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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]

This study analyzes the samarium diiodide‐promoted cyclizations of 5‐arylpentan‐2‐ones to dearomatized bicyclic products utilizing density functional theory. The reaction involves a single electron transfer to the carbonyl group, which occurs synchronously with the rate determining cyclization event, and a second subsequent proton‐coupled electron transfer. These redox reactions are accurately computed employing small core pseudo potentials explicitly involving all f‐electrons of samarium. Comparison of the energies of the possible final products rules out thermodynamic control of the observed regio‐ and diastereoselectivities. Kinetic control via appropriate transition states is correctly predicted, but to obtain reasonable energy levels the influence of the co‐solvent hexamethylphosphortriamide has to be estimated by using a correction term. The steric effect of the bulky samarium ligands is decisive for the observed stereoselectivity. Carbonyl groups in para‐position of the aryl group change the regioselectivity of the cyclization and lead to spiro compounds. The computations suggest again kinetic control of this deviating outcome. However, the standard mechanism has to be modified and the involvement of a complex activated by two SmI2 moieties is proposed in which two electrons are transferred simultaneously to form the new C−C bond. Computation of model intermediates show the feasibility of this alternative+ mechanism. [ABSTRACT FROM AUTHOR]

For the first time, the transformation of biobased 5-HMF derivatives succeeded in a 2 × [4 + 2] cascade cycloaddition reaction, leading to a drastic (3–5-fold) increase in molecular complexity as a result of one synthetic step. A new approach to the use of plant biomass in organic synthesis using a cascade Diels–Alder reaction of 5-HMF dimer derivatives with alkynes has been developed. This reaction proceeds under thermodynamic control, diastereoselectively and regioselectively, providing rapid access to compounds of high molecular complexity with the same synthetic availability as previously obtained regular cycloadducts. As a concept illustration, under conditions of kinetic control, cycloadditions of two molecules of dienophiles are realized, and the resulting products, when heated, rearrange into thermodynamically more favorable cascade products. Reaction pathways were studied in detail using quantum chemical calculations to reveal major factors influencing the selectivity of the process. Discovery of a new sustainability pathway should be noted – to date, oligomeric derivatives are considered a waste of 5-HMF degradation, while the present study highlights them as a valuable material for the synthesis of nonplanar scaffolds. [ABSTRACT FROM AUTHOR]

Chiral trans‐hydrindanes (bicyclo[4.3.0]nonanes) are important building blocks of polycyclic natural products. In order to access 5/6/5‐ and 5/6/6‐carbotricyclic scaffolds scope and limitation of [4+2] cycloadditions of tetrahydroindanones with various dienes were studied. Cyclopentadiene gave a tetracylic endo‐(R,R)‐diastereomer under acid‐catalysis, whereas thermal conditions provided the endo‐(S,S)‐diastereomer with the opposite diastereofacial selectivity. The stereodivergent outcome was rationalized by high‐level quantum‐chemical computations which revealed the acid‐catalysis to be a kinetically controlled reaction and the thermal cycloaddition to be under thermodynamic control. Stereochemical assignment of the cycloadducts was facilitated by conversion of the 1,3‐dicarbonyls with BF3 ⋅ OEt2 into BF2‐chelate complexes. Subsequent thermal Diels‐Alder reaction of BF2‐ or BBN‐chelates (from 9‐BBN‐OTf) gave endo/exo‐mixtures of the (R,R)‐ and (S,S)‐diastereomers, while more elevated temperatures yielded primarily the endo/exo‐(S,S)‐diastereomers. Thermal [4+2] cycloadditions with 2,3‐dimethylbutadiene proceeded with lower diastereoselectivity as the reaction was kinetically controlled according to calculations. Attempted Diels‐Alder‐reactions with furan gave furyl‐substituted indanones rather than cycloadducts. [ABSTRACT FROM AUTHOR]

