1,3-dipolar cycloaddition reactions of porphyrins with azomethine ylides

[reaction: see text] The behavior of porphyrins as dipolarophiles in 1,3-dipolar cycloadditions with azomethine ylides was studied. Depending on the nature of the substituent groups on the porphyrin macrocycles, the reaction can give monoadducts (chlorins) or bisadducts (isobacteriochlorins and bacteriochlorins). When a large excess of azomethine ylide is used, trisadducts can also be obtained. Mixed isobacteriochlorin derivatives were prepared from the reaction of azomethine ylides with the chlorin monoadducts previously obtained via Diels-Alder reactions.     

Etude DFT du mécanisme des réactions de cycloaddition dipolaire-1,3 de la C,N-diphénylnitrone avec des dipolarophiles fluorés de type éthylénique et acétylénique

Structures and energetics of reactants, transition states and cycloadducts of cycloadditions of nitrone with three-fluorinated dipolarophiles have been investigated with the density functional theory method B3LYP/6-31G^*. Analysis of the results on the different reaction pathways shows that the reaction takes place along a concerted mechanism and proceeds more or less synchronously. The FMO analysis shows a strong HOMO_dipole-LUMO_{dipolarophile} interaction as the principal reason for the reactivity in these 1,3-dipolar cycloaddition reactions. Regioselectivity of the products of the reaction is predicted reliably by our calculations, the results provide a good prediction of the relatives rates observed experimentally as the dipolarophiles are varied.     

Phosphonylated thiocarbonyl ylides from the reaction of aromatic thioketones with diethyl diazomethylphosphonates

The reaction of diazomethylphosphonates with aromatic thioketones at −65 °C to room temperature yields 2,5-dihydro-1,3,4-thiadiazole-2-phosphonates, which eliminates N₂ to give phosphonylated thiocarbonyl ylides as reactive intermediates. These sulfur-centered 1,3-dipoles undergo typical reactions of thiocarbonyl ylides, i.e., 1,3-dipolar cycloadditions, cyclodimerization, and electrocyclic ring closure, depending on the involved thioketone and, therefore, on the reaction conditions. In the case of the most reactive thiofluorenone, the phsophonylated thiocarbonyl methanide can be intercepted with thiobenzophenone, a phosphonodithioformate, and tetracyanoethylene. In the absence of such reactive dipolarophiles, cyclodimerization occurs to give the corresponding 1,4-dithiane.     

(Benzylthio)- und (Arylthio)-substituierte Nitril-ylide: Thermische Erzeugung und Reaktionen

Thermal Generation and Reactions of (Benzylthio)-and (Arylthio)-Substituted Nitrile Ylides Thermolysis of 4-(benzylthio)- and 4-(arylthio)-1,3-oxazol-5(2H)-ones 6 , at 110–155° in the presence of dipolarophiles with activated C≡C, C?C, C?O, C?S, and N?N bonds, led to 5-membered cyclo-adducts and CO² (cf. Schemes 3, 5-7). Heating 6a and 6c in the presence of ethyl propiolate yielded ethyl quinoline-3-carboxylate ( 19 ) and ethyl pyridine-3-carboxylate( 22 ), respectively (cf. Scheme 8). These results are rationalized on the basis of the intermediate formation of thio-substituted nitrile ylides of type 7 (cf. Scheme 2), which undergo regioselective 1,3-dipolar cycloadditions with reactive dipolarophiles. In the absence of such a dipolarophile, the nitrile ylides isomerize via a [1,4]-H shift to give 2-aza-1,3-butadienes of type 20 . The latter are trapped in a Diels-Alder reaction with ethyl propiolate (cf. Scheme 8).     

