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Quinazolinone and isoxazoline systems have attracted much attention due to their interesting pharmacological properties. The association of these two pharmacophores in a single hybrid structure can boost the biological activity or bring a new one. Inspired by this new paradigm, in the present work we report the synthesis and spectroscopic characterization of new quinazolinone–isoxazoline hybrids. The target compounds were obtained via 1,3-dipolar cycloaddition reactions of arylnitriloxides and N-allylquinazolinone. The synthesized compounds were characterized using spectroscopic techniques such as IR, 1D NMR (1H and 13C), 2D NMR (COSY and HSQC), and high-resolution mass spectrometry (HRMS). The spectral data show that this reaction leads only to the 3,5-disubstituted isoxazoline regioisomer, and that the observed regiochemistry is not affected by the nature of the substituents in the phenyl ring of the dipole. In addition, a theoretical study was performed using density functional theory (DFT) to support the experimental results in regard to the regiochemistry of the studied reactions. The computational mechanistic study was in good agreement with the experimental data.

ACS applied materials & interfaces 14(23), 27040 - 27047 (2022). doi:10.1021/acsami.2c04712, The metal-organic framework MOF-808 contains Zr$_6$O$_8$ nodes with a high density of vacancy sites, which can incorporate carboxylate-containing functional groups to tune chemical reactivity. Although the postsynthetic methods to modify the chemistry of the Zr$_6$O$_8$ nodes in MOFs are well known, tackling these alterations from a structural perspective is still a challenge. We have combined infrared spectroscopy experiments and first-principles calculations to identify the presence of node vacancies accessible for chemical modifications within the MOF-808. We demonstrate the potential of our approach to assess the decoration of MOF-808 nodes with different catechol–benzoate ligands. Furthermore, we have applied advanced synchrotron characterization tools, such as pair distribution function analyses and X-ray absorption spectroscopy, to resolve the atomic structure of single metal sites incorporated into the catechol groups postsynthetically. Finally, we demonstrate the catalytic activity of these MOF-808 materials decorated with single copper sites for 1,3-dipolar cycloadditions., Published by ACS Publ., Washington, DC

A highly efficient and environmentally benign 1,3-dipolar cycloaddition of C, N - cyclic azomethine imines with 5-alkenyl thiazolones and 2-arylidenindane-1,3-diones is developed for the construction of congested quaternary spiro-carbon centers. All these transformations can be smoothly performed in ethanol at room temperature, providing a catalyst-free and atom-economical access to diversely substituted novel isoquinoline-fused spirocycles in almost quantitative yields with high diastereoselectivities. The promising anti-tumor activity of these structurally novel spirocyclic compounds is reported as well.

The Thorpe–Ingold effect was applied to the design of a chiral ligand of π–copper(II) catalysts for the enantioselective α-fluorination of N-acyl-3,5-dimethylpyrazoles, and also for the enantioselective Mukaiyama–Michael, Diels–Alder, and 1,3-dipolar cycloaddition reactions of N-acryloyl-3,5-dimethylpyrazoles. The use of β,β-dimethyl-β-arylalanine-type ligand gave desired products with higher enantioselectivity compared to with previously reported β-arylalanine-type ligands.

N-fused pyrrolidinyl spirooxindole belongs to a class of privileged heterocyclic scaffolds and is prevalent in natural alkaloids and synthetic pharmaceutical molecules. To realize the switchable synthesis of divergent N-fused pyrrolidinyl spirooxindoles for further biological activity evaluation via a substrate-controlled strategy, a chemically sustainable, catalysis-free, and dipolarophile-controlled three-component 1,3-dipolar cycloaddition of isatin-derived azomethine ylides with diverse dipolarophiles is described in this work. A total of 40 functionalized N-fused pyrrolidinyl spirooxindoles were synthesized in 76–95% yields with excellent diastereoselectivities (up to >99:1 dr). The scaffolds of these products can be well-controlled by employing different 1,4-enedione derivatives as dipolarophiles in EtOH at room temperature. This study provides an efficient strategy to afford a spectrum of natural-like and potentially bioactive N-fused pyrrolidinyl spirooxindoles.

