Oxide Cycloaddition Reactions Research Articles

Visible-light-induced [3+3] cycloaddition reaction of phenol and hydrazone to access 1,3,4-oxadiazines scaffolds

In this study, we present a novel photocatalytic-mediated approach for facilitating the [3 + 3] oxidative cycloaddition reaction of phenols and hydrazones. By utilizing visible light irradiation, this reaction is executed in an efficient, mild, and eco-friendly manner, without requiring any oxidants or additives. The versatility of this method is evidenced by the successful synthesis of 1,3,4-oxadiazine derivatives with various substituents in satisfactory yields. Furthermore, the possible mechanism for the reaction is elucidated through controlled experiments and density functional theory calculations (DFT).

PIDA Mediated Synthesis of Benzopyranoisoxazoles via an Intramolecular Nitrile Oxide Cycloaddition (INOC): Application to the Synthesis 4H‐chromeno[4,3‐c]isoxazol‐4‐ones.

AbstractPresented herein is an approach for the synthesis of highly substituted tricyclic benzopyranoisoxazoles from the corresponding aldoximes via an intramolecular nitrile oxide cycloaddition (INOC) reaction using a hypervalent iodine reagent (Diacetoxyiodo)benzene (PIDA/DIB/(PhI(OAc)2) as the single inexpensive oxidizing agent. The key step involved in this reaction is a sequential intramolecular C−C and C−O bond formation. A variety of benzopyranoisoxazoles were constructed in moderate to high yields. In addition, some of the benzopyranoisoxazoles were converted to 4H‐chromeno[4,3‐c]isoxazol‐4‐ones via allylic oxidation using CrO3 as an oxidant.

Oxidative Cycloaddition Reactions of Arylboron Reagents via a One-pot Formal Dehydroboration Sequence.

Arylboron compounds are widely available and synthetically useful reagents in which the boron group is typically substituted. Herein, we show that the boron group and ortho-hydrogen atom are substituted in a formal cycloaddition reaction. This transformation is enabled by a one-pot sequence involving diaryliodonium and aryne intermediates. The scope of arylboron reagents and arynophiles is demonstrated, and the method is applied to the formal synthesis of an investigational drug candidate.

Aerobic Oxidative Cycloaddition Reactions for Pyrazole Synthesis

Key words aerobic cycloaddition - pyrazoles - copper - regioselectivity

Design of Amine-Modified Zr-Mg Mixed Oxide Aerogel Nanoarchitectonics with Dual Lewis Acidic and Basic Sites for CO2/Propylene Oxide Cycloaddition Reactions.

The utilization of CO2 attracts much research attention because of global warming. The CO2/epoxide cycloaddition reaction is one technique of CO2 utilization. However, homogeneous catalysts with both Lewis acidic and basic and toxic solvents, such as DMF, are needed in the CO2/epoxide cycloaddition reaction. As a result, this study focuses on the development of heterogeneous catalysts with both Lewis acidic and basic sites for the CO2 utilization of the CO2/epoxide cycloaddition reactions without the addition of a DMF toxic solvent. For the first time, the Zr–Mg mixed oxide aerogels with Lewis acidic and basic sites are synthesized for the CO2/propylene oxide (PO) cycloaddition reactions. To further increase the basic sites, 3-Aminopropyl trimethoxysilane (APTMS) with -NH2 functional group is successfully grafted on the Zr–Mg mixed oxide aerogels. The results indicate that the highest yield of propylene carbonate (PC) is 93.1% using the as-developed APTMS-modified Zr–Mg mixed oxide aerogels. The as-prepared APTMS-modified Zr–Mg mixed oxide aerogels are great potential in industrial plants for CO2 reduction in the future.

Efficient Catalytic Synthesis of Condensed Isoxazole Derivatives via Intramolecular Oxidative Cycloaddition of Aldoximes.

