Catalytic enantioselective 1,3-dipolar cycloaddition reactions of cyclic nitrones: a simple approach for the formation of optically active isoquinoline derivatives

The first highly diastereo- and enantioselective catalytic 1, 3-dipolar cycloaddition reaction of cyclic nitrones activated by chiral Lewis acids with electron-rich alkenes has been developed. The nitrones, mainly 3,4-dihydroisoquinoline N-oxides, are activated by chiral 3,3'-aryl BINOL-AlMe complexes and undergo a regio-, diastereo-, and enantioselective 1,3-dipolar cycloaddition reaction with especially alkyl vinyl ethers, giving the exo diastereomer of the cycloaddition products in high yield, >90% de and up to 85% ee. The reaction has been investigated under various conditions, and it is demonstrated that the reaction is an attractive synthetic procedure for the introduction of a chiral center in the 1-position of the isoquinoline skeleton. The mechanism of the reaction is discussed on the basis of the assignment of the absolute configuration of the cycloaddition product and theoretical calculations.     

Efficient synthesis of isoxazolidine-tethered monolayer-protected gold nanoparticles (MPGNs) via 1,3-dipolar cycloadditions under high-pressure conditions

A maleimide-modified 2.5 +/- 0.5 nm mixed monolayer protected gold nanoparticle (2-C(12)MPGN) containing approximately 30% maleimide-terminated dodecanethiolate/dodecanethiolate ligands was prepared. The 2-C(12)MPGN was reacted with a series of nitrones (a-i) at both atmospheric and hyperbaric (11 000 atm) conditions to form the corresponding isoxazolidine-modified nanoparticles (3-C(12)MPGN) via an interfacial 1,3-dipolar cycloaddition. At atmospheric pressures, the reaction proceeds slowly (if at all) and makes this reaction impractical for the synthetic modification of the nanoparticles. However, by performing the reaction under the high-pressure conditions, the reaction proceeds efficiently and quantitatively. TEM shows that the use of high pressure does not affect the size of the gold nanoparticle core. The 3-C(12)MPGNs were characterized by (1)H NMR spectroscopy by comparing the spectra obtained with those of model reactions utilizing N-dodecylmaleimide (4) with the same nitrones (a-i) to form 5. Additionally, the cycloaddition reaction also occurs more readily with 4 than with 2-C(12)MPGN with all nitrones, indicating that the environment of the latter affects the cycloaddition reaction.     

Synthesis of 5-Fluoroalkyl Isoxazolidines via 1,3-Dipolar Cycloaddition of Ethyl 2-Hydropolyfluoroalk-2-enoates with Nitrones

1,3-Dipolar cycloaddition reactions of ethyl 2-hydropolyfluoroalk-2-enoates (1) with some nitrones were described. The reaction of 3,4-dihydroisoquinoline N-oxide (2) with 1 took place readily in methylene chloride at room temperature to give the corresponding 5-fluoroalkylisoxazolidines regioselectively as a mixture of two diastereoisomers (trans and cis) in high yields, while longer reaction time and higher temperature were needed in the case of non-cyclic nitrones. Under similar conditions the reaction of quinoline N-oxide (14) with 1 did not give the expected adducts and a ring-opening product was obtained.     

Microwave Induced 1,3-Depolar Cycloaddition Reactions of Nitrones

1,3-Dipolar cycloaddition reactions involving unreactive nitrones have been carried out successfully under microwave irradiations. The reaction of nitrones 1 and alkene 2 proceeded regiospecifically at atmospheric pressure and the corresponding isoxazolidines 3 were obtained in high yields.     

Asymmetric “Acetylenic” [3+2] Cycloaddition of Nitrones Catalyzed by Cationic Chiral PdII Lewis Acid

Highly enantioselective [3+2] cycloaddition of ynones and nitrones has been developed. Very bulky ligand, DTBM‐SEGPHOS, was used for an effective asymmetric induction over distal reaction centers on the linear ynone dipolarophile and for prevention of Pd^II catalyst deactivation by coordination of the nitrones. The reaction has wide scope of substrates in both ynones and nitrones.     