The pseudo-multicomponent reaction between propargyl amine, an aldehyde and an electron-deficient alkene is described. The C–H activation takes place thermally and allows the obtaining of cycloadducts in very good yields with high diastereoselectivities. The relative configuration is determined by X-ray diffraction analysis of the chiral molecule, obtained as a single diastereoisomer, using a chiral maleimide. A brief study of the stability of the possible ylides involved in the process is also mentioned, confirming the high diastereoselectivity observed. The high functional group density of these cycloadducts permits the synthesis of complex heterocycles. After allylation or propargylation of the pyrrolidine nitrogen atom, RCM-DA cycloaddition or cyclotrimerization with an alkyne is studied, respectively. In this last example, the resulting tetracyclic structures are of potential interest as drugs for the treatment of cystic fibrosis. We gratefully acknowledge financial support from the Spanish Ministerio de Ciencia, Innovación y Universidades (project RED2018-102387-T) the Spanish Ministerio de Economía, Industria y Competitividad, Agencia Estatal de Investigación (AEI) and Fondo Europeo de Desarrollo Regional (FEDER, EU) (projects CTQ2017-82935-P and PID2019-107268GB-I00), the Generalitat Valenciana (IDIFEDER/2021/013, GVA-COVID19/2021/079 and CIDEGENT/2020/058), Medalchemy S.L. (Medalchemy-18T) and the University of Alicante (VIGROB-068, UAUSTI21-05).

Background Aggressive antimicrobial infections together with an increasing in resistance to antimicrobial medications cause a threat to immunocompromised individual. In this context, spiro compounds play an important role in drug discovery research due to their diverse biological activities including antimicrobial activity which is well documented in literature, because of their unique structural properties allow for easy interaction with the target enzyme of the biological system. This biological precedent encouraged us to design and synthesis of novel dispirooxindolopyrrolidine hybrid heterocycles via multicomponent cycloaddition protocol. Materials and methods Novel class of dispirooxindolopyrrolidine hybrid heterocycles has been synthesized by multicomponent 1,3-dipolar cycloaddition methodology and the structure of the products was determined through spectroscopic analysis. The synthesized organic compounds were evaluated for their antimicrobial activities using sensitivity test with standard agar well diffusion method. Results The synthesized new class of dispiropyrrolidine embedded indandione hybrids showed significant antimicrobial activity against carbapenemase producing Klebsiella pneumoniae (CKPs) isolated from hospital patients. Compound that possessing chlorine substituted on the aryl ring exhibited more potent antimicrobial activities and the zone of inhibitions was observed between 7.00 ± 0.09 and 18.40 ± 0.70 mm. The MIC value of compound 4b was 0.030 mg/mL against tested CKP. Conclusion A new class of dispiropyrrolidine heterocyclic hybrids were synthesized in good to excellent yield employing multicomponent 1,3-dipolar cycloaddition strategy. Among them, compounds bearing 4-chloro substituted on the aryl ring exhibited notable activity just equal to the standard drug, ciprofloxacin. Future studies are needed to elucidate the pharmacological properties of new compounds that were synthesized in our laboratory for the novel therapeutic development.

Cu-catalyzed endo-selective asymmetric 1,3-dipolar cycloaddition of azomethine ylides with ethenesulfonyl fluorides (ESFs) was successfully developed, this protocol provided an efficient and facile method to a wide range of chiral pyrrolidine-3-sulfonyl fluorides with good to excellent results (up to 87% yield, >20:1 dr, 94% ee). Some other chiral sulfonyl derivatives, such as sulfonamide and sulfonate, were easily accessible through simple transformations with high yields, which demonstrated that the cycloaddition products could be synthetically useful in the sulfur(VI) fluoride exchange (SuFEx) chemistry.

A diastereoselective synthesis of biologically interesting spirobarbiturates has been achieved via [3+2] cycloaddition of alloxan-derived azomethine ylides to 3-R-1,2-diphenylcyclopropenes. With this approach, a range of spirobarbiturate-3-azabicyclo[3.1.0]hexanes and spirobarbiturate-cyclopropa[a]pyrrolizines were obtained in moderate to good yields with excellent diastereoselectivities. DFT calculations (M11 density functional theory) were carried out to shed light on the molecular mechanism of 1,3-dipolar cycloaddition of alloxan-derived azomethine ylides to cyclopropenes. The cytotoxic activity of some obtained compounds against human erythroleukemia (K562) cell line was evaluated in vitro by MTS-assay.