The intramolecular oxidative cycloaddition reaction of alkyne- or alkene-tethered aldoximes was catalyzed efficiently by hypervalent iodine(III) species to afford the corresponding polycyclic isoxazole derivatives in up to a 94% yield. The structure of the prepared products was confirmed by various methods, including X-ray crystallography. Mechanistic study demonstrated the crucial role of hydroxy(aryl)iodonium tosylate as a precatalyst, which is generated from 2-iodobenzoic acid and m-chloroperoxybenzoic acid in the presence of a catalytic amount of p-toluenesulfonic acid.

α,β-Unsaturated β-Methyl-δ-lactones in Nitrile Oxide Cycloaddition Reactions. Synthesis of Saturated Lactones and Lactams

α,β-Unsaturated β-Methyl-δ-lactones in Nitrile Oxide Cycloaddition Reactions. Synthesis of Saturated Lactones and Lactams

Diacetate Naphthoquinone Derivatives Tethered to 1,2,3-Triazoles: Synthesis and Cytotoxicity Evaluation in Caco-2 Cells

Acetylated compounds prepared from naphthoquinones have been reported as antitumoral prodrugs. Exploring the synthetic versatility of the naphthoquinone and triazolic nuclei, herein we report a simple and efficient synthetic route to prepare a series of sixteen prodrugs prototype of 1,2,3-triazoles-naphthoquinodoic acetyl derivatives. The compounds 10a-10h and 11a-11h were obtained by oxidative cycloaddition reaction between lawsone and 4-vinyl-1H-1,2,3-triazoles promoted by ceric ammonium nitrate (CAN) in alkaline medium followed by reductive acetylation of the quinones in excess of metallic zinc and acetic anhydride in yields up to > 98%. All derivatives revealed to be hemocompatible and the compound 11e exhibited the most promising profile against Caco-2 cells showing the higher selectivity index. Molecular docking suggests that these compounds could exert their cytotoxic activity through inhibition of one topoisomerase II isoform, at least.

Convenient Synthesis of Pyrazolo[4',3':5,6]pyrano[4,3-c][1,2]oxazoles via Intramolecular Nitrile Oxide Cycloaddition.

A simple and efficient synthetic route to the novel 3a,4-dihydro-3H,7H- and 4H,7H-pyrazolo[4′,3′:5,6]pyrano[4,3-c][1,2]oxazole ring systems from 3-(prop-2-en-1-yloxy)- or 3-(prop-2-yn-1-yloxy)-1H-pyrazole-4-carbaldehyde oximes has been developed by employing the intramolecular nitrile oxide cycloaddition (INOC) reaction as the key step. The configuration of intermediate aldoximes was unambiguously determined using NOESY experimental data and comparison of the magnitudes of 1JCH coupling constants of the iminyl moiety, which were greater by approximately 13 Hz for the predominant syn isomer. The structures of the obtained heterocyclic products were confirmed by detailed 1H, 13C and 15N NMR spectroscopic experiments and HRMS measurements.

D-Ring modification of steroids: synthesis of isoxazole annulated steroids from des D-formyl alkyne via 1,3-dipolar cycloaddition reaction

The reaction of 17,17-dichloro-androst-16(E)-chloromethylene with secondary amine base afforded substitution products of exocyclic D-ring ketones, in contrast to the reaction of alkaline base which cleaved steroidal D-ring to des-D formyl alkyne. The des-D formyl alkyne was employed to prepare D-ring annulated isoxazolo steroid via 1,3-dipolar nitrile oxide cycloaddition reaction.

The multifunctional design of metal–organic framework by applying linker desymmetrization strategy: synergistic catalysis for high CO2-epoxide conversion

A novel copper-organic framework was synthesized by a linker desymmetrization strategy. Synergistic catalysis with Lewis and Brønsted acid sites promoted a high catalytic efficiency towards the CO2-propylene oxide cycloaddition reaction.

