Cycloaddition Of Alkenes Research Articles

Synthesis of 5-(Fluoroalkyl)isoxazole Building Blocks by Regioselective Reactions of Functionalized Halogenoximes.

A comprehensive study on the synthesis of 5-fluoroalkyl-substituted isoxazoles starting from functionalized halogenoximes is reported. One-pot metal-free [3 + 2] cycloaddition of CF3-substituted alkenes and halogenoximes bearing ester, bromo, chloromethyl, and protected amino groups was developed for the preparation of 5-trifluoromethylisoxazoles. The target 3,5-disubstituted derivatives were obtained in a regioselective manner in good to excellent yield on up to 130 g scale. 5-Fluoromethyl- and 5-difluoromethylisoxazoles were synthesized by late-stage deoxofluorination of the corresponding 5-hydroxymethyl or 5-formyl derivatives, respectively, in turn prepared via metal-free cycloaddition of halogenoximes and propargylic alcohol. An alternative approach based on nucleophilic substitution in 5-bromomethyl derivatives was found to be more convenient for the preparation of 5-fluoromethylisoxazoles. Reaction of isoxazole-5-carbaldehydes with the Ruppert-Prakash reagent was used for the preparation of (β,β,β-trifluoro-α-hydroxyethyl)isoxazoles. Utility of described approaches was shown by multigram preparation of side-chain functionalized mono-, di-, and trifluoromethylisoxazoles, for example, fluorinated analogues of ABT-418 and ESI-09.

M. Kevin Brown.

"The best advice I have ever been given is 'Don't listen to everyone else's advice!' My favorite quote is 'Simplicity is the ultimate sophistication' …" Find out more about M. Kevin Brown in his Author Profile.

Visible-Light-Triggered Selective Intermolecular [2+2] Cycloaddition of Extended Enones: 2-Oxo-3-enoates and 2,4-Dien-1-ones with Olefins.

Photosensitization has recently re-emerged owing to the current interest in visible-light catalysis. One of the photoreactions investigated in this context, namely, photo[2+2]cycloaddition of olefins, is established to show high selectivity and wide generality. Here, we describe the results of our studies on selective intermolecular cycloaddition between extended enones (2,4-dien-1-ones and 2-oxo-3-enoates) and olefins under visible-light sensitization. With Ru(bpy)3Cl2 as the triplet energy sensitizer, [2+2] addition of 2,4-dien-1-ones to olefins resulted in the addition to the "ene" part of enones with high efficiency. Generality and functional group tolerance were established by examining a number of enones. 2-Oxo-3-enoates also underwent addition to olefins in the presence of Ru(phen)3(PF6)2. Both additions were more efficient in the presence of the triplet sensitizer than upon direct irradiation. No Paternò-Büchi product was detected. Density functional theory calculations revealed the origin of high selectivity in the two extended enone systems. Together with spectroscopic studies and control experiments, the cycloaddition has been demonstrated to occur from the excited triplet state of these extended enones, which were generated via the energy transfer process.

Synthesis of 3-Acyl-isoxazoles and Δ2-Isoxazolines from Methyl Ketones, Alkynes or Alkenes, and tert-Butyl Nitrite via a Csp3-H Radical Functionalization/Cycloaddition Cascade.

A novel metal-free tandem Csp3-H bond functionalization of ketones and 1,3-dipolar cycloaddition has been developed. An efficient approach to a variety of oxazole and isoxazoline derivatives is demonstrated using the 1,3-dipolar cycloaddition of alkynes and alkenes to nitrile oxides generated by reactions of methyl ketones with tert-butyl nitrite. This new protocol provides access to a variety of isoxazolines with diverse functionalities. An isoxazole generated in this way was found to have significant antifungal activity.

Scalable Sonochemical Synthetic Strategy for Pyrazolo[1,5-a]pyridine Derivatives: First Catalyst-Free Concerted [3 + 2] Cycloaddition of Alkyne and Alkene Derivatives to 2-Imino-1H-pyridin-1-amines.

