Spiro Heterocycles Research Articles

Synthesis and Biological Activities of Some Novel Spiro Heterocyclic Pyrrolizidine Derivatives of 11H-indeno[1,2-b]quinoxaline through 1,3-Dipolar Cycloaddition

The synthesis of spiropyrrolidines by the Knoevenagel condensation has been reported as highly bioactive natural and synthetic organic products. The synthesis was initiated by Knoevenagel condensation of indole-2-one with an appropriate benzaldehyde in presence of L-proline to afford spiropyrrolidines. Herein, a design and pathway of syntheses of a library of spiropyrrolidines bearing spiro heterocyclic indeno[1,2-b]quinoxaline-11-one motifs were reported, which also demonstrated an exceptional inhibitory activity against the anticancer cells. A novel series of dispiroindenoquinoxaline pyrrolizidines were synthesized by the condensation of indeno[1,2-b]quinoxalin-11-one and starting material (a product of ninhydrin and aldehyde derivatives). The structure of the synthesized compounds was established by spectral data.

Synthesis of Spiro[benzo[h]chromene-4,3′-indoles] and Spiro[benzo[f]chromene-1,3′-indoles

New spiro heterocycles, spiro[benzo[h]chromene-4,3′-indoles] and spiro[benzo[f]chromene-1,3′-indoles], have been synthesized in 50–60% yield by three-component condensation of substituted isatins with malononitrile or ethyl cyanoacetate and naphthalen-1-ol or naphthalen-2-ol. The described reactions follow a cascade cyclization pathway and provide a regioselective method of synthesis of the title compounds.

Spiro[indene-1,4'-oxa-zolidinones] Synthesis via Rh(III)-Catalyzed Coupling of 4-Phenyl-1,3-oxazol-2(3H)-ones with Alkynes: A Redox-Neutral Approach.

Transition-metal-catalyzed C-H activation synthesis of heterocyclic spiro[4,4]nonanes has persistently witnessed the use of additional stoichiometric transition-metal oxidant when employing C═C bond as the spiro ring closure site. Herein, we have addressed the issue by reporting a redox-neutral strategy for spiro[indene-1,4'-oxa-zolidinones] synthesis via Rh(III)-catalyzed coupling of 4-phenyl-1,3-oxazol-2(3H)-ones with alkynes. The synthesis features a broad substrate scope and high regiospecificity.

Spiroindolone Analogues as Potential Hypoglycemic with Dual Inhibitory Activity on α-Amylase and α-Glucosidase.

Inhibition of α-amylase and α-glucosidase by specified synthetic compounds during the digestion of starch helps control post-prandial hyperglycemia and could represent a potential therapy for type II diabetes mellitus. A new series of spiroheterocyclic compounds bearing oxindole/benzofuran/pyrrolidine/thiazolidine motifs were synthesized via a 1,3-dipolar cyclo-addition reaction approach. The specific compounds were obtained by reactions of chalcones having a benzo[b]furan scaffold (compounds 2a–f), with a substituted isatin (compounds 3a–c) and heterocyclic amino acids (compounds 4a,b). The target spiroindolone analogues 5a–r were evaluated for their potential inhibitory activities against the enzymes α-amylase and α-glucosidase. Preliminary results indicated that some of the target compounds exhibit promising α-amylase and α-glucosidase inhibitory activity. Among the tested spiroindolone analogues, the cycloadduct 5r was found to be the most active (IC50 = 22.61 ± 0.54 μM and 14.05 ± 1.03 μM) as α-amylase and α-glucosidase inhibitors, with selectivity indexes of 0.62 and 1.60, respectively. Docking studies were carried out to confirm the binding interaction between the enzyme active site and the spiroindolone analogues.

Spiropyrazolines: A Worthy Insight into the Recent Strategies and Synthetic Applications

The structural diversity of spiro heterocycles has achieved an extensive attention of organic chemists due to their vast synthetic applications. Among these, spiropyrazolines are gaining considerable prominence due to their biological and pharmacological activities, electrophotographic photosensitivity as well as their application as beneficial synthons for spirocyclopropanes, cyclobutanes, pyrrolidinones, pyrazoles, 3-amino oxindoles and several natural products molecular architecture. In view of all these, this review aims to provide the classical and advanced regioselective approaches as well as synthetic applications of spiropyrazolines. The key reactions for its synthesis are 1,3-dipolar cycloaddition and condensations that are described completely in this piece of work.

