A theoretical investigation on the regioselectivity of the [3+2] cycloaddition of nitrile oxide and N-vinylpyrrole

Theoretical calculations were performed on the [3+2] cycloaddition (32CA) reaction of nitrile oxide and N-vinylpyrrole. The regiochemistry of the reaction has been studied based on potential energy surface analysis and global and local reactivity indices of the reactants. The global electron density transfer (GEDT) calculations at the possible transition states revealed that this cycloaddition has a nearly non-polar character. The ELF topological analyses of the selected structures involved in the intrinsic reaction coordinate (IRC) of TS1a suggests that this 32CA reaction takes place through a two-stage one-step mechanism.     

[3+2] Cycloaddition reactions: a simple entry to the 1-aza-2-oxo-3,4,5,6-tetrahydroxybicyclo[3.3.0]octane ring system

The [3+2] intramolecular nitrone cycloaddition (INC) reaction on appropriately designed olefinic nitrones derived from d-glucose, having the nitrone at C-1 and α,β-unsaturated ester functionalities at C-5 of the sugar backbone, afforded the isoxazolidine fused carbocycles 11-13, which were subsequently transformed into the chiral, tetrahydroxylated cis-azabicyclo[3.3.0]octanones 14-18 in good yields.     

Structures of the phosphinidene germylenoid HP=GeLiF and its cycloaddition reaction with ethylene

The structures of phosphinidene germylenoid HP=GeLiF were studied for the first time by using DFT (density functional theory) calculations. The geometries were optimized at the B3LYP/6-311+G (d, p) level at first and then the single-point energies were calculated at QCISD/6-311++G (d, p) level. Theoretical calculations predicted that HP=GeLiF has two equilibrium structures, the p-complex (1) and the three-membered-ring (2) structures, in which structure 1 has the lower energy and is more stable than 2. To exploit the reactivity of HP=GeLiF, the cycloaddition reaction of 1 and ethylene was investigated at the same level of theory. From the potential energy profile, we predicted that the cycloaddition reaction has one dominant reaction pathway. The calculated result shows that the dominant reaction pathway is a [2?+?2] cycloaddition reaction which is the interaction of two π bonds in HP=GeLiF and ethylene molecule, and a four-membered-ring P-heterocyclic germylene is formed. Since sp³ hybridization of Ge atom in this four-membered-ring germylene, it may further react with another ethylene and finally forming a spiro-Ge-heterocyclic compound involving phosphorus. This means that this reaction involves a [2?+?2] cycloaddition as the initial step, and then a [2?+?1] cycloaddition carried out.     

Gold-catalyzed intermolecular [4C+3C] cycloaddition reactions

In the presence of the N-heterocyclic carbene gold catalyst (NHC-AuIPr, 7), propargyl esters 1a-f and 13 undergo a [4C+3C] cycloaddition reaction with cyclopentadiene and furan under mild conditions. The evidence suggests that the formation of the seven-membered ring occurs by a direct cycloaddition process, rather than a stepwise cyclopropanation/Cope rearrangement sequence.     

Synthesis of novel 5,6,7,8,9,10-hexahydropyrimido[4,5-b]quinoline derivatives for antimicrobial and anti-oxidant evaluation

Because of the well-known chemotherapeutic activity of pyrimidoquinolines, a new series of the title compounds were synthesized and biologically screened for their antimicrobial and anti-oxidant activities. The intermediate compound, 2-amino-1-cyclohexyl-4-(3,4-dimethoxyphenyl)-1,4,5,6,7,8-hexahydroquinoline-3-carbonitrile (2), was prepared and allowed to react with oxalyl chloride to give the corresponding strategic starting material, 10-cyclohexyl-5-(3,4-dimethoxyphenyl)-4-oxo-3,4,5,6,7,8,9,10-octahydropyrimido[4,5-b]quinoline-2-carbonyl chloride 3. Compound 3 underwent diverse reactions with amines to give the corresponding carboxylic amides 4, with alcohols to give the carboxylic esters 5 and with hydrazine to give the carbohydrazide 8. Compound 8 reacted with aldoses to give the corresponding polyhydroxy(-)alkyl Schiff bases 9, which upon reaction with thioglycolic acid afforded the thiazolidinone-C-acyclic nucleosides 10. Several other pyrimidoquinolines incorporated to oxadiazole, iminothiazolidinones and thiadiazoles were synthesized starting from the 2-carbohydrazide derivative 8. Most of the newly prepared derivatives showed considerable antimicrobial activity against Gram +ve and Gram ?ve bacteria and anti-oxidant activity.     