The 1,3-dipolar Cycloadditions (DCs) of Nitrile Oxides (NOs) have been used as a powerful tool in synthetic organic chemistry. The cycloadducts arising from Cycloadditions (CAs) of NOs to alkenes and alkynes (2-isoxazolines and isoxazoles respectively) are valuable synthetic intermediates because, among others, their capacity to mask other functionalities including α, β -unsaturated ketones, β -hydroxy carbonyl compounds and 1,3- aminoalcohols. In particular, the β-hydroxy ketone functionality is an illustrative example, making the NOs alkenes CAs reactions a synthetically equivalent methodology of aldol reactions. The vast majority of these reactions are carried out in organic solvents. Nevertheless, the use of water as an alternative solvent has evident advantages on the “Green Chemistry” concept. The critical discussion on the use of water instead of “conventional” solvents in the 1,3-DCs reactions of NOs is the objective of the present review.

A novel series of diosgenin-triazole conjugates (10a–d, 11a–c, 12a–c, 13a–c) was designed and synthesized as antifungal agents by using a 1,3-dipolar cycloaddition reaction in the presence of a Cu(I) catalyst. All the title compounds were characterized by 1H NMR, 13C NMR, and Q-TOF-MS. Results of preliminary antifungal tests against seven human pathogenic fungi in vitro revealed that half of the target compounds exhibited moderate or even better antifungal activities against Y0109 and C. albicans SC5314 species. Compound 10d showed excellent antifungal activities toward C. albicans Y0109 and C. albicans SC5314 than itraconazole, with MIC80 value of 1 μg/mL, respectively.

Isoxazoline derivatives of the natural products eugenol, 1’- S-acetoxychavicol acetate and sclareol are prepared through 1,3-dipolar cycloaddition reactions in an aqueous buffered system. The compounds are evaluated for their antitubercular and antibacterial activities. Compounds 2, 2a and 3f display strong antitubercular activity with minimum inhibitory concentration values of 26.68, 17.89 and 14.58 µM, respectively. Furthermore, derivative 3f exhibits antibacterial activity against Bacillus cereus (minimum inhibitory concentration value of 29.16 µM). Isoxazoline derivatives of 1’- S-acetoxychavicol acetate demonstrate improvements in cytotoxicity, and derivative 3f of sclareol demonstrates improved antitubercular and antibacterial activities. Isoxazolines derived from natural products exhibit Mycobacterium tuberculosis enoyl-acyl carrier protein reductase (InhA) inhibitory activity, and molecular modelling predicts that they form hydrogen bonding and hydrophobic interactions with NADH and with the key residues of the InhA binding site.

Highly regioselective synthesis of 12 new dispiroheterocycles containing aurone scaffold was reported via a three-component 1,3-dipolar cycloaddition reaction of azomethine ylide and (Z)-2-benzylidene-6-methoxybenzofuran-3(2H)-one derivatives in excellent yields (60–94%). The structures of all the desired products were fully confirmed by 1H NMR, 13C NMR, and FT-IR spectral data and CHN elemental analysis. In the second part of the paper, the 1,3-dipolar cycloaddition reaction between N-(1,3-dioxo-1,3-dihydro-2H-inden-2-ylidene)-N-methylmethanideaminium II as a 1,3-dipole and 2-benzylidene-6-methoxybenzofuran-3(2H)-one III as a dipolarophile was studied theoretically using density functional theory (DFT) at the B3LYP/6–31 + + G(d, p) computational level to shed light on the regioselective and mechanistic aspects. Two possible routes for the reaction were considered, and the regioselectivity was also studied. The DFT results showed that the high regioselectivity is in complete agreement with the experimental results.

A series of new triterpenic and sitosterol derivatives containing 1,2,3,4-(tetrazol-5-yl)ethoxy and -ethoxyimine fragments at positions C-2, C-3, and C-12 have been synthesized by 1,3-dipolar cycloaddition of nitriles to sodium azide. The structure of the obtained compounds was confirmed by NMR spectroscopy, including two-dimensional correlation experiments, and mass spectrometry. It was found that such steric factors as the presence of 23,24-gem-dimethyl groups or a second cyanoethyl group at position C-2 affect the yield of the reaction product. In vitro studies have shown that methyl 2-[2-(1Н-tetrazol-5-yl)]-2,4-seco-3-norlupa-4(23),20(29)-dien-28-oate and 24-ethyl-3-[2-(1Н-tetrazol-5-yl)ethoxy]cholestan-5-ene have the highest anticancer and α-glucosidase inhibitory activities, respectively.

