Nitrous oxide as a 1,3-dipole: a theoretical study of its cycloaddition mechanism

The 1,3-dipolar cycloadditions of nitrous oxide and substituted alkynes have been studied at the B3LYP/6-31G(d,p) level. The reaction is controlled by LUMO (dipole)--HOMO (dipolarofile) and involves aromatic transition structures. The shape of the potential energy surface and the regioselectivity are not affected by the polarity of the solvents, except in the case of N2O + HC triple bond CSiH3. Different reactivity criteria including FMO coefficients product C, local softness differences Delta, magnetic susceptibility anisotropy chi(anis), and nucleus-independent chemical shifts NICS were used to predict the regioselectivity in all studied cases; the C, Delta criteria turn out to give the best results among them. The aromaticity of the transition structure is not a factor in determining the regiochemistry of the cycloaddtition reactions.     

Synthesis of spiropyrrolidines: 1,3‐dipolar cycloaddition reactions of an azomethine ylide to unusual dipolarophiles; a molecular orbital study of the cycloaddition reaction

A simple and efficient method for the synthesis of novel spiropyrrolidines has been accomplished by regioselective 1,3‐dipolar cycloaddition reactions of an azomethine ylide generated by thermal‐ring opening of cis‐1‐cyclohexyl‐2‐phenyl‐3‐benzoyl aziridine with various (E)‐3‐arylidene‐4‐chromanones. The synthesis proceeds in good yield to afford novel spiropyrrolidines, 1‐cyclohexyl‐2‐phenyl‐3‐aryl‐5‐benzoylpyrrolidine‐spiro‐[4.3′]4′‐chromanones. The X‐ray crystal structure analysis of one of the products confirms its structure. Molecular orbital calculations were performed to investigate the regioselectivity of the cycloaddition process. © 1999 John Wiley & Sons, Inc. Heteroatom Chem 10: 500–507, 1999     

1,3-Dipolar cycloaddition of azomethine ylide with ethene and 2-butene: a computational study

B3LYP/6-311 + G(d,p) has been used to calculate the relative energies and geometrical parameters of the respective reactants, transition states, and cycloadducts from the cycloadditions of azomethine ylide and ethene, (Z)-2-butene, and (E)-2-butene. The half-chair (envelope) transition state structures are consistent with a synchronous concerted cycloaddition mechanism.     

Diastereoselective synthesis of pyrrolidines via 1,3-dipolar cycloaddition of a chiral azomethine ylide

1,3-Dipolar cycloaddition of d-glucose-derived azomethine ylides for the synthesis of chiral pyrrolidines accompanied an unexpected 1,2-elimination in the furanose moiety of the products. The C3′ alkoxy/hydroxy group of the furanose moiety was invariably eliminated under the reaction conditions. Also, in contrast to the previous reports, moderate to good exo-diastereoselectivity was observed in the reaction products.     

Rapid annulation of tropolone units via a pyrylium ylide 1,3-dipolar cycloaddition reaction

The tropolone subunit of the naturally occurring alkaloid rubrolone aglycon is synthesized via a short reaction sequence starting with a 1,3-dipolar cycloaddition of a pyrylium ylide and indenone, followed by enone oxidation, oxygen-bridge elimination and finally hydroxy group oxidation.     

The stereoselective synthesis of novel macrolide antibacterial agents via an intramolecular 1,3-dipolar cycloaddition of azomethine ylide

An intramolecular 1,3-dipolar cycloaddition of azomethine ylide, generated in situ via the reaction of C12-glycinate derivative of macrolide with formaldehyde, provided a novel tricyclic macrolide. The high stereoselectivity of this [2+3] reaction was achieved by introducing a suitable directing group at C-6 position of macrolide.     

A novel reaction cascade leading to a spontaneous intramolecular dipolar cycloaddition through simultaneous generation of 1,3-dipole and dipolarophile

Ornithine methyl ester reacts with aromatic aldehydes to generate bis-Schiff bases, which depending on the structure of the aromatic aldehyde, further undergo an intramolecular cycloaddition through the transient formation of a reactive 1,3-dipole.     

