]‐cycloaddition to a donor‐acceptor substituted cyclopropane, follows a cascade reaction involving SN1‐type ring‐opening addition and cyclization. Thiourea, being a cost‐effective and odorless reagent, acts as an N,N‐bis‐nucleophile to generate bicyclic compounds containing an N‐substituted γ‐lactam moiety. [ABSTRACT FROM AUTHOR]

Dearomative cycloadditions are powerful synthetic transformations utilizing aromatic compounds for cycloaddition reactions. They have been extensively applied to the synthesis of biologically relevant compounds not only because of the complexity generated from simplicity but also the atom‐ and step‐economy. For the most studied yet challenging benzene ring systems, ortho‐ and para‐cycloadditions have been realized both photochemically and thermally, while the meta‐cycloadditions are still limited to the photochemical processes tracing back to the 1960s. Herein, we for the first time realized the thermal cycloadditions of benzene rings with alkenes in a meta fashion via Wheland intermediates. A broad spectrum of readily available C(sp2)‐rich aniline‐tethered enynes were transformed into C(sp3)‐rich 3D complex polycyclic architectures simply by stirring in TFA. Moreover, the reaction could be performed in gram‐scales and the products could be diversely elaborated. [ABSTRACT FROM AUTHOR]

Dearomative cycloadditions are powerful synthetic transformations utilizing aromatic compounds for cycloaddition reactions. They have been extensively applied to the synthesis of biologically relevant compounds not only because of the complexity generated from simplicity but also the atom‐ and step‐economy. For the most studied yet challenging benzene ring systems, ortho‐ and para‐cycloadditions have been realized both photochemically and thermally, while the meta‐cycloadditions are still limited to the photochemical processes tracing back to the 1960s. Herein, we for the first time realized the thermal cycloadditions of benzene rings with alkenes in a meta fashion via Wheland intermediates. A broad spectrum of readily available C(sp2)‐rich aniline‐tethered enynes were transformed into C(sp3)‐rich 3D complex polycyclic architectures simply by stirring in TFA. Moreover, the reaction could be performed in gram‐scales and the products could be diversely elaborated. [ABSTRACT FROM AUTHOR]

Cobalt catalysts have recently gained considerable attention as alternatives to catalysts based on precious transition metals such as Rh and Ir. Recently, Co/photoredox cooperative catalysis has emerged as a powerful tool that enables versatile transformations, including cycloaddition reactions of unsaturated compounds. In particular, 1,6‐diyne derivatives are fascinating substrates for these reactions because the corresponding exocyclic 1,3‐diene products can be further transformed into sp3‐rich carbocycles and heterocycles via functionalization of the diene moiety. The dual catalytic system can facilitate not only the cycloaddition based on the activation of the π‐bond only, such as alkyne cyclotrimerization, but also the cycloaddition involving σ‐bond activation. This Concept highlights the recent advances in Co/photoredox cooperative‐catalysis‐enabled cycloaddition reactions, focusing on the reactions of 1,6‐diyne substrates, which are difficult to perform when well‐defined cationic CoI catalysis is employed. [ABSTRACT FROM AUTHOR]

A formal [4+3] cycloaddition of 2‐alkylidenetrimethylene carbonates with quinazoline‐derived azomethine imines is described. Under Pd catalysis, the reaction works efficiently under room temperature to afford angular quinazoline‐fused seven‐membered N,N,O‐heterocycles. A variety of cyclic carbonates and azomethine imines were well tolerated under mild reaction conditions. This work demonstrates the synthetic utility of decarboxylative cycloadditions of 2‐alkylidenetrimethylene carbonates for the synthesis of angular polycyclic aromatic molecules. [ABSTRACT FROM AUTHOR]

Unstable tetra(methoxycarbonyl)cyclopentadienone was investigated in the synthesis of electron-deficient cycloheptatrienes via [4+2]-cycloaddition/cycloelimination reaction with cyclopropenes. The use of its stable dimer did not afford the product although similar reactions with alkynes have been reported. Quantum chemical calculation revealed that cyclopentadienone is not generated from the dimer and the reaction with alkynes proceeds via a more complicated cycloelimination/cycloaddition/cycloelimination cascade. However, the formation of cycloheptatrienes was found favorable over the formation of the dimer. Therefore, the trapping of tetra(methoxycarbonyl)cyclopentadienone upon formation was successful to give cycloheptatrienes with five ester groups. The use of methyl coumalate as a four-electron component was successful with cyclopropenes containing only one ester group to afford only two ester groups in the product. [ABSTRACT FROM AUTHOR]

A novel two‐step access to polysubstituted pyrroles from nitroalkenes was developed. It involves [4+2]‐cycloaddition with enol ethers to give six‐membered cyclic nitronates followed by reductive ring contraction with Ra−Ni/AcOH or Ra−Ni/EtOH systems. The process is applicable to a variety of nitroalkenes and enol ethers bearing electron‐rich and electron‐poor substituents and functional groups. The anti‐inflammatory drug Bimetopyrol and its structural modifications were successfully synthesized by the strategy developed. The key side products were identified that provided an insight into the mechanism of the developed reductive ring contraction to pyrroles. [ABSTRACT FROM AUTHOR]