The intramolecular oxidative coupling of electron-rich aromatic groups in 5-(het)aryl-1-(het)arylalkyl-1H-1,2,3-triazoles was studied in detail. Under treatment with phenyliodoso bis(trifluoroacetate) and boron trifluoride etherate these substrates afforded products of either ortho/ortho or ortho/ipso coupling depending on the nature of aromatic groups and reaction conditions applied. It was found that for substrates which are capable for both types of coupling, ortho-/ipso-adducts are formed under kinetic control while ortho-/ortho-products are formed under thermodynamic control. The developed procedures allow preparation of complex polycyclic azaheterocycles from simple precursors in two steps only. [ABSTRACT FROM AUTHOR]

The cycloaddition of azomethine ylides to [60]fullerene (C60) has been studied in ortho‐dichlorobenzene (o‐DCB) by evaluating the impact of an ionic liquid (IL) additive. The solvent effect has been addressed by evaluating the activation parameters of the cycloaddition and the boosting effect of the microwave (MW) induced dielectric heating. The IL additive plays a twofold role of stabilizing the dipolar ylide intermediate and favoring the retro‐cycloaddition at high temperature regime. Under the conditions explored, a combined kinetic and thermodynamic preference favors the selective formation of trans bis‐fulleropyrrolidine regioisomers, in agreement with the DFT computational analysis. [ABSTRACT FROM AUTHOR]

In quantum chemical calculations, the Diels–Alder (DA) cycloaddition reaction of furan with maleic anhydride favors the endo‐isomer kinetically in the gas phase. This preference, however, changes in favor of the exo‐isomer on inclusion of solvent effects. For example, in acetonitrile, the exo‐isomer was calculated to form twice as fast as the endo‐isomer at room temperature, an observation that corroborates well with the experiments. The free energy change of the reaction is such that it allows faster reversal of the endo‐isomer to the reactants in an equilibrium process and, thus, the predominance of the more stable exo‐isomer eventually. The reaction of furan with maleimide is similar to that with maleic anhydride. However, it predominantly favors endo‐selectivity at temperatures below 320 K, which is also in excellent agreement with the experimental studies of temperature dependence of this DA reaction. Further, a gedanken calculation of the DA reaction of furan with cyclopropene has been investigated to delineate the effect of the retro‐pathway on stereoselectivity. [ABSTRACT FROM AUTHOR]

In this study, mechanism and stereochemistry of multicomponent domino Knoevenagel/Diels–Alder reaction were investigated theoretically. Structures of reagents, transition states, intermediates, and products were optimized at M062X/6-31 + G(d,p) level of theory. Although the mechanism of this reaction involved several processes, including bond rotation, isomerization, asymmetric cycloaddition, acid-base, and nucleophile–electrophile competitions, critical processes were studied to provide a clearer picture of the mechanism of this valuable reaction in terms of stereochemistry considerations. According to the results, the ring closure step of reaction performed via a polar Dield-Alder mechanism, having enthalpy at approximately 40 kcal/mol. The diastereoselectivity of the reaction was controlled by the interaction of dienophile with the less hindered face of diene through a more stable endo transition state (Δ G # = 2 3. 2 1 and 27.31 in methanol and gas phase, respectively). HSAB criteria could explain the regioselectivity of this reaction by considering the least softness difference (Δ S) for interacting C-atoms based on Hirshfeld populations. The result was the creation of cis-spiro cyclohexanone under kinetic and thermodynamic controls as a predominant diastereoselective and regioselective product. Based on the M062X/6-31+G(d,p) calculations, diastereoselectivity of the Knoevenagel/Diels-Alder reaction was controlled kinetically by the interaction of dienophile with the less hindered face of diene through a more stable endo transition state(ΔG# = 23.21 kcal/mol). HSAB criteria could explain the regioselectivity of this reaction by considering the least softness difference (ΔS) for interacting C-atoms based on Hirshfeld populations. [ABSTRACT FROM AUTHOR]