Methods for the synthesis of two types of isomeric dispirocompounds based on imidazothiazolotriazine and pyrrolidineoxindole, differing in the structure of imidazothiazolotriazine fragment, namely, linear dispiro[imidazo[4,5-e]thiazolo[3,2-b][1,2,4]triazine-6,3′-pyrrolidine- 4′,3″-indolines] and angular dispiro[imidazo[4,5-e]thiazolo[2,3-c][1,2,4]triazine-7,3′-pyrrolidine-4′,3″-indolines] were proposed. The first method relies on a 1,3-dipolar cycloaddition of azomethine ylides generated in situ from paraformaldehyde and N-alkylglycine derivatives to the corresponding oxindolylidene derivatives of imidazothiazolotriazine. The cycloaddition leads to a mixture of two diastereomers resulted from anti- and syn-approaches of azomethine ylide in approximately a 1:1 ratio, which were separated by column chromatography. Another method consists in rearrangement of linear dispiro[imidazo[4,5-e]thiazolo[3,2-b][1,2,4]triazine-6,3′-pyrrolidine-4′,3″-indolines] into hitherto unavailable angular dispiro[imidazo[4,5-e]thiazolo[2,3-c]-[1,2,4]triazine-7,3′-pyrrolidine-4′,3″-indolines] upon treatment with KOH. It was found that the anti-diastereomer of linear type underwent rearrangement into the isomeric angular syn-diastereomer, while the rearrangement of the linear syn-diastereomer gave the angular anti-diastereomer.

In this paper, we report a novel magnetically separable silica coated copper nano-magnetite NHC-benzimi@Cu complex as heterogeneous catalyst for the multicomponent click reaction via Huisgen 1,3-dipolar cycloaddition reaction of alkyl or aryl halide, sodium azide and terminal alkyne, which affords various1,4-disubstituted 1,2,3-triazoles. The multistep prepared nano catalyst has been characterized by various spectroscopic methods such as FT-IR, TGA, EDX, XRD, TEM and VSM. The heterogeneous nano catalyst structures coated on the copper surface are responsible for the excellent catalyst performances in the reaction. The reusability of the catalyst makes the present protocol more fascinating from an environmental and economic point of view.

A novel series of 3,5-disubstituted isoxazoles bearing kojic acid moiety were synthesized via Cu(I)-catalyzed 1,3-dipolar cycloaddition reaction of terminal alkynes with nitrile oxide formed in situ from the corresponding hydroximoyl chloride. Structures of the synthesized compounds were characterized using spectroscopic analysis data. Antimicrobial activity of the isoxazole conjugates was determined as MIC values by broth microdilution method against different bacteria: Staphylococcus aureus, Bacillus subtilis, Escherichia coli, Salmonella typhi, and fungi Candida kefyr. The obtained results revealed notable antibacterial and antifungal activities of the compounds.

A regio- and stereoselective method for the synthesis of (trifluoro(trichloro)methyl)-substituted spiro[chromeno(thia)pyrrolizidineoxindoles] in 53–97% yields was developed on the basis of the three-component reaction of 3-nitro-2-(trifluoro(trichloro)methyl)-2Hchromenes with azomethine ylides generated in situ from isatins and L-(thia)proline in EtOH at 30°C. The obtained compounds demonstrated high cytotoxic activity against HeLa human cervical cancer and RD human embryonic rhabdomyosarcoma cells.

In our previous work [Edeleva et al. Chem. Commun. 2019, 55, 190-193], we proposed a versatile approach to the activation of the homolysis of an aldonitrone group-containing alkoxyamine by 1,3-dipolar cycloaddition to a vinyl monomer. Both nitroxide- and alkoxyamine-containing aldonitrones were found to be capable of reacting with the activated alkenes. In the present study, the kinetics of these reactions with 11 different vinyl monomers were investigated using EPR and NMR spectroscopy, and apparent activation energies as well as pre-exponential factors were determined. The influence of monomer structure on the rate of the 1,3-dipolar cycloaddition is discussed. For the vinyl monomers typically used in nitroxide mediated polymerization (styrene, methyl methacrylate) the rate coefficient of cycloaddition to the nitroxide is around k(353 K) ∼4 ⋅ 10-4 L mol-1 s-1 , whereas for n-butyl acrylate and methyl vinyl ketone we observed the fastest cycloaddition reaction with k(353 K)=8 ⋅ 10-3 and 4 ⋅ 10-2 L mol-1 s-1 respectively.