Highly enantioselective asymmetric 1,3-dipolar cycloaddition of azomethine ylide catalyzed by a copper(I)/ClickFerrophos complex

A copper(I)/ClickFerrophos complex catalyzed the asymmetric 1,3-dipolar cycloaddition reaction of methyl N-benzylideneglycinate (the source of azomethine ylides) with vinyl sulfone to give the exo-2,4,5-trisubstituted pyrrolidine in good yield with high enantioselectivity (99% ee). The complex also effectively catalyzed reactions of other dipolarophiles such as acrylates, maleate, and maleimides to give the exo-2,4,5-, and 2,3,4,5-substituted pyrrolidine derivatives with high diastereo- and enantioselectivities.     

Thermoylysis of 1-phenyl-5-alkylsulfonyltetrazole in the presence of arylhydrazines. An instance of migration of an alkylsulfonyl group in a 1,3-dipole

When 1-phenyl-5-alkylsulfonyltetrazoles are heated with arylhydrazines, the heteroring is cleaved to give nitrogen and 1-arylamino-2-phenyl-3-alkylsulfonylguanidine. According to the proposed scheme, the intermediate product of nucleophilic addition of the arylhydrazine to the tetrazole decomposes to give nitrogen and a 1,3-dipole, which is stabilized by migration of an alkylsulfonyl group.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 4, pp. 549–552, April, 1977.     

Analysis of an intermediate in a 1,3-dipolar cycloaddition of methylsulfonyl azide

MNDO-PM3 calculations, carried out on an experimentally determined structure of an intermediate in the cycloaddition of an electrophilic azide and a nucleophilic 1,3-dipolarophile, show that the semiempirical MO scheme models this structure closely. Transition structures for formation of the intermediate and ring closure of the latter are described.     

Annulation reactions of allene-derived 1,3-dipole with 3-substituted-chromones: unusual recognition of 4pi-component in 3-(N-Aryliminomethyl)chromones through

All-carbon dipole derived by the interaction of triphenylphosphine with allenic ester is able to locate the polarized 2pi-component in 3-formylchromones through a regioselective [2 + 3] addition to the C2-C3 pi-bond, which is followed by deformylation leading to novel 3a,9a-dihydro-1-ethoxycarbonyl-1-cyclopenteno[5, 4-b]benzopyran-4-ones. On the contrary, the dipole recognizes azadiene in 3-(N-aryliminomethyl)chromones through [4 + 3] annulation and initially formed adducts undergo tandem rearrangements to afford novel N-aryl-2, 3-dihydro-4-ethoxycarbonylchromano[2,3-b]azepine-6-ones in good yield.     

A novel[2 + 3]cycloaddition reaction: singlet oxygen mediated formation of 1,3-dipole from iminodiacetic acid dimethyl ester and its addition to maleimides

Sensitized photolysis of iminodiacetic acid methyl ester and maleimides follows a [2 + 3] cycloaddition pathway yielding pyrrolidine derivatives. This is similar to the photochemical reaction between C(60) and amines. A series of pyrrolidine derivatives are prepared by the method including multipyrrolidines from bis- and tris-maleimide starting materials. The yields range from 13% to 85%. The reaction is highly stereoselective. All the isolated products have the 1,3-dimethoxycarbonyl groups in the cis configuration. Various sensitizers may be used with slightly different yields. A plausible mechanism is proposed that involves the singlet oxygen abstraction of two alpha hydrogen atoms from the iminodiacetate and formation of a 1,3-dipole with a structure similar to the classical thermally generated 1,3-dipole.     

A new method for the functionalization of [60] fullerene: an unusual 1,3-dipolar cycloaddition pathway leading to a C60 housane derivative

[reaction: see text] A variant of the Huisgen 1,3-dipolar cycloaddition reaction provides a new and convenient functionalization of fullerenes. This method complements the widely used Prato and Bingel-Hirsch reactions. The derived, highly functionalized cyclopentenone and cyclopentenamine fullerene compounds upon hydrolysis are suitable for further functionalization and may serve well in the synthesis of new C60 derivatives possessing uncommon and interesting properties.     