Hypervalent Iodine-Mediated Synthesis of Spiroheterocycles via Oxidative Cyclization

Hypervalent iodine reagents have been widely used in the construction of many important building blocks and privileged scaffolds of bioactive natural products. This review article aims to briefly discuss strategies that have used hypervalent iodine reagents as oxidants to synthesize spiroheterocyclic compounds and to stimulate further study for novel syntheses of spiroheterocyclic core structures using hypervalent iodine reagents under metal-free conditions.

Two Stages in the Spiro Heterocyclization of 1H-Pyrrole-2,3-dione with a Carbocyclic Enol

Methyl 3-benzoyl-1-(4-methylphenyl)-4,5-dioxo-4,5-dihydro-1H-pyrrole-2-carboxylate reacted with a carbocyclic enol, 2-hydroxy-1,4-naphthoquinone, to give 3′-benzoyl-4′-hydroxy-1′-(4-methylphenyl)-2H-spiro[naphtho[2,3-b]furan-3,2′-pyrrole]-2,4,5′,9(1′H)-tetraone. The intermediate product (Michael adduct) in this spiro heterocyclization, methyl 3-benzoyl-4-hydroxy-2-(3-hydroxy-1,4-dioxo-1,4-dihydronaphthalen-2-yl)-1-(4-methylphenyl)- 5-oxo-2,5-dihydro-1H-pyrrole-2-carboxylate, was isolated for the first time.

Three-Component Spiro Heterocyclization of Pyrrolediones with Indan-1,3-dione and Acyclic Enamines

Ethyl 4,5-dioxo-2-phenyl-4,5-dihydro-1H-pynole-3-carboxylates reacted with indan-1,3-dione and 3-amino-1-phenylbut-2-en-1-one or 3-aminobut-2-enenitrile to give 3-benzoyl-2-methyl-2′,5-dioxo-5′-prienyl-1,1′,2′,5-tetrahydrospiro[indeno[1,2-b]pyridine-4,3′-pyrroles] and 2-methyl-2′,5-dioxo-5′-phenyl-1,1′,2′,5-tetrahydrospiro[indeno[1,2-b]pyridine-4,3′-pyrrole]-3-carbonitriles, respectively.

Copper-Catalyzed Domino Addition, Hydroamination, and Cyclization: A Multicomponent Approach to Spiro Oxazolidinone Derivatives.

A copper-catalyzed one-pot multicomponent protocol has been developed for construction of spiro heterocycles. The domino approach leads to the synthesis of spiro oxazolidinones starting from ketones, arylacetylenes, and isocyanates via catalytic addition, hydroamination, and cyclization involving consecutive C-C, C-O, and C-N bond formations.

Solvent-free Synthesis and Antimicrobial Properties of Some Novel Furanone and Spiropyrimidone Derivatives

Background: The regioselective synthesis of spiro-heterocyclic compounds is intriguing since those compounds have unique non-planar structures and great potential for binding to biomolecules because of their inherent rigid chiral structure. A novel class of furanone and spiro-heterocyclic derivatives were synthesized and evaluated for antifungal activities to establish structure-activity relationship (SAR). Results: The synthesis was carried out through one-pot multicomponent reaction (MCR) of 4-aryl-4-oxo-2- butenoic acids, camphor, urea, and hydrogen peroxide in the presence of sodium ethoxide as a catalyst using a microwave irradiation method and / or a traditional thermal method. They are used as key starting materials to synthesize some heterocyclic compounds. Structures of all synthesized compounds were elucidated by elemental analyses and spectroscopic data. Conclusion: A facile and efficient method for the preparation of a new furanone, chalcone and spiropyrimidone derivatives via the one-pot MCR with the microwave-assisted irradiation was established.