A highly efficient and convenient one-pot sonochemical synthetic strategy has been sophisticated for synthesizing a novel class of polysubstituted pyrazolo[1,5-a]pyridines via [3 + 2] cycloaddition of dialkyl acetylenedicarboxylates, ethyl propiolate, and alkenes to 2-imino-1H-pyridin-1-amines under catalyst-free conditions. A series of uniquely substituted pyrazolo[1,5-a]pyridines has been synthesized with a very good to excellent yield, and the mechanistic pathway that involves a [3 + 2] annulation process was also proposed. In this study, several spectroscopic tools of analyses were employed for structure elucidation, and the X-ray single-crystal technique was utilized to confirm the proposed mechanism and the regioselectivity.

High-Performance Jet Fuels Derived from Bio-Based Alkenes by Iron-Catalyzed [2+2] Cycloaddition.

A series of high-performance cycloparaffinic fuels have been generated by [2+2] cycloaddition of the bio-derived alkenes 1-hexene, isoprene, and 1-pentene, catalyzed by a low-valent iron pyridine(diimine) complex [(Me PDI)Fe(N2 )2 (μ-N2 )] [Me PDI=N,N'-(2,6-pyridinediyldiethylidyne)bis(2,6-dimethylbenzenamine)]. Reactions with 1-pentene and 1-hexene resulted in 85 % selectivity to 1,2-cyclobutanes, and 12 % selectivity to acyclic alkenes generated by β-hydride elimination. Self-dimerization of isoprene was sluggish and generated heavier oligomer products, but cross-dimerization of isoprene with 1-hexene afforded primarily a 1,3-cyclobutane product, along with isomers of acyclic C11 mixed dimers. Hydrocarbon mixtures were hydrogenated and fractionally distilled to yield finished fuel mixtures in overall yields of 83-93 % at the multigram scale. The fuels exhibited densities ranging between 0.767 and 0.783 g mL-1 , and net heats of combustion (NHOC) of up to 120.6 kBtu gal-1 (43.8 MJ kg-1 ). These values are higher than conventional synthetic paraffinic kerosenes owing to the higher density and ring strain afforded by the cyclobutane rings. The fuel mixtures also exhibited extremely low viscosities ranging from 2.38 to 4.78 mm2 s-1 at -20 °C, due in part to the presence of the acyclic dimers. The excellent fuel properties of the product mixtures, selectivity for dimer products, high yields, and the ability to use simple bio-derived alkenes as substrates, make the [Fe]-catalyzed [2+2] cycloaddition of unactivated alkenes a compelling route to the synthesis of sustainable high-performance fuels.

KOAc-Catalyzed One-Pot Three-Component 1,3-Dipolar Cycloaddition of α-Diazo Compounds, Nitrosoarenes, and Alkenes: An Approach to Functionalized Isoxazolidines.

A direct, highly efficient KOAc-catalyzed one-pot three-component approach for the preparation of various functionalized isoxazolidines via the 1,3-dipolar cycloaddition reactions of readily accessible diazo compounds, nitrosoarenes, and alkenes has been reported. The cheap and readily available catalyst and starting materials, excellent functional group compatibility, wide substrate scope, high yields, and excellent chemo-, regio-, and diastereoselectivities make this protocol an attractive alternative.

Asymmetric [3+2] Cycloaddition of Olefins with Morita–Baylis–Hillman Carbonates Catalyzed by BINOL-Based Bifunctional Phosphine

We have developed a series of novel BINOL-based phosphines. These bifunctional organocatalysts can be used in the [3+2] cycloaddition of electron-deficient olefins and Morita–Baylis–Hillman (MBH) carbonates. Moderate to excellent yields (up to >99%) and good to excellent enantioselectivities (up to 95% ee) can be obtained in the cycloaddition reaction of maleimides and MBH carbonates. The application of these novel phosphines can be further extended to the asymmetric synthesis of chiral spirooxindoles (up to 85% ee). The results in this study indicate that the BINOL moiety plays an important role in stereocontrol.

