Intramolecular Cycloaddition Reaction Research Articles

Allylic Azide Rearrangement in Tandem with Intramolecular Huisgen Cycloaddition for Iminosugar and Glycomimetic Synthesis: Functionalized Piperidine, Pyrrolidine, and Pyrrolotriazoles from d-Mannose

Intramolecular Huisgen azide-alkene cycloaddition reaction of 7-azido-hepta-1,5-diene-3,4-diols, prepared from methyl α-<sc>d</sc>-man­no­pyranoside, were carried out. Allylic azide rearrangement to secondary azides occurred in tandem with triazoline formation and this intermediate was then decomposed in the presence of nucleophilic reagents to give pyrrolidines, piperidines, or azepanes depending on whether cyclic constraint was incorporated or not, on diol stereochemistry and on the nucleophile. The tandem reaction worked best when aziridine formation from the triazoline was efficient, and this efficiency improved on removal of cyclic constraint. Proposals to account for the observed diastereoselectivities are provided. The allylic azide rearrangement in tandem with the intramolecular Huisgen azide-alkyne cycloaddition was also investigated from azidoheptaenyne diols and gave dihydropyrrolotriazoles. All reactions were diastereoselective, and this was high in some cases. Two X-ray crystal structural determinations, ¹³C NMR data, and 1D and 2D NOESY experiments were used for stereochemical assignments.

Intramolecular Nitrone Cycloaddition of α-(Trifluoromethyl)styrenes. Role of the CF3 Group in the Regioselectivity.

The intramolecular 1,3-dipolar cycloaddition of ortho-substituted 1,1,1-trifluoromethylstyrene-derived nitrones is described. Tricyclic fused isoxazolidines were obtained as major or exclusive products, in contrast to the case for nonfluorinated substrates, which rendered the bridged derivatives. This change in the regioselectivity was attributed to the electronic and, particularly, steric requirements of the trifluoromethyl group in comparison to the methyl group. It is worth mentioning that trifluoromethylstyrenes have been employed for the first time as dipolarophiles in a 1,3-dipolar intramolecular cycloaddition reaction, leading to the corresponding isoxazolidines bearing a quaternary trifluoromethyl moiety. Finally, the synthetic utility of the developed methodology has been illustrated with the synthesis of a family of bicyclic fluorinated 1,3-amino alcohols.

Click and Release: SO2 Prodrugs with Tunable Release Rates.

Employing an intramolecular cycloaddition reaction, we have developed a series of SO2 prodrugs with tunable release rates with half-lives ranging from minutes to days.

Synthesis of tetrazole fused azepanes and quantum chemical topology study on the mechanism of the intramolecular cycloaddition reaction

Syntheses of novel tetrazolo azepanes by intramolecular 1,3-dipolar cycloaddition are described. Cyclization mechanistic topology study showed a pseudo concerted mechanism.

Polycyclic Ring Formation Using Bis-diazolactams for Cascade Stitching.

The chemoselective reaction of donor/acceptor (D/A) and acceptor/acceptor (A/A) diazo moieties in the same molecule was examined using 3-diazo-1-(ethyl 2-diazomalonyl)indolin-2-one under rhodium(II) catalysis. The metallo carbenoid derived from the D/A diazo group is preferentially formed and undergoes selective CH, NH, and OH insertion reactions, cyclopropanation, cyclopropenation, sulfur ylide formation/2,3-sigmatropic rearrangement, as well as nitrogen ylide formation followed by azetidine ring expansion. The initial reaction can be paired with a subsequent tandem cascade sequence involving dipole formation/cycloaddition in either an intra- or intermolecular sense to generate polycyclic N-heterocycles in one pot, with the formation up to three new rings in a single operation. Excellent diastereoselectivity was observed in the intramolecular cycloaddition reaction producing 5 to 7-membered rings.

Biomimetic Total Synthesis of the Pentacyclic Amaryllidaceae Alkaloid Derivative Gracilamine

The illustrated azomethine ylide, produced through a Schiff base condensation of the corresponding aldehyde-containing C3a-arylhexahydroindole with ethyl l-leucinate, engages in a stereoselective intramolecular cycloaddition reaction to give adduct 23 that has been elaborated, over eight steps, into the racemic modification of the alkaloid derivative gracilamine (1). The formation of this ylide and its conversion into isomer 23 mimics the proposed biogenesis of the pentacyclic framework of compound 1.

ChemInform Abstract: A Simple and Efficient Intramolecular 1,3‐Dipolar Azidoalkyne Cycloaddition: Synthesis of 6‐Perfluoroalkylated Fused exo‐Bicyclic 1,2,3‐Triazolo‐1,4‐oxazines.