The microwave-assisted 1,3-dipolar cycloaddition of furanyl and benzyl oximes and several methyl acrylates effectively provided several isoxazoline when mediated by diacetoxyiodobenzene. The selected isoxazoline, methyl-5-(3-methoxy-3-oxopropyl)-3-phenyl-4,5-dihydro isoxazole-5-carboxylate, was rapidly transformed to the γ-lactone carboxylic acid, 2-(2-amino-2-phenylethyl)-5-oxotetrahydrofuran-2-carboxylic acid, in reasonable yield. The biological activity of this γ-lactone carboxylic acid increased the growth of E. coli organisms by about 44% and has a potential significance in stem cell research.

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...

Cycloaddition reactions have emerged as rapid and powerful methods for constructing heterocycles and carbocycles. [3+2] Cyclo­additions of nitroalkenes with various 1,3-dipoles have been an interesting research area for many organic chemists. This review outlines the synthesis of N-substituted and NH-1,2,3-triazoles along with other five-membered N-heterocycles through cycloaddition reactions of nitro­alkenes.1 Introduction2 Synthesis of 1,2,3-Triazoles2.1 Synthesis of NH-1,2,3-Triazoles2.2 Synthesis of N-Substituted 1,2,3-Triazoles3 Synthesis of Pyrrolidines and Pyrroles4 Synthesis of Pyrazoles5 Conclusion

In this work, we introduced a multifunctional Ag(I)/CAAA-amidphos complex catalyzed asymmetric 1,3-dipolar cycloaddition of acrylates with α-imino esters, affording a series of 2,4,5-trisubstituted endo-pyrrolidines in good yields (up to 97%) with high enantioselectivities (up to 98% ee). Meanwhile, the catalytic system was also applied in the three-component one-pot reaction of α-imino esters formed in situ under the action of N,N′-diisopropylcarbodiimide. In addition, the gram-scale reaction was realized for the formal synthesis of (+)-ibophyllidine in eight steps.

A highly enantioselective 1,3-dipolar cycloaddition of α-substituted diazoesters with exocyclic enones was achieved with chiral scandium(III)/N,N’-dioxide complex as the catalyst. This protocol provided a facile and efficient route to optically active 1-pyrazoline-based spirochromanones and others with good outcomes (up to 97% yield, 98% ee with >95:5 dr). Moreover, enantioenriched 2-pyrazoline-based spirochromanones were also accessible by switching α-substituted diazoesters to α-diazoacetates. The further specific transformations of chiral pyrazoline-based spiro-compounds to spirocyclopropane derivatives were disclosed as well.

Inspired by the chemistry and biology of butyrolactones, pyrrolidines, and chromanones, we successfully developed a simple domino 1,3-dipolar cycloaddition of homoserine-lactone-derived azomethine ylides for the construction of biologically important spiro[butyrolactone–pyrrolidine–chromanone] hybrids in the presence of Et3N as a catalyst under mild conditions. The reaction is based on the application of carboxylic-acid-activated chromones as dienophiles, followed by a decarboxylation process. This reaction displayed good substrate tolerance and gave the desired products in moderate to good yields with high diastereoselectivities (up to 85% yield and >20:1 diastereomeric ratio) via an exo-transition state. This is the first example of an introduction of a chromanone moiety into a spiro[butyrolactone-pyrrolidine] framework, which might be valuable in medicinal chemistry.

The cycloaddition of azomethine ylides to [60]fullerene (C-60) has been studied in ortho-dichlorobenzene (o-DCB) by evaluating the impact of an ionic liquid (IL) additive. The solvent effect has been addressed by evaluating the activation parameters of the cycloaddition and the boosting effect of the microwave (MW) induced dielectric heating. The IL additive plays a twofold role of stabilizing the dipolar ylide intermediate and favoring the retro-cycloaddition at high temperature regime. Under the conditions explored, a combined kinetic and thermodynamic preference favors the selective formation of trans bis-fulleropyrrolidine regioisomers, in agreement with the DFT computational analysis.