Kinetic and thermodynamic aspects in the 1,3-dipolar cycloaddition of five-membered cyclic nitrones to α,β-unsaturated γ- and δ-lactones

The 1,3-dipolar cycloaddition of five-membered ring nitrones to the α,β-unsaturated δ-lactones is kinetically controlled, whereas the same reactions involving γ-lactones, upon heating and prolonged reaction times, display visible reversibility of the reaction and as the consequence, the formation of the more stable, thermodynamic products can be observed. Owing to this and to the high stereoselectivity of the cycloaddition, δ-lactones can be used for kinetic resolution of racemic nitrones whereas γ-ones cannot. In addition the reversibility of the cycloaddition, as well as racemization of 5-substituted 2-(5H)-furanones (γ-lactones), complicates the composition of the post-reaction mixtures and may lead to the formation of partially racemic adducts. The possible asymmetric transformation of cycloaddition involving γ-lactones, which eventually provide the most stable thermodynamic products in high yield, cannot be performed due to the low stability of cyclic nitrones which undergo decomposition.     

The formal [4+3] cycloaddition between donor-acceptor cyclobutanes and nitrones

The formal [4+3] cycloaddition of 2-alkoxy-1,1-dicarboxylate activated donor-acceptor cyclobutanes with nitrones is disclosed. The reaction forms structurally unique oxazepines in moderate to high yield with a wide scope of nitrones. In most cases either a diastereomeric mixture or a single diastereomer may be formed, depending on the reaction conditions.     

Copper(I)-Catalyzed Highly Enantioselective [3+3]-Cycloaddition of β-Aryl/Alkyl Vinyl Diazoacetates with Nitrones

β-Aryl/alkyl vinyl diazoacetates were investigated in metallo-vinylcarbene reactions with nitrones, revealing a Rh₂(OAc)₄-catalyzed cyclopropene dimerization reaction and a copper(I) catalyzed [3+3]-cycloaddition of nitrones. The chiral cyclopropyl-In-SaBox ligand with copper(I) catalysis could realize the asymmetric version of the cycloaddition reaction, delivering various 3,6-dihydro-1,2-oxazine derivatives in good yield and with excellent enantioselectivity under mild conditions.     

Catalytic enantioselective 1,3-dipolar cycloadditions of nitrones with propioloylpyrazoles and acryloylpyrazoles induced by chiral π-cation catalysts

A chiral copper(II) complex of 3-(2-naphthyl)-l-alanine amide successfully catalyzes the enantioselective 1,3-dipolar cycloaddition reaction of nitrones with propioloylpyrazole and acryloylpyrazole derivatives. The asymmetric environment created by intramolecular π-cation interaction gives the corresponding adducts in high yields with excellent enantioselectivity. This is the first successful method for the catalytic enantioselective 1,3-dipolar cycloaddition of nitrones with acetylene derivatives. The 1,3-dipolar cycloadducts can be stereoselectively converted to β-lactams via reductive cleavage of the N-O bond using SmI(2).     

A general synthesis of N-vinyl nitrones

A general synthesis of a new type of heterodiene, the N-vinyl nitrone, is described. The synthetic sequence begins with the conjugate addition of benzeneselenol to nitroalkenes (in turn derived from Henry reaction of an aldehyde and a nitroalkane) to provide 2-selenenylnitroalkenes. These selenonitroalkanes are reduced to the corresponding hydroxylamines which are combined with aldehydes to form nitrones. The phenylselenenyl-containing nitrones are then oxidized to selenoxides which undergo syn-selenoxide elimination to provide N-vinyl nitrones. Three X-ray crystal structures of substituted N-vinyl nitrones were obtained. In addition, the first [4+2] cycloaddition of an N-vinyl nitrone is reported.     

Organocatalysis "on water". Regioselective [3 + 2]-cycloaddition of nitrones and allenolates

The first example of a regioselective and organocatalyzed 1,3-dipolar cycloaddition reaction between conjugated alkynoates and nitrones "on water" is described.     

A Weinreb nitrile oxide and nitrone for cycloaddition

[reaction: see text] The cycloaddition of Weinreb amide functionalized nitrile oxide/nitrones with a range of dipolarophiles has been explored.     