Regioselective synthesis of 1,5-disubstituted 1,2,3-triazoles by 1,3-dipolar cycloaddition: Role of Er(OTf)3, ionic liquid and water

A simple procedure to obtain 1,5-disubstituted 1,2,3-triazoles, using the Er(OTf)3/[mpy]OTf/H2O catalytic system is described. The reaction proceeds through an eliminative azide–olefin cycloaddition (EAOC) offering a highly regioselective approach and good yields (81–94%). The advantages of this method include simple operations of work-up and the ability of the catalytic system to be re-used five times without an evident loss in yield. The role of IL and water were speculated, invoking also a probable ionic self-assembly (ISA) effect.

Catalytic asymmetric cycloaddition of unsymmetrical EWG-activated alkenes to fully substituted pyrrolidines bearing three different carbonyl groups.

A unique 1,3-dipolar [3+2] cycloaddition of alkyl 4-oxo-4-arylbut-2-enoates bearing two different electron-withdrawing groups was completed by using the silver/(R)-DTBM-Segphos catalyst system, which gives the corresponding fully substituted pyrrolidines with four stereogenic centers in good yields and with excellent enantioselectivities (up to 98% ee).

In Situ Generation of Nitrile Oxides from NaCl-Oxone Oxidation of Various Aldoximes and Their 1,3-Dipolar Cycloaddition.

Reported is a new green protocol for the efficient in situ generation of nitrile oxides through NaCl/Oxone oxidation of aldoximes and their dipolar cycloaddition. The key feature is the use of a green chemistry approach to address the substrate scope of aldoximes: broad scope (aliphatic, aromatic, and alkenyl aldoximes) without production of organic byproducts derived from oxidant and/or catalyst. Importantly, NaCl/Oxone-promoted three-component cycloaddition of aldehyde, hydroxylamine hydrochloride, and alkene was demonstrated to be competent (63-81%).

A new route to synthesis of substituted pyrazoles through oxidative [3+2] cycloaddition of electron deficient alkenes and diazocarbonyl compounds

A collection of 3,5-disubstituted pyrazoles are constructed by the oxidative [3+2] cycloaddition of electron deficient terminal olefins with α-diazoesters and amides in the presence of Oxone and cetyltrimethyl ammonium bromide. The highlights of this protocol are; (i) shorter reaction time (ii) moderate to excellent yield (iii) good regioselectivity.

Excellent Performances of Dealuminated H-Beta Zeolites from Organotemplate-Free Synthesis in Conversion of Biomass-derived 2,5-Dimethylfuran to Renewable p-Xylene.

Direct synthesis of renewable p-xylene (PX) by cycloaddition of biomass-derived 2,5-dimethylfuran (2,5-DMF) and ethylene was achieved over Al-rich H-beta zeolites synthesized by an organotemplate-free approach and their dealuminated counterparts with different Si/Al ratios. Among them, H-beta zeolite with an Si/Al ratio of 22, obtained from an Al-rich parent by dealumination, was found to be an excellent catalyst for the synthesis of PX. A PX yield of 97 % and 2,5-DMF conversion of 99 % were obtained under optimized conditions. These results are even better than those of a commercial H-beta zeolite prepared using a organotemplate synthesis with a similar Si/Al ratio of 19. The excellent performance of the H-beta zeolite with Si/Al ratio of 22 is closely related to its acidity and porous structure. A moderate Brønsted/Lewis acid ratio can improve the conversion of 2,5-DMF to as high as 99 %. Furthermore, dealuminated H-beta zeolite has a secondary pore system that facilitates product diffusion, which increases the selectivity to PX. In addition, this catalyst shows better regeneration. After five successive regeneration cycles, the yield of PX was still as high as 85 % without obvious dealumination. This work provides a deeper understanding of the more general Diels-Alder cycloaddition of furan-based feedstocks and olefins and significantly improves the potential for the synthesis of chemicals from lignocellulosic biomass.

