1,3-Dipolar cycloadditions of prop-1-ene-1,3-sultone with nitrile oxides/nitrones

The scope and limitations of dipolar cycloaddition reactions between nitrile oxides/nitrones and prop-1-ene-1,3-sultone have been investigated. A remarkably high degree of regioselectivity and stereoselectivity was observed. The homochiral sultam 8e was synthesized in a four-step reaction sequence starting from the substituted isoxazoline 4e obtained from the cycloaddition. The absolute stereochemistry of this material was assigned by an X-ray crystallographic investigation of the intermediate 7e.     

An MEDT study of the mechanism and selectivities of the [3+2] cycloaddition reaction of tomentosin with benzonitrile oxide

The [3+2] cycloaddition (32CA) reaction of tomentosin with benzonitrile oxide yielding a spiro-isoxazoline has been studied within the Molecular Electron Density Theory at the B3LYP/6-31(d,p) computational level. Given the multifunctionality of tomentosin, this 32CA reaction can take place along 16 competitive reaction paths. The chemo-, regio-, and stereoisomeric reaction paths involving the two C C double bonds of tomentosin have been studied. Density functional theory (DFT) calculations account for the total chemo- and regioselectivity, in complete agreement with the experimental outcomes, being suggestive of low diastereofacial selectivity. Analysis of the conceptual DFT indices accounts for the nonpolar character of this 32CA reaction. On the other hand, the topological analysis of the electron localization function of the selected points of the intrinsic reaction coordinate associated with the formation of the C C and C O single bonds emphasizes the zw-type reactivity of the phenyl nitrile oxide; the reaction taking place through a non-concerted two-stage one-step mechanism initialized with the formation of the C C single bond involving the β-conjugated carbon of tomentosin.     

[3 + 2] Cycloaddition of nitrile oxides to dichloropropenes and 1,3-dichlorobut-2-ene: A regioselectivity issue

The reaction of nitrile oxides with 2,3-dichloroprop-1-ene, 1,3-dichloroprop-1-ene, and 1,3-dichlorobut-2-ene leads to 5-(chloromethyl)isoxazoles, 4-(chloromethyl)isoxazoles, or to mixtures of both regioisomers. The direction of cycloaddition and reactivity of substrate is determined by the steric hindrance at the terminal carbon atom of the alkene double bond. It has been found that the isomeric products of cycloaddition of nitrile oxides to 1,3-dichloropropene have significantly different dehydrochlorination capabilities. The experimental data on the regioselectivity of cycloaddition and the relative reactivity of substrates are in agreement with the results of quantum chemical calculations.     

Selectivity in cycloadditions—X : Regiochemistry of cycloadditions of nitrile oxides to thiophene and benzothiophene 1,1-dioxides

Thiophene-1,1-dioxide undergoes regioselective cycloaddition to benzonitrile oxide. In the reaction with the less reactive mesitonitrile oxide the sulfur dioxide deriving from the dimerization of the dipolarophile causes a catalytic decomposition of the nitrile oxide, which competes with the cycloaddition. Benzothiophene-1,1-dioxide and the vinyl sulfone system of 2,3-dihydrothiophene-1,1-dioxide and nitrile oxides with lower regioselectivity. The directing effect of the sulfonyl group has been elucidated with the aid of CNDO/2 calculations.     

Electrophilic Vinylation of Thiols under Mild and Transition Metal-Free Conditions

The iodine(III) reagents vinylbenziodoxolones (VBX) were employed to vinylate a series of aliphatic and aromatic thiols, providing E-alkenyl sulfides with complete chemo- and regioselectivity, as well as excellent stereoselectivity. The methodology displays high functional group tolerance and proceeds under mild and transition metal-free conditions without the need for excess substrate or reagents. Mercaptothiazoles could be vinylated under modified conditions, resulting in opposite stereoselectivity compared to previous reactions with vinyliodonium salts. Novel VBX reagents with substituted benziodoxolone cores were prepared, and improved reactivity was discovered with a dimethyl-substituted core.     