Application of Conjugated Carbonyls in the Synthesis of Heterocycles via Oxidative Cycloaddition and Cyclization Reactions

AbstractSynthesis of pharmaceutically active heterocycles is always appealing as the majority of the widely used drugs contain heterocyclic moieties as their core structure. So, the straightforward construction of heterocycles from readily available/accessible reagents is one of the prime targets of the synthetic chemists. In this context, C−H functionalization has emerged as an effective tool for the designing and synthesis of various heterocyclic moieties as it offers a straight‐forward and step‐economic pathway. On the other hand, the readily available/accessible conjugated carbonyls are well‐known reagents for the construction of carbocycles and heterocycles over the years. However, the employment of C−H functionalization of the two C−H bonds of the conjugated alkene in carbocycle/heterocycle synthesis was not so explored. In the last decade, much focus has been paid on the synthesis of various pharmaceutically active heterocycles through C−H bond functionalization of α,β‐unsaturated aldehydes/ketones. These protocols have been developed through either oxidative coupling of conjugated carbonyls with suitable coupling partners or intramolecular C−H bond functionalization of conjugated carbonyls. In this review, we will discuss all the methodologies developed for the synthesis of heterocycles employing intermolecular C−H bond functionalization of conjugated carbonyls. The mechanistic pathways and usefulness of the methodologies will be also highlighted.magnified image

Synthesis and Antitubercular Activity of 4,5‐Disubstituted N1‐(5′‐deoxythymidin‐5′‐yl)‐1,2,3‐triazoles

AbstractSynthesis of fifteen C4‐aroyl‐C5‐aryl‐N1‐(5′‐deoxythymidin‐5′‐yl)‐1,2,3‐triazoles have been reported starting from azidation of 5′‐p‐toluenesulfonyloxythymidine followed by azide‐alkene oxidative cycloaddition reaction of the resulted 5′‐azido‐5′‐deoxythymidine with 1,3‐diarylpropenones in dimethylformamide (DMF) in the presence of tetra‐n‐butylammonium hydrogen sulfate (n‐Bu4N+HSO4−, TBAHS) as catalyst in 60 to 79% overall yields. Further, they were also synthesized by one pot sequential reaction of tosylated thymidine with sodium azide in DMF and then with 1,3‐diarylpropenones in presence of n‐Bu4N+HSO4− in superior yield of 70 to 95% than 60 to 79% in two step procedure. All fifteen synthesized compounds were screened for their in vitro anti Mycobacterium tuberculosis activity against sensitive reference strain H37Rv and multi drug resistant (MDR) clinical isolate 591, and found to exhibit minimum inhibitory concentration (MIC) ranging from 2 to 15 μg/mL, which was equivalent to the MIC of first line anti‐tubercular drug streptomycin. All compounds qualify for their drug likeness when their physicochemical parameters were assessed using online MolSoft and Lipinski filter software, except their molecular weight. The cytotoxicity of potent compounds evaluated human monocytic cell line THP‐1 by 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyl‐2H‐tetrazolium bromide (MTT) assay was found to be less as compared to the first line drug, isoniazid.

Nitrile oxide cycloaddition reactions of alkenes or alkynes and nitroalkanes substituted with O-alkyloxime groups convertible to various functional groups

Nitrile oxides, which are easily generated in situ from widely available nitroalkanes, can be used to directly access 2-isoxazoline heterocycles through 1,3-dipolar cycloaddition reactions with alkenes. These heterocycles are not only useful core fragments in pharmaceutical and agricultural chemistry, but also valuable building blocks convertible to multifunctional groups, such as β-hydroxy ketones. Herein, we have developed nitrile oxide cycloaddition reactions between nitrile oxides derived from O-alkyloxime-substituted nitroalkanes and various alkenes. This methodology can be applied to construct 2-isoxazolines possessing electron-withdrawing groups, which are difficult to access using the conventional approach.