1,3-Dipolar cycloaddition of azomethine ylides and electron deficient alkenes is widely studied for rapid installation of pyrrolidine frameworks. Despite significant advances, the major limitations of this process are creating chiral pyrrolidines bearing a quaternary stereogenic center and controlling the diastereoselectivity. Herein, we present an exo-selective asymmetric 1,3-dipolar cycloaddition to access chiral pyrrolidines with four contiguous stereogenic centers, including a fluorinated quaternary stereogenic center at C4, wherein a Cu(OAc)2/(S)-tol-BINAP catalyst and α-fluoro-α,β-unsaturated arylketone dipolarophiles are used. Epimerization promoted by 5.0 equiv of DBU at 90 °C results in the formation of chiral 4-fluoropyrrolidines (exo') while maintaining the optical purity.

Three-component 1,3-dipolar cycloaddition reactions between isatin, benzylamine, and α,β-unsaturated ketones at room temperature afforded substituted spiro[indole-3,2′-pyrrolidine] derivatives with good yields. In some cases, only one diastereoisomer was formed. The reaction involved in situ generation of azomethine ylide from isatin and benzylamine. The possibility of formation of different regio- and stereoisomers was analyzed by PM7 semiempirical quantum chemical calculations and NMR spectroscopy.

A regio- and stereoselective method for the synthesis of N-unsubstituted 3-aryl-4-(trifluoromethyl)-4H-spiro[chromeno[3,4-c]-pyrrolidine-1,3'-oxindoles] in 24–79% yields, based on the three-component reaction of 3-nitro-2-(trifluoromethyl)-2H-chromenes with azomethine ylides generated in situ from benzylamines and isatins by refluxing in CH2Cl2 for 24 h has been developed. 3-Phenyl-4-(trifluoromethyl)-4H-spiro[chromeno[3,4-c]pyrrolidine-1,3'-oxindoles] were obtained in 36–71% yields via the three-component reaction of 3-nitro-2-(trifluoromethyl)-2H-chromene, isatins, and L-phenylglycine proceeding in EtOH at 60°C for 5 h. The resulting compounds exhibited cytotoxic activity against human cervical cancer HeLa cells in the micromolar concentration range.

Ena izmed pomembnih reakcij v klik kemiji je 1,3-dipolarna cikloadicija, ki spada med periciklične reakcije. Cikloadicija se uporablja za sintezo heterocikličnih sistemov z lihim številom atomov v obroču. V uvodu diplomskega dela se bom posvetil lastnostim in sintezi azometin iminov in pirazolidin-3-onom, ki lahko služijo kot izhodne spojine za pripravo najrazličnejših heterociklov, med katerimi bom več pozornosti namenil pirazolo[1,2-a]pirazolom. Eksperimentalni del diplomskega dela vključuje sintezo azometin iminov iz pirazolidin-3-onov in 1,3-dipolarno cikloadicijo azometin iminov na terminalne alkine za sintezo pirazolo[1,2-a]pirazolov ter njihove fotokemične pretvorbe. One of the most important reactions in click chemistry is 1,3-dipolar cycloaddition, which belongs to the pericyclic reactions. Cycloaddition is used to synthesise heterocyclic systems with an odd number of atoms in the ring. In the introduction of my work, I will focus on the properties and synthesis of azomethine imines and pyrazolidin-3-ones, which can serve as starting compounds for the preparation of a variety of heterocycles, paying more attention to pyrazolo[1,2-a]pyrazoles. The experimental part of the work includes the synthesis of azomethine imines from pyrazolidin-3-ones and 1,3-dipolar cycloaddition of azomethine imines to terminal alkynes for the synthesis of pyrazolo[1,2-a]pyrazoles and their photochemical transformations.