1,3-Dipolar cycloaddition-decarboxylation reactions of an azomethine ylide with isatoic anhydrides: formation of novel benzodiazepinones

A nonstabilized azomethine ylide reacts with a wide range of substituted isatoic anhydrides to afford novel 1,3-benzodiazepin-5-one derivatives, which are generally isolated in high yield. The transformations involve 1,3-dipolar cycloaddition reactions of the ylide with the anhydrides to give transient, and in a representative case spectroscopically observable, oxazolidine intermediates that undergo ring-opening-decarboxylation-ring-closing reaction cascades to yield the 1,3-benzodiazepin-5-one products.     

Density functional study of the relative reactivity in the concerted 1,3‐dipolar cycloaddition of nitrile ylide to disubstituted ethylenes

Density functional theory was used to perform a theoretical evaluation of (E)‐1,2‐disubstituted ethylenes as dipolarophiles for the 1,3‐dipolar cycloaddition reaction. The reactivities of electron‐withdrawing and ‐donating substituted ethylenes were examined by estimating their activation energies. The calculated activation energies predicted that the most reactive species is (E)‐1,2‐C₂H₂(NO)₂, whereas the least reactive is (E)‐2‐butene. Namely, it was demonstrated that 16‐electron 1,3‐dipole reactants with more electropositive substituents in terminal positions and ethylenes that possess more strongly electron‐withdrawing substituents facilitate 1,3‐dipolar cycloaddition reactions. All of the theoretical results can be rationalized using the configuration mixing model. © 2001 John Wiley & Sons, Inc. Int J Quant Chem 83: 318–323, 2001     

An ab initio study of substituent effects in [1,3]-hydrogen shifts

Reports in the literature place the TS for the [1,3]-H shift in propene comparable to or higher in energy than loss of the allylic H. However, [1,3]-H shifts have been repeatedly observed experimentally in enolates. We used GAUSSIAN 98 to examine the origin of this apparent contradiction. We found the first TS for an antarafacial [1,3]-H shift that is clearly lower in energy than simple dissociation of the migrating H. This occurs in the [1,3]-H shift in the acetone enolate. Symmetrical substituents (H, O(-), ethynyl) have TSs with C(2) symmetry, implying that they, and probably most [1,3]-H shift TSs, are antarafacial. Conjugating substituents at C2 lower the energy of [1,3]-H shifts and raise the energy of dissociation by loss of a hydrogen atom from C3, increasing the likelihood of the former type of reaction. Strongly electron-donating and electron-withdrawing substituents are more effective than neutral substituents in lowering the energy requirement of [1,3] shifts. Our best calculations predict that a [1,3]-H shift is lower in energy than dissociation by loss of the H by 27.8 kJ/mol in 2-methyl-1-butene-3-yne, by 36.8 kJ/mol in isoprene, by 55.9 kJ/mol in 2-aminopropene, by 114.5 kJ/mol in the acetone enolate, and by 120.8 kJ/mol in the 1-methylacryloyl cation. Thus, there is a chance of experimental observation of [1,3] shifts in conjugated alkenes and related species.     

An unusual formal migrative cycloaddition of aurone-derived azadienes: synthesis of benzofuran-fused nitrogen heterocycles

Aurone-derived azadienes are well-known four-atom synthons for direct [4 + n] cycloadditions owing to their s-cis conformation as well as the thermodynamically favored aromatization nature of these processes. However, distinct from this common reactivity, herein we report an unusual formal migrative annulation with siloxy alkynes initiated by [2 + 2] cycloaddition. Unexpectedly, this process generates benzofuran-fused nitrogen heterocyclic products with formal substituent migration. This observation is rationalized by less common [2 + 2] cycloaddition followed by 4π and 6π electrocyclic events. DFT calculations provided support to the proposed mechanism.

A HNTf₂-catalyzed formal migrative cycloaddition of aurone-derived azadienes with siloxy alkynes has been developed to provide access to benzofuran-fused dihydropyridines.