Synthesis of Oxazoline and Oxazole Derivatives by Hypervalent-Iodine-Mediated Oxidative Cycloaddition Reactions

Organohypervalent iodine reagents are widely used for the preparation of various oxazolines, oxazoles, isoxazolines, and isoxazoles. In the formation of these heterocyclic compounds, hypervalent iodine species can serve as the activating reagents for various substrates, as well as the heteroatom donor reagents. In recent research, both chemical and electrochemical approaches toward generation of hypervalent iodine species have been utilized. The in situ generated active species can react with appropriate substrates to give the corresponding heterocyclic products. In this short review, we summarize the hypervalent-iodine­-mediated preparation of oxazolines, oxazoles, isoxazolines, and isoxazoles starting from various substrates.1 Introduction2 Synthesis of Oxazolines3 Synthesis of Oxazoles4 Synthesis of Isoxazolines5 Synthesis of Isoxazoles6 Conclusion

Amine-oxide hybrid materials in combination with cobalt for the catalyzed cycloaddition of carbon dioxide and propylene oxide

Amine-oxide materials synthesized starting from small silica particles and porous silica in combination with polyethyleneimine have been prepared by co-condensation. The materials showing different surface areas and porosity were attained for M2 and M3 with low and high surface areas, respectively. In the new porous materials prepared CO2 adsorption capacity is enhanced at higher temperatures. The morphology of the resulting hybrid material influences the catalytic performance of salphenic cobalt catalysts in the CO2/propylene oxide coupling reactions. Depending on the catalytic reaction conditions (catalyst, cocatalyst, CO2 pressure and reaction temperature), high yields of the CO2/propylene oxide-cycloaddition reaction is favored over the copolymerization reaction.

Carbene‐Catalyzed Formal [3+3] Cycloaddition Reaction for Access to Substituted 2‐Phenylbenzothiazoles

A carbene‐catalyzed oxidative cycloaddition reaction is developed for efficient access to multi‐functionalized 2‐phenylbenzothiazoles. A broad scope of heavily substituted arenes bearing 2‐benzothiazole groups have been prepared in good to excellent yields. The remote C(sp2)–H bond in the substituted arene products can be activated by Pd catalysts in regio‐selective fashion with the direction of the 2‐benzothiazole groups.

A new scalable synthesis of entecavir

A new synthesis of entecavir from d-glucose in an average total yield of 3.5% was achieved via an intramolecular nitrile oxide cycloaddition (INOC) reaction and a Peterson olefination as key-steps. The present process was designed for industrial application, using widely available raw materials, simple and cheap reagents and avoiding low reaction temperatures, which are very common in the synthetic approaches towards similarly complex structures.

Bifunctional ZIF-78 heterogeneous catalyst with dual Lewis acidic and basic sites for carbon dioxide fixation via cyclic carbonate synthesis

Zeolitic imidazole framework-78 (ZIF-78) hexagonal prisms, a combination of Zn metal and imidazolate linkers, were successfully synthesized using a facile hydrothermal process. The as-prepared ZIF-78 hexagonal prisms possessed a bifunctional property with dual Lewis acidic (Zn atom) and basic sites (-NH groups of the imidazolate linkers). This bifunctional property allowed the ZIF-78 crystals to be a potential heterogeneous catalyst in the CO2/propylene oxide (PO) cycloaddition reaction for the synthesis of propylene carbonate (PC). To the best of our knowledge, this is the first work to use microporous ZIF-78 crystals as a catalyst for the CO2/PO cycloaddition reaction without the addition of any co-catalyst or solvent. The effects of reaction temperature, pressure and reaction time on the PO conversion, PC selectivity and yield were also investigated in this work. The highest PC yield of 54% was obtained at a reaction temperature of 150°C, pressure of 10kg/cm2 and reaction time of 15h. Moreover, a possible mechanism of the cycloaddition reaction was also proposed in this study.

Nitrile oxide cycloaddition to 4-hydroxy-2-cyclopentenone: Solvent effect and selectivity

The facial selectivity in the nitrile oxide cycloaddition reactions of 4-hydroxy-2-cyclopentenone and its bulky t-butyloxy derivative is reported. A quantitative evaluation of the solvent effect on the hydrogen bonding directing ability is given, showing the presence of some syn-stereoselectivity even in good H-bond acceptor solvents. The stereoselectivities of the O-t-butyl derivative may serve as reference data for more complex systems and point to the existence of a sole steric effect on the directivity; M(II) ions did not significantly improve the selectivity. The results are also discussed in light of the potential application of these scaffolds in the nucleoside analogue synthesis.