Klik kemija je ena izmed novejših načinov organske sinteze, pri kateri se sintetizirajo nove spojine s C–X–C vezmi. Da reakcija spada med klik kemijo, morajo biti izpolnjeni določeni pogoji. Ena izmed najbolj pomembnih reakcij v klik kemiji je 1,3-dipolarna cikloadicija, ki spada med periciklične reakcije in se uporablja za sintezo heterocikličnih sistemov z lihim številom atomov v obroču. Poleg tega sem se v uvodu posvetil azometin iminom, ki so vključeni v sintezo najrazličnejših heterociklov. Zadnji del uvoda opisuje biciklične pirazolidinone. Eksperimentalni del diplomskega dela vključuje sintezo azometin iminov iz 3-pirazolidinonov in 1,3-dipolarno cikloadicijo azometin iminov na terminalne alkine za sintezo pirazolo[1,2-a]pirazolov. Click chemistry is one of the newer methods of organic synthesis, where new compounds with C–X–C bonds are synthesized. For a reaction to be defined as click chemistry, certain conditions must be met. One of the most important reactions in click chemistry is 1,3-dipolar cycloaddition, which is a pericyclic reaction and is used to synthesize heterocyclic systems with an odd number of atoms in the ring. In addition, in the introduction I focused on azomethine imines, which are involved in the synthesis of wide variety of heterocycles. The last part of the introduction describes bicyclic pyrazolidinones. The experimental part of the thesis includes the synthesis of azomethine imines from 3-pyrazolidinones and the 1,3-dipolar cycloaddition of azomethine imines to terminal alkynes for the synthesis of pyrazolo[1,2-a]pyrazoles.

The metal-organic framework MOF-808 contains Zr₆O₈ nodes with a high density of vacancy sites, which can incorporate carboxylate-containing functional groups to tune chemical reactivity. Although the postsynthetic methods to modify the chemistry of the Zr₆O₈ nodes in MOFs are well known, tackling these alterations from a structural perspective is still a challenge. We have combined infrared spectroscopy experiments and first-principles calculations to identify the presence of node vacancies accessible for chemical modifications within the MOF-808. We demonstrate the potential of our approach to assess the decoration of MOF-808 nodes with different catechol–benzoate ligands. Furthermore, we have applied advanced synchrotron characterization tools, such as pair distribution function analyses and X-ray absorption spectroscopy, to resolve the atomic structure of single metal sites incorporated into the catechol groups postsynthetically. Finally, we demonstrate the catalytic activity of these MOF-808 materials decorated with single copper sites for 1,3-dipolar cycloadditions.

The novel enantiopure synthesis of protected proline-cysteine analogs by means of 1,3-dipolar cycloaddition of homochiral thiazolines and azomethine ylides is described. The important role of the oxidation state of the sulfur atom of the dipolarophile in such reaction is demonstrated affecting strongly the regioselectivity and reactivity of the 1,3-dipolar cycloaddition. Mono-oxidized sulfur atom (sulfoxide group) and di-oxidized (sulfone group) led to 2,3 regio-addition whereas reactions starting from non-oxidized sulfur atom resulted in the 2,4 addition. Besides, sulfur oxidized thiazolines reacted smoothly upon heating in an organic solvent media but the non-oxidized sulfur thiazoline required metal catalysis. Diastereofacial selectivity was observed to be independent of the oxidation state of the sulfur atom but controlled by the bulky tert-butyl group at the thiazoline ring. The highly substituted and functionalized enantiopure pyrrolidine-thiazolidine bicyclic compounds are considered as novel (homo)cysteine-proline analogs with important properties to discover. Enantiopure proline-cysteine analogs were obtained by 1,3-dipolar cycloaddition between homochiral thiazolines and azomethine ylides. The reactivity and regioselectivity are controlled by the oxidation state of the thiazoline sulfur atom. Sulfoxide and sulfone groups led to 2,3 addition whereas reactions starting from the thioether group resulted in 2,4 addition. Diastereofacial selectivity is controlled by the bulky tert-butyl group at the thiazoline ring., The authors thankfully acknowledge MINECO (Ministerio de Economía y Competitividad, grant CTQ2013-40855-R) and Gobierno de Aragon-FEDER (Grupo Aminoácidos y Péptidos E19_20R; FEDER 2014–2020‘Construyendo Europa desde Aragón’), for the financial support provided to this work. J. G.-V. thanks the Gobierno de Aragón–FSE for a pre-doctoral Grant.

An unprecedented 1,3-dipole cycloaddition between acyclic CF3-ketimines and N-benzyl azomethine ylide has been allowed by tungsten catalysis, furnishing a range of novel imidazolidines bearing a trifluoromethylated tetrasubstituted carbon center. This reaction appears as one of rare examples that challenging acyclic CF3-ketimines have been engaged in 1,3-cycloaddition reactions. The capability for gram-scale synthesis and variant derivatizations of cycloaddition adducts illustrates the synthetic potential of this approach. This protocol provides a facile access to a rapidly enlarging pool of motifs with a trifluoromethylated fully substituted carbon.