Role of Water in the Reaction Mechanism and endo/exo Selectivity of 1,3-Dipolar Cycloadditions Elucidated by Quantum Chemistry and Machine Learning

Asymmetric 1,3-dipolar cycloadditions of azomethine ylides with activated olefins are among the most important and versatile methods for the synthesis of enantioenriched pyrroline and pyrrolidine derivatives. Despite both theoretical and practical importance, the role of water molecules in the reactivity and endo/exo selectivity remains unclear. To explore how water accelerates the reactions and improves the endo/exo selectivity of the cycloadditions of 1,3-dipole phthalazinium-2-dicyanomethanide ( 1 ) and two dipolarophiles, an ab initio-quality neural network potential that overcomes the computational bottleneck of explicitly considering water molecules was used. It is demonstrated that not only the nature of both the dipolarophile and the 1,3-dipole, but also the solvent medium, can perturb or even alter the reaction mechanism. An extreme case was found for the reaction of 1,3-dipole 1 with methyl vinyl ketone, in which the reaction mechanism changes from a concerted to a stepwise mode on going from MeCN to H₂O as solvent, with formation of a zwitterionic intermediate that is a very shallow minimum on the energy surface. Thus, high stereocontrol can still be expected despite the stepwise nature of the mechanism. The results indicate that water can induce global polarization along the reaction coordinate and highlight the role of microsolvation effects and bulk-phase effects in reproducing the experimentally observed aqueous acceleration and enhanced endo/exo selectivity.     

Novel syntheses of polysubstituted pyrroles and oxazoles by 1,3‐dipolar cycloaddition reactions of benzotriazole‐stabilized nitrile ylides

1,3‐Dipolar cycloadditions of benzotriazole‐stabilized nitrile ylides with benzyl α,β‐unsaturated‐carboxy‐lates and aldehydes as dipolarophiles proceeded smoothly and efficiently to give polysubstituted pyrroles and oxazoles, respectively, in good yields.     

Cu-Fesulphos complexes: efficient chiral catalysts for asymmetric 1,3-dipolar cycloaddition of azomethine ylides

The Cu^I-Fesulphos catalyst system (≤3 mol %) shows an excellent performance in the asymmetric 1,3-dipolar cycloaddition of azomethine ylides. High to very high levels of reactivity, endo/exo selectivity, and enantioselectivity (69->99% ee) are generally achieved with a very wide range of azomethine ylides and dipolarophiles. Based on experimental and computational studies data, a model that accounts for this high enantiocontrol is proposed.     

Asymmetric 1,3-dipolar cycloadditions of a chiral nonracemic glyoxylic azomethine imine

The reactivity of a chiral nonracemic glyoxylic azomethine imine has been investigated. This species reacts with a wide range of dipolarophiles, with a complete regio- and facial stereoselectivity. The introduction of an electron-withdrawing substituent on the ylide leads to a lower endo selectivity with electron-withdrawing dipolarophiles, but to an improved exo selectivity with styrene derivatives when compared to the reactivity of aliphatic- or aromatic-substituted ylides.     

Selectivity in cycloadditions—-XII : The directive effect of enol ethers and thioenol ethers in cycloadditions of nitrile oxides

Cycloadditions of nitrile oxides to 2,3-dihydrofuran are highly regioselective whereas the regioselectivity of the cycloadditions to 2,3-dihydrothiophen is only moderate. The directing effect of oxygen and sulfur in these cycloadditions could be evaluated at 2.8 and 1.1 Kcal mol^-1 respectively. The related acyclic sulfur dipolarophiles, (E)-propenyl methyl and phenyl sulfides, similarly undergo cycloadditions with moderate regiochemistry.The different regioselectivities and reactivities of the dipolarophiles can be related to differences in energies and shapes of their highest occupied orbitals, which are also responsible for the diverging behaviour observed in the electrophilic reactions and 2 + 2 cycloadditions of enol and thioenol ethers.     