Three-Component Spiro Heterocyclization of Pyrrolediones with Malononitrile and Cyclic Enols

Ethyl 4,5-dioxo-2-phenyl-4,5-dihydro-1H-pyrrole-3-carboxylates reacted with malononitrile and five-membered cyclic enols, indan-1,3-dione and cyclopentane-1,3-dione to give 1-substituted ethyl 2-amino-3- cyano-2′,5-dioxo-5′-phenyl-1′,2′-dihydro-5H-spiro[indeno[1,2-b]pyran-4,3′-pyrrole]-4′-carboxylates and ethyl 2-amino-3-cyano-2′,5-dioxo-5′-phenyl-1′,2′,6,7-tetrahydro-5H-spiro[cyclopenta[b]pyran-4,3′-pyrrole]-4′-carboxylates, respectively.

Microwave Assisted Synthesis of Spiro Heterocyclic Systems: A Review

Microwave Assisted Synthesis of Spiro Heterocyclic Systems: A Review

The Rich Chemistry Resulting from the 1,3‐Dipolar Cycloaddition Reactions of Enamines and Azides

Enamines exhibit exceptionally high reactivity in their 1,3‐dipolar cycloaddition reactions with azides in comparison with other dipolarophiles. This review includes the reactions of various types of enamines with azides of different nature, including catalytic processes. The initial products of the reaction, 1,2,3‐triazolines, are generally unstable and very reactive compounds which are prone to undergo various ring transformations. This provides the background for new synthetic methods and novel reaction types. The formation of a variety of products derived from the reaction of enamines with azides such as mono‐, di‐and tri‐substituted 1,2,3‐triazoles, including N‐unsubstituted derivatives, fused, conjugated and spiro heterocycles, two types of amidines and diaminoalkenes are classified in this review according to the type of stabilization/transformation of the intermediate triazolines.

Organo-Catalyzed Asymmetric Michael-Hemiketalization-Oxa-Pictet-Spengler Cyclization for Bridged and Spiro Heterocyclic Skeletons: Oxocarbenium Ion as a Key Intermediate.

A Michael-hemiketalization-oxa-Pictet-Spengler cyclization has been developed for the construction of chiral bridged and spiro heterocyclic skeletons with one spiro stereogenic carbon center and two bridgehead carbon centers, utilizing cooperative catalysts of a Takemoto thiourea catalyst and a triflimide. In particular, an oxocarbenium ion acts as a key intermediate for this cyclization reaction. Additionally, biological evaluation of this type of novel structure has revealed obvious antiproliferative activity against some cancer cell lines.

Generation of ϵ,ϵ-Difluorinated Metal-Pentadienyl Species through Lanthanide-Mediated C-F Activation.

Heavy metal on Lewis acid: The combination of lanthanide metals and AlCl3 has been employed for selective single C-F activation in benzofulvenes comprising an exocyclic CF3 substituent. Intermediate ϵ,ϵ-difluorinated metal-dienyl species react with a large variety of aldehydes in a highly regio- and diastereoselective fashion to afford 1,1-disubstituted indenes bearing a difluorovinyl group. These new building blocks have been further transformed through a hydrogenation-cyclization process into fluorinated heterocyclic spiro compounds.

Synthesis of unprecedented steroidal spiro heterocycles as potential antiproliferative drugs

Herein we report the straightforward preparation of novel conformationally-restricted steroids from trans-androsterone and estrone, decorated with spiranic oxazolidin-2-one or 2-aminooxazoline motifs at C-17 as potential antiproliferative agents. Such unprecedented pharmacophores were accessed using an aminomethylalcohol derivative at C-17 as the key intermediate; reaction of such functionality with triphosgene, or conversion into N-substituted thioureas, followed by an intramolecular cyclodesulfurization reaction promoted by yellow HgO, furnished such spirocycles in excellent yields.Title compounds were tested in vitro against a panel of six human tumor cell lines, named A549 (non-small cell lung), HBL-100 (breast), HeLa (cervix), SW1573 (non-small cell lung), T-47D (breast) and WiDr (colon), and the results were compared with steroidal chemotherapeutic agents (abiraterone and galeterone); the A-ring of the steroidal backbone, the nature of the heterocycle and the N-substituents proved to be essential motifs for establishing structure-activity relationships concerning not only the potency but also the selectivity against tumor cell lines. Estrone derivatives, particularly those bearing a spiranic 2-aminooxazoline scaffold were found to be the most active compounds, with GI50 values ranging from the low micromolar to the submicromolar level (0.34–1.5 μM). Noteworthy, the lead compounds showed a remarkable increase in activity against the resistant cancer cell lines (T-47D and WiDr) compared to the anticancer reference drugs (up to 120-fold).