Abstract: An unprecedented organocatalytic approach towards highly substituted cyclic carbonates from tri‐ and tetrasubstituted oxiranes and carbon dioxide has been developed. The protocol involves the use of a simple and cheap superbase under mild, additive‐ and metal‐free conditions towards the initial formation of a less substituted carbonate product that equilibrates to a tri‐ or even tetrasubstituted cyclic carbonate under thermodynamic control. The latter are conveniently trapped in situ, providing overall a new domino process for synthetically elusive heterocyclic scaffolds. Control experiments provide a rationale for the observed cascade reactions, which demonstrate similarity to the well‐known Payne rearrangement of epoxy alcohols. [ABSTRACT FROM AUTHOR]

The intramolecular [3+2] cycloaddition (IM32CA) reactions of cyclic nitrones Z‐7 and E‐7 have been studied within the Molecular Electron Density Theory at the MPWB1K/6‐311G(d) computational level. For these IM32CA reactions, which take place through a one–step mechanism, two regioisomeric reaction paths associated with the formation of the 6,6,5‐ring fused and 6,5,5‐ring bridged isoxazolidines have been considered. Analysis of the relative Gibbs free energies indicates that under thermodynamic control, these IM32CA reactions are completely regioselective, stereoselective and stereospecific, cyclic nitrones Z‐7 and E‐7 yielding the fused isoxazolidines 8 and 9, respectively, as the only product, in complete agreement with the experimental outcomes. The low electrophilic character of nitrones Z‐7 and E‐7 together with the strain caused by the chain along these intramolecular processes are responsible for the high activation energies found in these IM32CA reactions. An ELF topological analysis of the asynchronous TSs associated with the IM32CA reaction of cyclic nitrone Z‐7 indicates that along the more favourable fused reaction path, the IM32CA reaction begins with the formation of the C−O single bond involving the most nucleophilic and electrophilic centers of the molecule. [ABSTRACT FROM AUTHOR]

The tandem [4+2] cycloaddition between hexafluoro-2-butyne and bis-furyl dienes, like difurfuryl ester, at room temperature leads to the kinetically controlled “pincer”-adducts – annulated 4a,8a-bis(trifluoromethyl)hexahydro-1,4:5,8-diepoxynaphthalenes. On the other hand, if these reactions proceed at 140 °C, only the thermodynamically controlled “domino”-adducts – annulated 2,3-bis(trifluoromethyl)hexahydro-1,4:5,8-diepoxynaphthalenes – are formed. Therefore, a very rare and unexpected example of full kinetic and thermodynamic control in the Diels–Alder reaction is reported in this paper. [ABSTRACT FROM AUTHOR]

An extension of the Jacobson--Stockmayer theory is presented to include the reversible formation of [2]catenanes in a ring--chain system under thermodynamic control. The extended theory is based on the molar catenation constant, measuring the ease of catenation of two ring oligomers, whose expression was obtained in a previous work. Two scenarios have been considered: that of "thick" (hydrocarbon-like) chains and that of "thin" (DNA-like) chains. In the case of "thick" chains, the formation of catenanes can be neglected, unless in the unlikely case of a very large value of the equilibrium constant for linear propagation (K ≈ 108 mol-1 L, or larger). For K tending to infinity, the system becomes a chain-free system where only ring--catenane equilibria occur. Under this condition, there is a critical concentration below which only rings are present at equilibrium and above which the ring fraction remains constant, and the excess monomer is converted only into catenanes. In the case of "thin" chains, the formation of catenanes cannot be neglected even for values of K as low as 10² mol-1 L, thus justifying the use of the extended theory. [ABSTRACT FROM AUTHOR]

A density functional theory study was performed on the [3+2] cycloaddition (32CA) reaction of 1 H -phosphorinium-3-olate and 1-methylphosphorinium-3-olate with methyl acrylate. The thermodynamic and kinetic parameters were analysed by considering the regio- and stereoisomeric pathways in gas phase and solvents. The geometries indicate that the transition states are slightly more advanced and asynchronous in ethanol. Electron localisation function topological analysis of the bonding changes along the most favourable reaction pathway associated with the 32CA reaction of 1 H -phosphorinium-3-olate with methyl acrylate indicates that the reaction takes place through a two-stage one-step mechanism. Non-covalent interactions analysis of TS6x-H reveals the existence of weak hydrogen bonding explaining the regioselectivity found in this low-polar zw-type 32CA reaction. On comparing these theoretical findings with the nitrogen analogues of the 32CA reactions, it is found that the regioselectivity is affected and the pathways are kinetically and thermodynamically enhanced. Therefore, a priori , the phosphorus cycloadducts could be synthesised. [ABSTRACT FROM AUTHOR]