Expedient synthesis of a highly substituted tropolone via a 3-oxidopyrylium [5+2] cycloaddition reaction

An expedient ten-step synthesis of a substituted tropolone is described. The synthesis involves a 3-oxidopyrylium [5+2] cycloaddition reaction with acrylonitrile as the key step, affording a highly functionalized [3.2.1]-bicycle 10 as a single regioisomer. The nitrile substituent of the reduced cycloadduct 12 permits efficient ether-bridge cleavage and tropolone 15 is obtained after a final bis-oxidation procedure. The pyranulose acetate cycloaddition precursor was derived from 3-methyl-2-furoate.     

Synthesis and spectroscopic studies of some new oxazepine derivatives throughout [2+5] cycloaddition reactions (III)

The present work included condensation reactions of o-tolidine with different aromatic aldehydes in absolute ethanol to give Schiff bases (w ₉ –w ₁₂ ) in high yield which, on reaction with maleic and phthalic anhydride by [2+5] cycloaddition reactions in the presence of suitable solvents, give the corresponding [1,3]oxazepine-4,7-dione (w ₉ m–w ₁₂ m) and [1,3]oxazepine-1,5-dione (w ₉ ph–w ₁₂ ph), respectively. The structure of the newly synthesized compounds were monitored by TLC and established on the basis of elemental analysis, FT-IR, and ¹H NMR.     

[3+2] Cycloaddition-mediated synthesis of 3-methylsulfanyl-pyrrolidine-3-carboxylic acid methyl ester

1,3-Dipolar cycloaddition reactions are fundamental processes in organic chemistry. Herein we report [3+2] annulation of thiomethylacrylate 2 and azomethine ylide precursor 3 towards the synthesis of novel 3-methylsulfanyl-pyrrolidine 5. Alternatively, we have also explored the alkylation of 7 with dimethyldisulfide/LDA for the introduction of thiomethyl group towards the synthesis of 5 in moderate to good yields. Efficacy of these two routes under various conditions/catalysts for the synthesis of 5 is presented.     

[4+2] Cycloaddition reactions of 4-sulfur-substituted 2-pyridones with electron-deficient dienophiles

[4+2] Cycloaddition reactions of 4-(phenylthio)-1-tosyl-2-pyridone (6a) and 4-(phenylsulfonyl)-1-tosyl-2-pyridone (6b) with electron-deficient dienophiles 7 (N-methylmaleimide, N-phenylmaleimide, and methyl acrylate) gave new isoquinuclidine products 8-10. The N-tosyl group of 6a and 6b was also efficiently converted to N-alkyl derivatives 6c-f, which showed different stereoselectivity toward reactions with dienophiles 7. Several other dienophiles 15 (dimethyl acetylenedicarboxylate, methyl vinyl ketone, ethyl vinyl ether, and methyl methacrylate) were found not to react with 6a or 6b, but led to the formation of tosyl migration products 4-(phenylthio)-O-tosyl-pyridinol (16a) and 4-(phenylsulfonyl)-O-tosyl-2-pyridinol (16b), respectively. The reactivity, regioselectivity, and stereoselectivity of the cycloaddition reactions were also compared with semi-empirical calculations.     

Synthesis and antimicrobial activity of novel fused [1,2,4]triazino[5,6-<Emphasis Type="Italic">b</Emphasis>]indole derivatives