Ab initio and DFT studies on the mechanism of the 1,3-dipolar cycloaddition reaction between nitrone and sulfonylethene chloride

The molecular mechanism for the 1,3-dipolar cycloaddition of nitrone with sulfonylethene chlorides has been studied using ab initio and DFT methods at the HF, MP2 and B3LYP levels together with the 6-31G* basis set. Relative rates, stereo and regioselectivity, have been analysed and discussed. For this cycloaddition four reactive channels associated with the formation of two pairs of diastereoisomeric regioisomers have been characterized. Analysis of the geometries of the corresponding transition structures shows that the cycloaddition takes place along a concerted but asynchronous mechanism. Activation energies as asynchronicity are dependent on the computation level. Thus, while HF calculations gave large barriers, MP2 calculations tend to underestimate them. DFT calculations gave reasonable values. These 1,3-dipolar cycloadditions present an endo stereoselectivity while the meta regioselectivity depends on the computational level. Thus, while HF and DFT calculations predict meta path, in agreement with the experimental results, MP2 calculation predict ortho regioselectivity. The frontier molecular orbitals analysis shows that the reaction is controlled by the (HOMO_dipole–LUMO_{dipolarophile}) interaction in agreement with the charge transfer analysis carried out at the transition structures. Inclusion of diffuse functions at the B3LYP/6-31+G* level increases the energy barriers about 4 kcal/mol, giving a similar endo/meta selectivity. Solvent effects have been taken into account, by means of self-consistent reaction field.     

Nickel-catalyzed dehydrogenative [4 + 2] cycloaddition of 1,3-dienes with nitriles

Pyridines, which comprise one of the most important classes of the six-membered heterocyclic compounds, are widely distributed in nature, and the transition-metal-catalyzed [2 + 2 + 2] cycloaddition reaction of two alkynes and a nitrile is one of the most powerful methods for preparing versatile, highly substituted pyridine derivatives. However, the lack of chemo- and regioselectivity is still a crucial issue associated with fully intermolecular [2 + 2 + 2] cycloaddition. The present study developed the Ni(0)-catalyzed intermolecular dehydrogenative [4 + 2] cycloaddition reaction of 1,3-butadienes with nitriles to give a variety of pyridines regioselectively.     

Stereoselectivity, periselectivity, and regioselectivity in the cycloadditions of 8-(p-chlorophenyl)-8-azaheptafulvene with cyclopentadiene and fulvenes

The stereoselectivity, periselectivity, and regioselectivity in the cycloaddition reactions of 8-(p-chlorophenyl)-8-azaheptafulvene with cyclopentadiene and symmetrical/unsymmetrical fulvenes is described.     

Stereochemistry modulates the catalytic hydrogenolysis of nitrile-substituted cyclopropanes

The study of Raney-Ni catalyzed chemo- and regioselective hydrogenolysis of diastereomeric nitrile-substituted spirocyclopropyloxindoles is presented. The chemoselectivity outcome of the reaction is remarkably influenced by the relative stereochemistry of the nitrile-substituted spirocyclopropyloxindoles. Chemo- and high regioselective cyclopropane ring-opening occurs from the syn diastereomers to give the corresponding 3-propylacetamide derivatives. X-ray crystallographic studies together with DFT model chemistry calculations indicate that chemo- and regioselectivity are directly dependent on the bond length asymmetry of the cyclopropane ring.     

Cyclization cascade of allenyl azides: a dual mechanism

A density functional theory based computational approach to describing the mechanistic course of the allene azide cycloaddition cascade sequence has been developed. The results of these calculations permit characterization of key reactive intermediates (diradicals and/or indolidenes) and explain the different behaviors observed in the experimental studies between conjugated and nonconjugated species. Furthermore, computational analysis of certain intermediates offer insight into issues of regioselectivity and stereoselectivity in cases where different reaction channels are in competition, suggesting suitable substitutions to achieve a single regioisomer in the indole synthesis via azide-allene cyclization.     

1,3-Dipolar cycloaddition approach to isoxazole, isoxazoline and isoxazolidine analogues of C-nucleosides related to pseudouridine

Isoxazole, isoxazoline and isoxazolidine analogues of C-nucleosides related to pseudouridine have been synthesized by 1,3-dipolar cycloaddition reactions of nitrile oxides and nitrones derived from mono and disubstituted uracil-5-carbaldehydes and 2,4-dimethoxypyrimidine-5-carbaldehyde. The dimethoxy derivatives have been easily deprotected to the corresponding uracils bearing the heterocyclic ring instead of a sugar moiety. The regio and stereoselectivity of the reactions are discussed.     

Synthesis and regiochemistry of spiro indane-1,3-dione compounds

Spiro indane-1,3-dione compounds have been synthesized by 1,3-dipolar cycloaddition of ninhydrin, l-proline, and an alkene (either a chalcone or an (E)-??-arylnitrostyrene). All these reactions proceed with good yield and with high regioselectivity and stereoselectivity. The structures were studied by NMR spectroscopy, MS, and X-ray diffraction analysis. It was found that these two kinds of alkene lead to different regioselectivity. This study has provided information about the regioselectivity of 1,3-dipolar cycloaddition reactions: regioselectivity may be controlled by ?ШC?? stacking state; the order of stability of stacking of the Ar and EWG part with the indane-1,3-dione part is: benzoyl group?>?phenyl group?>?nitro group.     