1,3-Dipolar cycloadditions of nonstabilized azomethine ylides to planar chalcones via regio- and stereoselective route: A three-component strategy

Simple and efficient strategies toward the synthesis of trisubstituted pyrrolizidines and disubstituted oxazolidine systems by 1,3-dipolar cycloaddition reactions using arylaldehydes and α-amino acids have been developed, followed by a one-pot, three-component strategy. Electron-deficient dipolarophiles, chalcones, were reacted with nonstabilized azomethine ylides derived from arylaldehyde and L-proline in dry dimethyl formamide, leading to substituted pyrrolizidines. The route to substituted oxazolidines involved cycloaddition to the C?O bond of a second molecule of the aldehyde. The structures and stereochemistry of the cycloadducts were established by infrared (IR), NMR spectroscopy, and single-crystal x-ray crystallographic analyses. Condensed Fukui functions and local electrophilicity indices have been computed to characterize the reactive sites and predict the preferred interactions of azomethine ylides to planar chalcones. The softness-matching indices have been evaluated to determine the regioselectivity of the cycloaddition reactions. The theoretical predictions were found to be in complete agreement with the experimental results, implying that the density functional theory (DFT)-based reactivity indices correctly predict the regioselectivities of 1,3-dipolar cycloadditions of azomethine ylides to planar chalcones. The frontier molecular orbital (FMO) energies, electronic chemical potentials, chemical hardness, chemical softness, and global electrophilicity indices of azomethine ylides have been calculated at the DFT/B3LYP/6-31 + G (d, p) level of theory.     

`Thiobenzophenone S‐Methylide' (=(Diphenylmethylidenesulfonio)methanide), and C,C Multiple Bonds: Cycloadditions and Dipolarophilic Reactivities

Thiobenzophenone and diazomethane afford thiadiazoline 1 at −78°. By elimination of N₂ from 1 at −45° (t_1/2 ca. 1 h), (diphenylmethylidenesulfonio)methanide ( 2 ), which cannot be isolated but is interceptible by dipolarophiles, is set free. The nucleophilic 1,3‐dipole 2 undergoes cycloadditions with electrophilic C,C multiple bonds; the structures of 16 cycloadducts were elucidated. One‐step and two‐step cycloaddition pathways are discussed in the light of the steric course observed for (E)/(Z)‐isomeric ethylene derivatives. Competition experiments with pairs of dipolarophiles at −45° and HPLC analysis of the adducts provided relative rate constants of 26 dipolarophiles, involving 2 C≡C, 13 C=C, 9 C=S, and 2 N=N bonds. In accordance with Sustmann`s reactivity model of concerted cycloadditions, 2 shows the highest selectivity of all known 1,3‐dipoles, i.e., the largest spread of rate constants (k_rel=1 for methyl propiolate and 33×10⁶ for TCNE). As a consequence of low LU energies, thiones are very active dipolarophiles, and fluorene‐9‐thione (k_rel=79×10⁶) stands at the top.     

A new chiral phosphine oxide ligand for enantioselective 1,3-dipolar cycloaddition reactions of azomethine ylides

A new set of phosphorus-containing chiral ligands has been synthesized and used with silver(I) for the catalytic asymmetric 1,3-dipolar cycloaddition reaction of azomethine ylides. One of these ligands (POFAM6) was found to produce an effective catalyst for the asymmetric 1,3-dipolar cycloaddition reaction of azomethine ylides with electron deficient dipolarophiles to form pyrrolidines in up to 97% yield and 89% ee.     

A facile regioselective 1,3-dipolar cycloaddition protocol for the synthesis of new class of quinolinyl dispiro heterocycles

The 1,3-dipolar cycloaddition reaction of azomethine ylides generated in situ from isatin and secondary amino acids with quinolinyl dipolarophiles in refluxing methanol afforded new class of quinolinyl dispiro heterocycles with multi hetero core units. The regio and stereochemistry of the product was unambiguously assigned by ¹H, ¹³C, 2D NMR techniques and single crystal X-ray analysis. The structures of the compounds are stabilized through the presence of intermolecular hydrogen bonding and intramolecular non-covalent interactions.     

Reaction of functionalized azomethine ylides with acetylenic dipolarophiles: the facile synthesis of functionalized 2H- and 1H-pyrroles

The reaction of functionalized azomethine ylides as C-unsubstituted nitrile ylide equivalents with acetylenic dipolarophiles is mentioned. Therein, the initially formed cycloadducts, 2,5-dihydropyrroles, by the reaction of the azomethine ylides with substituted acetylenes, undergo a fission reaction to afford 2H-pyrroles and the parent heterocyclic system. Some 2H-pyrroles isomerized to 1H-pyrroles under both thermal and acidic conditions.     