An approach for the preparation and stabilization of primary phosphine oxides is presented complementing previous methods of in situ generation. Specifically, RP(O)H2 where R=benzyl (Bn), cyclohexyl (Cy), 2‐naphthyl (2‐Naph), phenyl (Ph), tert‐butyl (t‐Bu) was prepared by controlled oxidation of the corresponding primary phosphine in presence of ferrocene as stabilizing reagent. The primary phosphine oxides were characterized using NMR and MS and studied in twofold hydrophosphorylation of diketones. The domino‐phospha‐aldol reaction catalysed with 5 mol% of sodium methoxide yielded five‐, six‐ and seven‐membered heterocyclic tertiary phosphine oxides with a high degree of stereoselectivity, as confirmed by single X‐ray diffraction. [ABSTRACT FROM AUTHOR]

The replacement of a CC unit with an isoelectronic BN unit in aromatic systems can give rise to molecules and materials with fascinating properties. We report here the synthesis, characterization, and reactivity of a 1,4,2,3‐diazadiborole species, 2, featuring an unprecedented 6π‐aromatic BN‐heterocyclic moiety that is isoelectronic to cyclopentadienide (Cp−). Bearing an unsymmetrical B=B entity, 2 exhibits reactivity toward oxidants, protic reagents, electrophiles, and unsaturated substrates. This reactivity facilitates the synthesis of a variety of novel mono‐ and bicyclic organoboron derivatives through mechanisms including ring retention, cleavage/recombination, annulation, and expansion. These findings reveal innovative synthetic routes to BN‐embedded aromatic compounds via desymmetrization, affording unique building blocks for synthetic chemistry. [ABSTRACT FROM AUTHOR]

Synthesis of bicyclic scaffolds has gained significant attention in drug discovery due to their potential to mimic benzene bioisosteres. Here, we present a mild and scalable Sc(OTf)3‐catalyzed [3+2] cycloaddition of bicyclo[1.1.0]butanes (BCBs) with ynamides, yielding a diverse array of polysubstituted 2‐amino‐bicyclo[2.1.1]hexenes in good to excellent yields. These products offer valuable starting materials for the construction of novel functionalized bicyclo[1.1.0]butanes. Preliminary mechanistic studies indicate that the reaction involves a nucleophilic addition of ynamides to bicyclo[1.1.0]butanes, followed by an intramolecular cyclization of in situ generated enolate and keteniminium ion. We expect that these findings will encourage utilization of complex bioisosteres and foster further investigation into BCB‐based cycloaddition chemistry. [ABSTRACT FROM AUTHOR]

The 4‐carboxylates of 1,2,3‐triazine 1‐oxides undergo [3+2] cycloaddition with in situ generated benzynes and naphthyne and also with cyclooctyne that, following extrusion of dinitrogen, form isoxazole‐3‐propenoate derivatives in high yields and diastereocontrol. This practical method occurs at room temperature and provides a wide range of isoxazole‐based heterocycles with diverse functionality. 1,2‐Naphthyne, an unsymmetrical alkyne, forms only one regioisomeric product, exemplifying inherent regioselectivity. Although high, stereoselectivity is not 100 % in most cases, indicating that the loss of dinitrogen is stepwise. Derivative reactions of benzisoxazoles suggest their versatility. [ABSTRACT FROM AUTHOR]

The replacement of a CC unit with an isoelectronic BN unit in aromatic systems can give rise to molecules and materials with fascinating properties. We report here the synthesis, characterization, and reactivity of a 1,4,2,3‐diazadiborole species, 2, featuring an unprecedented 6π‐aromatic BN‐heterocyclic moiety that is isoelectronic to cyclopentadienide (Cp−). Bearing an unsymmetrical B=B entity, 2 exhibits reactivity toward oxidants, protic reagents, electrophiles, and unsaturated substrates. This reactivity facilitates the synthesis of a variety of novel mono‐ and bicyclic organoboron derivatives through mechanisms including ring retention, cleavage/recombination, annulation, and expansion. These findings reveal innovative synthetic routes to BN‐embedded aromatic compounds via desymmetrization, affording unique building blocks for synthetic chemistry. [ABSTRACT FROM AUTHOR]

Synthesis of bicyclic scaffolds has gained significant attention in drug discovery due to their potential to mimic benzene bioisosteres. Here, we present a mild and scalable Sc(OTf)3‐catalyzed [3+2] cycloaddition of bicyclo[1.1.0]butanes (BCBs) with ynamides, yielding a diverse array of polysubstituted 2‐amino‐bicyclo[2.1.1]hexenes in good to excellent yields. These products offer valuable starting materials for the construction of novel functionalized bicyclo[1.1.0]butanes. Preliminary mechanistic studies indicate that the reaction involves a nucleophilic addition of ynamides to bicyclo[1.1.0]butanes, followed by an intramolecular cyclization of in situ generated enolate and keteniminium ion. We expect that these findings will encourage utilization of complex bioisosteres and foster further investigation into BCB‐based cycloaddition chemistry. [ABSTRACT FROM AUTHOR]