苯炔与硝酮[3+2]环加成制备二取代苯并异噁唑烷

采用[3 2]1,3-偶极环加成反应,苯炔前体邻-三甲硅基苯酚三氟甲磺酸酯在氟化铯的作用下与硝酮反应合成了9个2,3-二取代苯并[d]异噁唑烷,收率87%～97%。其结构经1H NMR,13C NMR和高分辨率MS确证。     

Catalyst-Free Regio- and Diastereoselective Synthesis of Heterocyclic Nucleosides in the Eco-friendly Solvent 2-Methyltetrahydrofuran†

An efficient and practical synthesis of heterocyclic nucleosides is developed by a catalyst-free highly regioselective and diastereoselective [3+2] annulation of α-purine-substituted acrylates with nitrones. The reaction operates with excellent functional group tolerance, very mild reaction conditions, and with the green, sustainable, and eco-friendly 2-methyltetrahydrofuran (2-MeTHF) as solvent. Compared with other reactions of electron-deficient olefin dipolarophiles with nitrones, different regioselective cycloaddition products were observed in this work. This 1,3-dipolar cycloaddition reaction gives a series of isoxazolidinyl nucleosides in good to excellent yields with promising applications in biochemistry and medicinal chemistry.      

Anionic inverse electron-demand 1,3-dipolar cycloaddition of nitrones with ynolates. Facile stereoselective synthesis of 5-isoxazolidinones leading to beta-amino acids

[reaction: see text] The inverse electron-demand 1,3-dipolar cycloaddition of nitrones with ynolates, followed by quenching with t-BuOH, produced substituted 5-isoxazolidinones with good trans-selectivity. These products were easily converted into beta-amino acids.     

Synthesis of benzisoxazolines by the coupling of arynes with nitrones

A variety of substituted benzisoxazolines have been synthesized by the [3 + 2] cycloaddition of nitrones and arynes. The reaction scope is broad, the reaction conditions are mild, and the process tolerates a variety of functional groups.     

Unusual Cycloadducts from the Dipolar Cycloaddition of Allenyl Perfluoroalkyl Sulfones to Nitrones

The dipolar cycloaddition reaction of allenyl perfluoroalkyl sulfones （1） to nitrones （2） was described. Unlike nonfluorine-containing allenyl sulfones, 1 reacted readily with 2 in ether at room temperatttre and unusual zwitterionic cycloadducts （3） were obtained in good yields due to the strong electron-withdrawing effect of perfluoroalkyl groups. The structure of 3 was characterized by spectral analyses and X-ray crystallography.     

A DFT study on the 1,3-dipolar cycloaddition reactions of C-(hetaryl) nitrones with methyl acrylate and vinyl acetate

The 1,3-dipolar cycloaddition of C-(hetaryl) nitrones with electron-poor and electron-rich alkenes is rationalized. The energetics of the cycloaddition reactions have been investigated through molecular orbital calculations at the B3LYP/6-31-G(d) theory level. By studying different reaction channels and reagent conformations the regio- and stereochemical preferences of the reaction are discussed.     

SYNTHESIS,CHARACTERIZATION, AND BIOLOGICAL STUDIES OF NOVEL ISOXAZOLIDINES: 1,3-DIPOLAR CYCLOADDITION REACTIONS

ABSTRACT

1,3-Dipolar cycloaddition reaction of nitrones to olefins is of synthetic interest. In the present work, isoxazolidines have been synthesized in high yield via intermolecular cycloaddition of N-arylnitrone with monosubstituted olefins and are employed for biological evaluation.     

The model of 1,3-dipolar cycloaddition reaction of 4,5-dihydro-1H-imidazole 3-oxide derivatives with alkynes

The influence of solvents and different structural factors on the rate of 1,3-dipolar cycloaddition reaction of the 4,5-dihydro-1H-imidazole 3-oxide derivatives with alkynes have been studied. Nitrones and alkynes have been ranged by their relative activity in this reaction. Using the DFT calculation with the triple zets basis set, the energy profile of the reaction has been plotted, and the structures and energy characteristics of the transition states have been determined. The mechanism of this reaction has been shown to be concerted and asynchronous. The validity of the used computational approach for the detailed investigation of 1,3-dipolar cycloaddition of nitrones has been demonstrated.