1,3-偶极环加成合成新型双螺异噁唑啉类化合物

双芳亚甲基环酮与睛氧化物进行l,3-偶极环加成反应,合成了15个新的双螺异噁唑啉类化合物. 采用元素分析、NMR、IR以及X射线单晶衍射等多种谱学技术对产物进行详细表征, 而产物的晶体结构表明了此类反应具有高度的区域选择性, 而密度泛函计算结果合理地解释了实验结果.     

Stereocontrolled intramolecular nitrile oxide cycloaddition reaction using a gauche-gauche interaction

A gauche-gauche interaction is proposed as a powerful controlling factor for the stereochemistry in the intramolecular nitrile oxide cycloaddition reaction derived from N-protected 3-(N-allylamino)propionaldehyde and 2-(N-homoallylamino)acetaldehyde oximes. High levels of stereoselectivity (76% de to perfect) were obtained from the reaction involving nitrile oxides with substituents at the adjacent carbon atom to the tether nitrogen.     

Atropisomerism-induced facial selectivity in nitrile oxide cycloadditions with 5-methylenehydantoins

N-Aryl 5-methylenehydantoins underwent nitrile oxide cycloaddition with benzonitrile oxide to give 5-spiro isoxazoline adducts with complete regioselectivity. Atropisomerism around the N-aryl bond also led to facial selectivity in these cycloadditions.     

Understanding the role of the Lewis acid catalyst on the 1,3-dipolar cycloaddition of N-benzylideneaniline N-oxide with acrolein: a DFT study

The Lewis acid (LA) catalyzed 1,3-dipolar cycloaddition of N-benzylideneaniline N-oxide with acrolein has been studied using DFT calculations. Coordination of AlCl₃ to the acrolein oxygen atom produces a drastic change in the mechanism along the more favorable meta reactive channel. The process is characterized by a strong nucleophile/electrophile interaction allowing the formation of a zwitterionic intermediate, a Michael-type addition. The subsequent ring closure constitutes the rate-determining step. The energies obtained with the inclusion of solvent effect by means of the polarizable continuum model are in good agreement with experimental findings. Analysis of the global and local electrophilicity allows to explain correctly the reactivity and regioselectivity of the LA catalyzed cycloaddition.     

1,3-Dipolar cycloaddition of nitrile oxides to (R)-1-(1-phenylethyl)-3-[(E)-arylmethylidene]tetrahydro-4(1H)-pyridinones: synthesis of enantiomerically pure spiro heterocycles

The 1,3-dipolar cycloaddition of (R)-1-(1-phenylethyl)-3-[(E)-arylmethylidene]tetrahydro-4(1H)-pyridinones to nitrile oxides proceeds chemo-, regio-, and stereoselectively affording moderate yields of enantiomerically pure spiro heterocycles comprising piperidine and isoxazoline/dioxazole rings.     

Reaction mechanism and chemoselectivity of gold(Ⅰ)-catalyzed cycloaddition of 1-(1-alkynyl) cyclopropyl ketones with nucleophiles to yield substituted furans

The mechanisms of gold(Ⅰ)-catalyzed cycloaddition of 1-(1-alkynyl) cyclopropyl ketones with nucleophiles have been investigated using density functional theory calculations at the B3LYP/6-31G(d,p) level of theory.A polarizable continuum model(PCM) has been established in order to evaluate the effects of solvents on the reactions.The results of the calculations indicate that the first step of the catalytic cycle is the cyclization of the carbonyl oxygen onto the triple bond which forms a new and stable resonance structure of an oxonium ion and a carbocation intermediate.The subsequent ring expansion step results in the formation of the final product and regeneration of the catalyst.Furthermore,the regioselectivity and effect of substituents has been discussed,including an analysis of energy,bond length,and natural bond orbital(NBO) charge distributions in the rate-determining step.Our computational results are consistent with earlier experimental observations.     

Mechanism of 1,3-dipolar cycloaddition reactions of indan-1-one enamines with aryl nitrile oxide: a DFT analysis

The mechanism (regioselectivity) of [3+2] cycloaddition reaction of indan-1-one enamines (1ad–1ce) with aryl nitrile oxide (2) has been investigated by density functional theory-based reactivity indices and activation energy calculations at B3LYP/6-31G(d) level of theory in the gas phase. Thermodynamic and kinetic parameters of the possible 3-regio/4-regio regioisomeric pathways have been determined. In all cases, the 3-regio pathways are more favorable compared to the 4-regio alternatives. Our results show that these cycloadditions follow an asynchronous one-step mechanism with a nonpolar character. Theoretical data are in good agreement with the experimental results.