International audience; Regioselective access to heterohelicenes through the 1,3-dipolar cycloaddition of sydnones with arynes is described. Novel access to sydnones and poly(hetero)aromatic aryne precursors allowed the introduction of chemical diversity over multiple positions of the helical scaffolds. The origins of the unconventional regioselectivity during the cycloaddition steps was systematically investigated using density functional theory (DFT) calculations, unveiling the key features that control this reactivity, namely, face-to-face ($\pi \cdot \cdot \cdot \pi$) or edge-to-face (C−H$\cdot \cdot \cdot \pi$) interactions, primary orbital interactions and distortion from coplanarity in the transition structures (TSs) of the transformation. From the library of 24 derivatives synthesized, a pyridyl containing derivative displayed reversible, red-shifted, pH-triggered chiroptical switching properties, with CPL-sign reversal. It is found that protonation of the helicene causes a change of the angle between the electric and magnetic dipole moments related to the S$_1$ → S$_0$ transition, resulting in this rare case of reversible CPL sign inversion upon application of an external stimulus.

A novel visible light mediated redox-neutral 1,3-dipolar cycloaddition of 2H-azirines with 2,4,6-triarylpyrylium tetrafluoroborate salts providing tetrasubstituted pyrroles has been developed. The 2,4,6-triarylpyrylium salt acts as dipolarophile as well as photosensitizer in the reaction, under blue light irradiation. The control experiments indicated single electron oxidation of 2H-azirines by photoexcited pyrylium salts, followed by coupling between an azaallenyl radical cation and triarylpyranyl radical as the key mechanistic feature. The mild conditions, wide substrate scope, and complete regioselectivity are the noticeable attributes of the reaction.

The mechanism of the Lewis base F- catalyzed 1,3-dipolar cycloaddition between CO2 and nitrilimines is interrogated using DFT calculations. F- activates the nitrilimine, not CO2 as proposed in the literature, and imparts a significant rate enhancement for the cycloaddition. The origin of this catalysis is in the strength of the primary orbital interactions between the reactants. The Lewis base activated nitrilimine-F- has high-lying filled FMOs. The smaller FMO-LUMO gap promotes a rapid nucleophilic attack and overall cycloaddition with CO2.

Series of 2-pyridyl[1,2,4]triazolo[1,5-a]azines have been synthesized by cycloaddition of cyanopyridines with N-aminoazinium mesitylenesulfonates under basic conditions (KOH/H2O). An improved protocol for pyridyl-substituted [1,2,4]triazolo[1,5-a]pyridines synthesis based on addition of H2O2 as internal oxidant has been suggested. In the case of quinolinium and isoquinolinium salts, only dimerization of the corresponding N-imines has been observed, while pyrazinium-N-imine has not shown any reactivity toward cycloaddition. DFT studies have shown that the cycloaddition proceeds through concerted mechanism.

A series of new 2-((1-((1-(4-methoxy-3-nitrophenyl)-1H-1,2,3-triazol-4-yl)methyl)1H-indol- 3-yl)me thylene)malononitrile derivatives were synthesized by the 1,3-dipolar cycloaddition reaction (click reaction) of 2-((1-(prop-2-yn-1-yl)-1H-indol-3-yl)methylene)malononitrile with different aryl azides in the presence of sodium ascorbate and copper sulphate in good yields. The advantages of this method are efficient, clean, high yields, easy workup procedures, and shorter reaction time. These reactions are very facile, giving products by simple processing that does not require purification by column chromatography. Spectroscopic methods confirmed all the newly synthesized compounds.

An efficient and practical methodology was developed for rapid and green synthesis of novel benzofuran-1,2,4-oxadiazole-1,2,3-triazole hybrids (6a–n) from 5-(chloromethyl)-3-(2-methylbenzofuran-3-yl)-1,2,4-oxadiazoles (4a–b) by in situ generation of 5-(azidomethyl)-3-(2-methylbenzofuran-3-yl)-1,2,4-oxadiazoles followed by 1,3-dipolar cycloaddition with substituted-1-(prop-2-yn-1-yloxy)benzenes (5a–g) through Click reaction under mild reaction conditions with good to excellent yields (70–86%).