A two-step synthesis of a strained π bowl, with hemifullerene skeleton from sumanene, was achieved in a high yield. The first step is a base-promoted condensation reaction with a benzophenone compound, bis(3,5-dimethylphenyl)methanone. The second step is the regioselective intramolecular oxidative cyclization, which is a key reaction for the hemifullerene skeleton synthesis. This regioselective cyclization is likely to be under thermodynamic control. This strategy will allow facile synthesis of various highly strained π bowls. [ABSTRACT FROM AUTHOR]

The cycloaddition of 2- or 2,3-substituted 1-thia- and 1-thia-3-aza-4-dimethylamino-buta-1,3-dienes with various dienophiles in the presence of a Lewis acid provides a rapid and diastereoselective access to the 3,4-dihydro-2H-thiopyran and 5,6-dihydro-4H-[1,3]thiazine backbones. The generally observed trans relationship between the two newly created strereogenic centres was demonstrated to be the expression of a thermodynamic control of the reaction. The use of chiral dienophile derived from chiral oxazolidin-2-ones allowed us to prepare enantiopure 5,6-dihydro-4H-[1,3]thiazines and 3,4-dihydro-2H-thiopyrans. In the asymmetric synthetic process the chiral auxiliary removal step was best accomplished in the presence of samarium triflate in methanol. [Copyright &y& Elsevier]

A 1,3-dithiane displaces tosylate by a 5-exo-tet cyclisation to give a bicyclic sulfonium salt. Nucleophilic attack on this 4-thia-7a-thioniaperhydroindene by azide ions kinetically favours opening to give a nine-membered ring α-azidosulfide, but 2-(3′-azidopropyl)-1,3-dithiane is the thermodynamic product from B3LYP/6-31G** calculations. A similar sulfonium salt generated from 2-(3′-hydroxypropyl)-1,3-dithiane with thionyl chloride rearranges to 2-(3′-chloropropyl)-1,3-dithiane. Azide ion displacement of the primary alkyl chloride is then faster than [1.4] sulfanyl participation from the thioacetal. An α-chlorosulfide derived from diphenyldithioacetal does not rearrange but undergoes direct displacement to give an α-azidosulfide. [Copyright &y& Elsevier]

Keywords: 1,3-Dipolar cycloaddition; Fullerenes; Ionic liquids; Microwaves; Temperature effect EN 1,3-Dipolar cycloaddition Fullerenes Ionic liquids Microwaves Temperature effect 3536 3536 1 07/21/21 20210707 NES 210707 B The Cover Feature b shows a kaleidoscopic vision of the frontier empty orbitals of [60]fulleropyrrolidine embracing diverse [6,6] bonds, which poses a severe regioselectivity challenge for further ylide cycloaddition, resulting in a multitude of polyfunctionalization products. Cover Feature: Microwave-Assisted 1,3-Dipolar Cycloaddition of Azomethine Ylides to [60]Fullerene: Thermodynamic Control of Bis-Addition with Ionic Liquids Additives (Eur. J. Org. 1,3-Dipolar cycloaddition, Fullerenes, Ionic liquids, Microwaves, Temperature effect. [Extracted from the article]

Cycloaddition reactions of diene 1a with various dienophiles lead to trans 4,5-disubstituted dihydro-1,3-thiazine adducts. We demonstrate that a thermodynamically-controlled process, in which the adduct N-3 nitrogen plays a prominent role, accounts for the observed trans relative configuration. [Copyright &y& Elsevier]