Abstract The synthesis of new 6-perfluoroalkylated 1,2,3-triazolo-1,4-oxazine ethers and thioethers as fused exo -heterobicyclic compounds was achieved from terminal perfluoroalkyl oxiranes by azide ion ring opening and propargylation reactions followed by a quick and spontaneous 1,3-dipolar intramolecular cycloaddition reaction.

Unified Approach to Pyrazole-Fused Heterocyclic and Carbocyclic Motifs through One-Pot Condensation and Intramolecular Dipolar Cycloaddition Reaction

A one-pot synthesis of highly substituted pyrazoles that are fused to dihydrochromenes, dihydroquinolines and cyclopentane motifs, from readily available precursors is reported. The reaction involves conversion of alkyne-tethered aldehydes into the corresponding tosylhydrazones, base-mediated generation of diazo compounds, and subsequent intramolecular dipolar cycloaddition reaction. A range of internal and terminal alkynes as well as bromoalkyne compounds can be employed as the tethered dipolarophile to afford the corresponding cycloadducts.

Tandem Knoevenagel Condensation and Intramolecular Cycloaddition Reactions of 2-Azidobenzaldehydes with 2-Cyanoacetamides in the Synthesis of 4-Thiocarbamoyltetrazolo-[1,5-a]Quinolines

The reaction of 2-azidobenzaldehydes with 2-thioamides of cyanoacetic acid proceeds without a solvent and base at 80–90°C selectively by one of the possible routes to form tetrazolo[1,5-a]quinolines. The proposed mechanism of the reaction involves the Knoevenagel condensation and subsequent intramolecular [3+2] cycloaddition of the azide group at the C≡N bond of an intermediate acrylonitrile.

An Efficient Synthesis of Benzazocines by Gold(I)-Catalyzed Tandem 1,2-Acyloxy Shift/[3+2] Cycloaddition of Terminal 1,9-Enynyl Esters.

An effective synthesis of structurally diverse benzazocines was accomplished in good to excellent chemical yields (55-82 %) through a gold(I)-catalyzed cascade reaction involving tandem 1,2-acyloxy shift/[3+2] cycloaddition of terminal 1,9-enynyl esters. The reaction proceeds under extremely mild conditions and represents one of the relatively few transition-metal-catalyzed intramolecular cycloaddition reactions for the synthesis of benzazocines.

Synthetic studies on the application of the intramolecular azide-alkene 1,3-dipolar cycloaddition reaction in the construction of the core structure of complex alkaloids

Synthesis of the core skeletons of the polycyclic alkaloids lycopodine and porantherine has been accomplished employing as a key step an Intramolecular Azide-Olefin Cycloaddition reaction (IAOC)/enamine addition/Mannich cascade reaction. Applying this methodology, the first synthesis of C15-desmethyl lycopodine has been developed.

A simple and efficient intramolecular 1,3-dipolar azidoalkyne cycloaddition: Synthesis of 6-perfluoroalkylated fused exo -bicyclic 1,2,3-triazolo-1,4-oxazines

Abstract The synthesis of new 6-perfluoroalkylated 1,2,3-triazolo-1,4-oxazine ethers and thioethers as fused exo -heterobicyclic compounds was achieved from terminal perfluoroalkyl oxiranes by azide ion ring opening and propargylation reactions followed by a quick and spontaneous 1,3-dipolar intramolecular cycloaddition reaction.

Asymmetric Diels–Alder reaction between 3,4-dimethyl-1-phenylphosphole and (Z/E)-diphenyl-1-styrylphosphine

The organopalladium complex containing ortho-metalated (S)-[1-(dimethylamino)ethyl]naphthalene as the chiral auxiliary has been successfully employed to promote the asymmetric Diels–Alder reaction between 3,4-dimethyl-1-phenylphosphole and (Z)-diphenyl-1-styrylphosphine or (E)-diphenyl-1-styrylphosphine. In the intramolecular cycloaddition reaction between (E)-diphenyl-1-styrylphosphine and 3,4-dimethyl-1-phenylphosphole, a pair of diastereomeric endo-cycloadducts were obtained in the ratio of 1:1. However, the asymmetric reaction between (Z)-diphenyl-1-styrylphosphine and 3,4-dimethyl-1-phenylphosphole also produced the same endo-product in the same stereoselectivity unexpectedly. The chiral naphthylamine auxiliary could be removed chemoselectively from the template by treatment with concentrated hydrochloric acid to generate the neutral stable dichloro complex [(P–P)PdCl2]. Treatment of the dichloro complex with KCN gave the pure bis-phosphine ligand in quantitative yield.

Photoassisted Diversity-Oriented Synthesis: Intramolecular Cycloadditions of Photogenerated Azaxylylenes with Oxazole Pendants, and Subsequent Postphotochemical Multicomponent Modifications.