Benzofuran is an important scaffold in biologically important natural molecules and therapeutic agents.¹ Among them, benzofuran-fused nitrogen heterocycles are particularly noteworthy owing to their broad spectrum of bioactivities for the treatment of various diseases (Fig. 1).² Consequently, the development of efficient methods for their assembly has been a topic receiving enthusiastic attention from synthetic chemists.³ Notably, aurone-derived azadienes (e.g., 1) have been extensively employed as precursors toward these skeletons owing to their easy availability and versatile reactivity (Scheme 1a).³ The polarized conjugation system, combined with the preexisting s-cis conformation, has enabled them to serve as ideal annulation partners for the synthesis of nitrogen heterocycles of variable ring sizes. Moreover, the aromatization nature of these processes by forming a benzofuran ring provides additional driving force for them to behave as a perfect four-atom synthon for [4 + n] cycloaddition.³ In contrast, the use of such species as a two-atom partner for [2 + n] cycloaddition has been less developed.^3c,k,4 Herein, we report a new migrative annulation leading to benzofuran-fused dihydropyridines of unexpected topology (Scheme 1b, with formal R² migration), which is initiated by the less common [2 + 2] cycloaddition.Open in a separate windowFig. 1Benzofuran-fused N-heterocyclic natural and bioactive molecules.Open in a separate windowScheme 1Synthesis of benzofuran-fused nitrogen heterocycles.Siloxy alkynes are another important family of building blocks in organic synthesis.^5–8 The presence of a highly polarized C–C triple bond enables such molecules to serve as versatile two-carbon cycloaddition partners in various annulation reactions.^5–7 In the above context and in continuation of our interest in the study of such electron-rich alkynes,⁷ we envisioned that the reaction between aurone-derived azadienes 1 and siloxy alkynes 2 should lead to facile electron-inversed [4 + 2] cycloaddition to form benzofuran-fused dihydropyridine products (Scheme 1b). Interestingly, the expected product 3′ from direct [4 + 2] cycloaddition was not observed. Instead, a dihydropyridine product 3 with formal R² migration was observed. Careful analysis of the mechanism suggested that a [2 + 2] cycloaddition followed by 4π and 6π electrocyclic steps might be responsible for this unexpected product topology (vide infra).We began our investigation with the model substrates 1a and 2a, which were easily prepared in one step from aurone and 1-hexyne, respectively.⁸ Various Lewis acids were initially examined as potential catalysts for this cycloaddition (Table 1). Unfortunately, common Lewis acids (e.g., TiCl₄, BF₃·OEt₂, Sc(OTf)₃, In(OTf)₃, and AgOTf) were all ineffective (entries 1–5). Substrate decomposition into an unidentifiable mixture was typically observed. However, further screening indicated that AgNTf₂ served as an effective catalyst, leading to benzofuran-fused dihydropyridine 3a in 44% yield (entry 6). Careful analysis by X-ray crystallography confirmed that it was not formed by simple [4 + 2] cycloaddition, as the positions of the phenyl and the siloxy groups were switched (vs. the expected topology). The distinct catalytic performance of AgNTf₂ (vs. AgOTf) suggested that the triflimide counter anion Tf₂N⁻ might be important. However, further screening of various metal triflimide salts did not improve the reaction efficiency (entry 7). Instead, we were delighted to find that the corresponding Brønsted acid HNTf₂ served as a better catalyst (57% yield, entry 8). However, triflic acid (TfOH) led to no desired product in spite of complete conversion (entry 9). After considerable efforts in the optimization of other reaction parameters, an improved yield of 75% was obtained with 2.5 mol% of HNTf₂ and 2.5 equivalents of 2a at 60 °C (entry 10). Solvent screening indicated that the reaction proceeded faster in DCE with comparable yield (entry 11). However, other solvents were all inferior (entries 12–15). Finally, with a reversed order of addition of the two reactants, the yield was slightly improved (entry 16). We believe that this might be related to the relative decomposition rates of the substrates.Reaction conditions^a