Synthesis of 1,5-Functionalized 1,2,3-Triazoles Using Ionic Liquid/Iron(III) Chloride as an Efficient and Reusable Homogeneous Catalyst

An efficient, eco-compatible, and very cheap method for the construction of triazoles via eliminative azide–olefin cycloaddition (EAOC) reaction has been developed by a catalytic system, IL/FeCl3, offering a highly regioselective approach to structurally diverse 1,5-disubstituted 1,2,3-triazoles in up to 95% yield. This strategy features the reuse of a catalytic system through simple operations. Mechanistic studies indicated that an asynchronous concerted dipolar cycloaddition–elimination process might be involved.

Enantioselective Palladium-Catalyzed [3C + 2C] and [4C + 3C] Intramolecular Cycloadditions of Alkylidenecyclopropanes

We report a highly enantioselective [3C + 2C] intramolecular cycloaddition of alkylidenecyclopropanes (ACPs) and alkenes. The best results are obtained by using sterically demanding chiral phosphoramidite ligands derived from Vapol. Moreover, we also show that related, but less bulky, phosphoramidites can also lead to very effective [4C + 3C] cycloadditions when dienes, instead of alkenes, are used as reacting partners. The reactions provide a practical, simple, and selective access to optically active, synthetically appealing 5,5- and 5,7-bicyclic systems.

Synthesis of (−)‐Hebelophyllene E: An Entry to Geminal Dimethyl‐Cyclobutanes by [2+2] Cycloaddition of Alkenes and Allenoates

AbstractThe first synthesis of hebelophyllene E is presented, along with assignment of its previously unknown relative configuration through synthesis of epi‐ent‐hebelophyllene E. Development of a catalytic enantioselective [2+2] cycloaddition of alkenes and allenoates provides access to the required chiral geminal dimethylcyclobutanes. Key to its success is the identification of a novel oxazaborolidine catalyst which promotes the cycloaddition in high enantioselectivities with good functional‐group tolerance (9 examples, up to 97:3 e.r.). Thus, a late‐stage cycloaddition using a fully functionalized alkene, followed by a diastereoselective reduction allows a concise entry to this class of natural products.

Synthesis of (-)-Hebelophyllene E: An Entry to Geminal Dimethyl-Cyclobutanes by [2+2] Cycloaddition of Alkenes and Allenoates.

The first synthesis of hebelophyllene E is presented, along with assignment of its previously unknown relative configuration through synthesis of epi-ent-hebelophyllene E. Development of a catalytic enantioselective [2+2] cycloaddition of alkenes and allenoates provides access to the required chiral geminal dimethylcyclobutanes. Key to its success is the identification of a novel oxazaborolidine catalyst which promotes the cycloaddition in high enantioselectivities with good functional-group tolerance (9 examples, up to 97:3 e.r.). Thus, a late-stage cycloaddition using a fully functionalized alkene, followed by a diastereoselective reduction allows a concise entry to this class of natural products.

Diastereo- and Enantioselective Formal [3 + 2] Cycloaddition of Cyclopropyl Ketones and Alkenes via Ti-Catalyzed Radical Redox Relay.

We report a stereoselective formal [3 + 2] cycloaddition of cyclopropyl ketones and radical-acceptor alkenes to form polysubstituted cyclopentane derivatives. Catalyzed by a chiral Ti(salen) complex, the cycloaddition occurs via a radical redox-relay mechanism and constructs two C-C bonds and two contiguous stereogenic centers with generally excellent diastereo- and enantioselectivity.

Catalytic asymmetric synthesis of pyrrolidine derivatives bearing heteroatom-substituted quaternary stereocenters

An enantioselective [3 + 2] cycloaddition of heteroatom-substituted alkenes with α-substituted isocyanoacetates has been developed. Excellent reactivity and enantioselectivity were obtained.

Enantioselective Indium(I)/Chiral Phosphoric Acid-catalyzed[4+2] Cycloaddition of Simple Olefin and β,γ-Unsaturated α-Keto Esters

Enantioselective Indium(I)/Chiral Phosphoric Acid-catalyzed[4+2] Cycloaddition of Simple Olefin and <i>β,γ</i>-Unsaturated <i>α</i>-Keto Esters