Photogenerated aza-o-xylylenes undergo intramolecular cycloaddition reactions to tethered oxazoles, with primary photoproducts featuring a reactive cyclic imine moiety suitable for multicomponent postphotochemical transformations. For example, the reaction of these imine photoproducts with bromoacetyl bromide leads to a key 1,4-dielectrophilic synthon, offering access to diverse polyheterocyclic molecular architectures. This reaction sequence is accompanied by rapid growth complexity in a very few simple synthetic steps, and is in keeping with the philosophy of diversity-oriented synthesis (DOS).

Ab initio study of the influence of resonance stabilization on intramolecular ring closure reactions of hydrocarbon radicals.

The intramolecular ring closure reactions of unsaturated hydrocarbon radicals potentially play an important role for the formation of molecular weight growth species, especially during the pyrolysis and oxidation of alkenes under low to intermediate temperatures. In this work we investigated a series of intramolecular cycloaddition reactions of both allylic- and alkyl-type dienyl radicals. In the first set of reactions, a resonant linear radical is converted into a non-resonant cyclic radical. In the second set, a non-resonant linear alkenyl radical isomerizes to either a resonant cyclic radical or a cyclic carbinyl radical. In both cases, three different reaction schemes are examined based on the location of the partially-formed resonance structure in the cyclic transition state. For each reaction scheme, both the endo- and exo-pathways were investigated. High pressure rate parameters are obtained from the results of CBS-QB3 electronic structure calculations combined with canonical transition state theory calculations. The results are discussed in the context of a Benson-type model to examine the impact of the partially-formed resonance stabilization on both the activation energies and pre-exponential factors. The results are compared to previously reported rate parameters for cycloaddition reactions of alkenyl radicals. The differences in the activation energies are primarily due to the bimolecular component of the activation energy. However, in some cases, the presence of the partial resonance structure significantly increases the strain energy for the ring that is formed in the transition state. The pre-exponential factors are also impacted by the formation of a partial resonance structure in the transition state. Lastly, the C6H9 potential energy surface is examined to show how the trends that are outlined here can be used to estimate rate parameters, which are needed to analyze pressure-dependent reaction systems.

Intramolecular heterocyclization of O-propargylated aromatic hydroxyaldehydes as an expedient route to substituted chromenopyridines under metal-free conditions.

A concise and regioselective approach to the synthesis of chromenopyridine and chromenopyridinone derivatives was developed. The synthetic strategy relies on the O-propargylation of aromatic hydroxyaldehydes followed by reaction with propargylamine. The intramolecular cycloaddition reaction between the alkyne and azadiene, which is formed as an intermediate, furnished the desired skeletons.

ChemInform Abstract: Halogen Effect on Tandem [4 + 2] Cycloaddition/Aromatization Sequence of Allenyl 2‐Halo‐3‐vinylcyclohex‐2‐enyl Ether.

Abstract Steric and enthalpic effects of substituents on diene moieties play a crucial role in intramolecular cycloaddition reactions. Allenyl 2-halogenated-3-vinylcyclohex-2-enyl ethers underwent a tandem [4+2] cycloaddition/aromatization reaction to afford the corresponding tetrahydro- 3H -naphtho[1,8- bc ]furan compound in high yield.

A Rapid and Stereocontrolled Synthesis of the Zizaane Ring System by Using an Intramolecular (4+3) Cycloaddition Reaction

We report herein a very short synthetic approach to the tricyclo[6.2.1.01,5]undecane scaffold through a convergent and stereocontrolled route by using an intramolecular (4+3) cycloaddition of a simple furfuryl alcohol precursor with a pendant cyclopentadiene moiety. The formation of alternative reaction products under various conditions is also discussed.

Gold‐Catalyzed 1,2‐Acyloxy Migration/Intramolecular [3+2] 1,3‐Dipolar Cycloaddtion Cascade Reaction: An Efficient Strategy for Syntheses of Medium‐Sized‐Ring Ethers and Amines

AbstractA highly efficient strategy for the formation of medium‐sized‐ring ethers and amines based on a gold‐catalyzed cascade reaction, involving enynyl ester isomerization and intramolecular [3+2] cyclization, has been developed. Various multisubstituted medium‐sized‐ring unsaturated ethers and amines were obtained through this transformation. This method represents one of the relatively few transition metal catalyzed intramolecular cycloaddition reactions for medium‐sized ring synthesis.

Gold-catalyzed 1,2-acyloxy migration/intramolecular [3+2] 1,3-dipolar cycloaddtion cascade reaction: an efficient strategy for syntheses of medium-sized-ring ethers and amines.

A highly efficient strategy for the formation of medium-sized-ring ethers and amines based on a gold-catalyzed cascade reaction, involving enynyl ester isomerization and intramolecular [3+2] cyclization, has been developed. Various multisubstituted medium-sized-ring unsaturated ethers and amines were obtained through this transformation. This method represents one of the relatively few transition metal catalyzed intramolecular cycloaddition reactions for medium-sized ring synthesis.