Synthesis of new fused systems of triazino[5,6-b]indole starting with preparation of 3-amino[1,2,4]-triazino[5,6-b]indole 1 by reaction of isatin with 2-aminoguanidinium carbonate in boiling acetic acid is presented [1]. Intermediate compound 1 reacted with aldehyde, ethyl chloroformate, triethyl orthoformate, and ninhydrine and gave new heterotetracyclic nitrogen systems, such as 3-(N ²-guanidinylimino)indole-2(1H)-one 2, 3-(N-ethoxycarbonylamino)-4H-[1,2,4]triazino[5,6-b]indole 3, 3-(N-ethoxymethyleneamino)-4H-[1,2,4]-triazino[5,6-b]indole 4, 3-(hydrazinothiocarbonylamino)-4H-[1,2,4]triazino[5,6-b]indole 5, respectively. N-(1,3-dioxoindene-2-ylidene)-4H-[1,2,4]triazino[5,6-b]indol-3-amine 6 was synthesized by reaction of compound 1 with aldehyde, ethyl chloroformate, triethyl orthoformate, and ninhydrine. New fused indole systems, pyrimido[2′,1′:3,4][1,2,4]triazino[5,6-b]indol-3(4H)-one 8, 9, 11, 12 and 1H-imidazo[2′,1′:3,4][1,2,4]triazino-[5,6-b]indol-2(3H)-one 10, were synthesized in the reaction of the intermediate 1 with bifunctional compounds. Structures of the products were elucidated from their elemental analysis and spectral data (IR, ¹H and ¹³C NMR and mass spectra). Antimicrobial activity of some synthesized compounds was tested.     

Synthesis,characterization and extraction properties of calix[4]crown with amine units and study of its complexes with Cu(II)

In this work, we have focused on the synthesis of p-tert-butyl calix[4]crown with amine units (H ₃ L) as a class of selective receptors for metal ions. The macrocyclic ligand (H ₃ L) with N₂O₇ donors was synthesized via condensation between 1,3-diaminocalix[4]arene and 2-[3-(2-formylphenoxy)-2-hydroxypropoxy] benzaldehyde, followed by reduction of the Schiff base product in situ with sodium borohydride, then it was characterized by FT-IR, ¹H NMR and X-ray crystallography. Two Cu(II) complexes were prepared from the reaction of H ₃ L with Cu(II) salts (CuX₂, X = ClO₄ ^? and Cl^?). FT-IR, UV–Vis, elemental analysis, molar conductivity and cyclic voltammetry techniques were used for study and characterization of these complexes. On the basis of liquid–liquid extraction experiments, ligand H ₃ L indicated good affinity toward Pb²⁺ and Cu²⁺.     

Asymmetric oxidopyrylium-alkene [5+2] cycloaddition: a divergent approach for the synthesis of enantiopure oxabicyclo[5.4.0]undecanes

A Chiron approach to the synthesis of enantiomeric oxabicyclic adducts 16 and 32 has been developed employing an intramolecular [5+2] cycloaddition of 3-oxidopyrylium with unsaturated sugars.     

Notable temperature effect on the stereoselectivity in the photochemical [2+2] cycloaddition reaction (Paternò-Büchi reaction) of 2,3-dihydrofuran-3-ol derivatives with benzophenone

A notable temperature effect (nonlinear Eyring plot) on stereoselectivity, trans-configured oxetane 2 versus cis-configured oxetane 2, is reported in the photochemical [2+2] cycloaddition reaction (Paternò-Büchi reaction) of 2,3-dihydrofuran-3-ol derivatives 1 with benzophenone.     

[3+2]- Versus [4+2]-cycloaddition reactions of 3-methylsulfanyl-2-arylazo-3-(pyrrolidin-1-yl)acrylonitriles with N-substituted maleimides involving pyrrolidine-derived azomethine ylides

3-Methylsulfanyl-2-arylazo-3-(pyrrolidin-1-yl)acrylonitriles do not enter into [4+2]-cycloaddition reactions with maleimides to form the expected pyrrolo-pyridazines. Instead the formation of novel pyrrolo-pyridazines of type 4 takes place via a formal [3+2]-cycloaddition of initially formed pyrrolidine-derived azomethine ylides 7. The mechanism leading to the final product is discussed.     

Anionic [4+2] cycloaddition strategy in the regiospecific synthesis of carbazoles: formal synthesis of ellipticine and murrayaquinone A

Anionic [4+2] cycloaddition of furoindolones (e.g., 7 and 10) has been developed as an effective means to the synthesis of carbazoles. This reaction has been shown to be feasible with a wide variety of Michael acceptors to give carbazoles and fused carbazoles in good yields. The scope and limitations of the reaction have been briefly studied. The nature of N-protection of the furoindolones (cf. 7) plays a major role in the success of annulation.     