Discovery of new mutually orthogonal bioorthogonal cycloaddition pairs through computational screening

Density functional theory (DFT) calculations and experiments in tandem led to discoveries of new reactivities and selectivities involving bioorthogonal sydnone cycloadditions. Dibenzocyclooctyne derivatives (DIBAC and BARAC) were identified to be especially reactive dipolarophiles, which undergo the (3 + 2) cycloadditions with N-phenyl sydnone with the rate constant of up to 1.46 M^–1 s^–1. Most significantly, the sydnone-dibenzocyclooctyne and norbornene-tetrazine cycloadditions were predicted to be mutually orthogonal. This was validated experimentally and used for highly selective fluorescence labeling of two proteins simultaneously.     

The first example of the generation of azomethine ylides from a fluorocarbene: 1,3-cyclization and 1,3-dipolar cycloaddition

The reaction of Schiff bases with fluorocarbene, generated by reduction of dibromofluoromethane with active lead in the presence of Bu₄NBr under ultrasound irradiation, involves the formation of fluoro-substituted azomethine ylides which undergo cyclization into aziridines. 1,3-Cyclization of ylides, generated from N-arylimines of benzaldehyde, proceeds stereoselectively. When carrying out the reaction of Schiff bases with fluorocarbene in the presence of dimethyl maleate or dimethyl acetylenedicarboxylate, the products of dehydrofluorination of the primary adducts of the 1,3-dipolar cycloaddition of fluoro-substituted azomethine ylides to multiple bonds of dipolarophiles were obtained. In the case of the reaction of N-alkylimines of benzaldehyde the cycloaddition of ylides to dimethyl maleate completely suppressed the cyclization to aziridines.     

Quantitative characterization of the global electrophilicity pattern of some reagents involved in 1,3-dipolar cycloaddition reactions

The global electrophilicity power, ω, of a series of dipoles and dipolarophiles commonly used in 1,3-dipolar cycloadditions may be conveniently classified within a unique relative scale. The effects of chemical substitution on the electrophilicity of molecules have been evaluated using a representative set of electron-withdrawing and electron-releasing groups for a series of dipoles including nitrone, nitrile oxide and azide derivatives. The absolute scale of electrophilicity is used to rationalize the chemical reactivity of these species as compared to the static reactivity pattern of the reagents involved in the Diels-Alder reactions.     

Synthesis of new calix[4]pyrrole derivatives via 1,3-dipolar cycloadditions

Octamethylcalix[4]pyrrole-2-carbaldehyde 1 and 3-(octamethylcalix[4]pyrrol-2-yl)propenal 5 were used as precursors of azomethine ylides, which were trapped in situ with a range of dipolarophiles, such as 1,4-benzoquinone, 1,4-naphthoquinone, and fumaronitrile. Aldehyde 1 showed very low reactivity but the azomethine ylide generated from the reaction of aldehyde 5 with N-methylglycine could be trapped with those dipolarophiles to afford new β-substituted octamethylcalix[4]pyrrole derivatives in moderate yields. The resulting cycloadducts show high affinity constants for fluoride and acetate anions; compounds 7 and 8 display sharp changes in color in the presence of these anions.     

X=Y-ZH systems as potential 1,3-dipoles. The stereochemistry and regiochemistry of cycloaddition reactions of imines of α-amino-acid esters.

The stereochemistry and regiochemistry of cycloadditions of α-amino acid ester imines is dependent both on imine structure and on the reactivity of the dipolarophile. Phenylglycine imines undergo competing dipole stereomutation and cycloaddition with some dipolarophiles.     

Adamantanethione and diazomethane; A re-examination

The title reaction affords the two regioisomeric cycloadducts which were isolated and differ in their rates of nitrogen extrusion; the spiro-1,3,4-thiadiazoline furnishes the adamantanethione S-methylide which undergoes in situ cycloadditions to electron-deficient dipolarophiles.