Solid-state photocycloaddition of 6,6′-dimethyl-4,4′-[bis(methylenoxy)phenylene]-di-2-pyrones with benzophenone

Photocycloaddition reactions of 6,6′-dimethyl-4,4′-[bis(methylenoxy)phenylene]-di-2-pyrones (4a-c) with benzophenone (2a) by mixing in the solid state (solid solution) afforded the corresponding oxetane derivatives (5a-c; 1:2 adducts) with high site- and regioselectivity across the C5-C6 and C5′-C6′ double bonds in 4 via the triplet excited state of benzophenone. The oxetane formation proceeded more effectively in the solid state than in solution. The reaction mechanism was inferred by MO methods to be initiated by electrostatic interaction between the C6 position of 4a-c and the carbonyl oxygen of 2a in their ground states. The solid-state interaction may be enhanced by the electron density at the carbonyl oxygen of the triplet 2a. The transition state (TS) analysis of the [2+2] cycloaddition reactions also suggested some triplet complexes and high regioselectivity. The hydrogen-bonding interaction between 2a and 4a-c and the triplet reaction mechanism were also explained by the IR analyses and the quenching experiments, respectively.     

Synthesis of 2-azaspiro[4.4]nonan-1-ones via phosphine-catalysed [3+2]-cycloadditions

The phosphine-catalyzed [3+2]-cycloaddition of the 2-methylene γ-lactams 4 and 5 and the acrylate 6 with the ylides derived from the ethyl ester, the amide or the chiral camphor sultam derivative of 2-butynoic acid (7a-c) give directly, or indirectly after reductive cyclization, spiro-heterocyclic products. The acid 32 underwent Curtius rearrangement and then acid hydrolysis to give two novel spiro-cyclic ketones, 41 and 42.     

Nickel-catalyzed [3+2+2] cycloaddition of ethyl cyclopropylideneacetate and diynes. Synthesis of 7,6- and 7,5-fused bicyclic compounds

The [3+2+2] cycloaddition reaction of ethyl cyclopropylideneacetate (1) and diynes proceeded in the presence of Ni(0) catalysts, and bicyclic compounds were isolated in good yields. The reaction provided a new approach to 7,6- and 7,5-fused bicyclic compounds.     

Molecular modeling and cyclization reactions of 2-(4-oxothiazolidine-2-ylidene) acetonitrile

Diazotization of 2-(4-oxothiazolidine-2-ylidene) acetonitrile 1 with aryl diazonium chloride derivatives afforded 4-thiazolidinones 2a, b, whereas 3a, b derivatives produced through reaction of arylcarbonohydrazonoyl dicyanide with thioglycolic acid. Cyclization of 2a with aromatic aldehydes and malononitrile gave the expected substituted thiazolo [3,2-a] pyridines 4a, b. The reaction of 1 with anthraldehyde (1:1 molar ratio) gave the expected 4,5-dihydro-4-oxothiazole derivatives 5 which condensed with other mole p-chlorobenzaldehyde and gave the corresponding bisarylidine derivative 6. Thiazolo [3,2-a] pyridine enaminonitrile derivative 7 produced through addition of malononitrile to bisarylidine 6. Also, compound 7 reacted with other mole of malononitrile and furnished thiazolo [3,2-a] pyridine 12, furthermore, compound 7 refluxed with phenyl hydrazine, thiourea, and formic acid, to form the corresponding thiazolo [3,2-a] pyridines 13, 15 and 17, respectively. Also, compound 1 reacted with phNCS in presence of KOH and afforded 19. The molecular modeling of the synthesized compounds has been drawn and their molecular parameters were calculated. Also, valuable information is obtained from calculation of the molecular parameters including electronegativity, net dipole moment of the compounds, total energy, electronic energy, binding energy, electrophilicity index, HOMO and LUMO energy.     

SiO2-NHC-Cu(I): an efficient and reusable catalyst for [3+2] cycloaddition of organic azides and terminal alkynes under solvent-free reaction conditions at room temperature

A novel SiO₂-NHC-Cu(I) 3b was developed and used as a highly efficient catalyst for [3+2] cycloaddition of organic azides and terminal alkynes. In the presence of SiO₂-NHC-Cu(I) 3b (1 mol %), the reactions of terminal alkynes with organic azides underwent smoothly to generate the corresponding regiospecific 1,4-disubstituted 1,2,3-triazoles in excellent yields under solvent-free reaction conditions at room temperature. Furthermore, catalyst 3b was quantitatively recovered from the reaction mixture by a simple filtration and reused for 10 cycles without loss of its activity.