Copper(II) complex derived from axial chiral heterocyclic spiro ligand: Crystal structure, characterization and SOD activity

A new Cu(II) coordination polymer (1) constructed from an axially chiral heterocyclic spiro ligand, 2,4,8,10-tetraoxaspiro[5,5]undecane-3,9-dicarboxylic acid (H2L) and 1,3-bis(4-pyridyl)propane (bpp), has been prepared and characterized by single-crystal X-ray diffraction analysis, infrared spectra (IR), elemental analysis, powder X-ray diffraction (PXRD), and thermogravimetric analysis (TGA). Structural analysis shows that 1 features a 2D undulated layer of rhombic meshes with (4, 4) topology. Interestingly, a 1D wave-like water tape formed by the cyclic centrosymmetric chairlike octamer water clusters (H2O)8 are observed between the 2D sheets. Furthermore, the experimental data and computational studies of superoxide dismutase (SOD) activity of H2L and 1 were investigated.

Synthesis of spiro heterocyclic systems from 2-(3-oxoisobenzofuran-1(3H)-ylidene)malononitrile and binucleophiles

The reaction of 2-(3-oxoisobenzofuran-1(3 H)-ylidene)malononitrile, generated from phthalic anhydride and malononitrile, with different binucleophiles led to the formation of spiro heterocycles possessing a phthalide ring system in good yields.

Efficient approach for regioselective synthesis of new trifluoromethyl-substituted spirotetracyclic isoxazolines and isoxazoles

This paper describes firstly an effective protocol for the synthesis of a new series of five examples of 3-(trifluoromethyl)-3,3a-dihydrospiro[chromeno[4,3-c]isoxazole-4,1′-cycloalkan]-3-ols (4), in which the cycloalkanes — cyclopentane, cyclohexane, cycloheptane, and 4′-methyl- and 4′-t-butyl-cyclohexane — were isolated at yields of 65–84%. The dihydro-isoxazolinols 4 were obtained regioselectively from the reactions of 2,2,2-trifluoro-1-[4-methoxy-spiro(2H-chromen-2,1′-cycloalkane)-3-yl]ethanones (3) with hydroxylamine hydrochloride, in the presence of sodium bicarbonate and methanol as solvent, for 24h at 60°C. The ethanone precursors 3 were synthesized by trifluoroacetylation reaction, employing trifluoroacetic anhydride and mixtures of enolethers and/or acetals derived from spiro[chroman-2,1′-cycloalkan]-4-ones (2) (Kabbe’s adducts), which were obtained beforehand from the reaction of cycloalkanones 1 with 2-hydroxyacetophenone and pyrrolidine. Subsequently, dehydration reactions of isoxazolinols 4, employing thionyl chloride and pyridine, enabled the isolation of another series of five novel spiro-isoxazoles 5 (76–95% yield). The structural features of the two series of new spiro heterocycles (4 and 5) were unequivocally determined with the aid of: one-dimensional 1H, 13C, and 19F NMR spectroscopy; two-dimensional 1H and 13C NMR spectroscopy (NOESY, gHMBC, and gHMQC); single crystal X-ray diffraction; and GC–MS.

Synthesis, characterization and pharmacological evaluation of novel spiro heterocyclic compounds as anti diabetic agents

Natural products possessing a spiro carbon in their molecules have proven their biological activity in agriculture and medicine. The present paper describes the synthesis, characterization of five newly synthesized Spiro-compounds characterized by means of chromatography, IR, 1 H-NMR and Mass spectral analysis. The author carried in vitro anti diabetic methods like alpha amylase and alpha glucosidase methods for anti diabetic activity of tilted compounds. The investigation of anti diabetic activity revealed that the test compounds of Spiro compounds showed favorable anti diabetic activity. Among the titled compounds some were having potent antidiabetic activity.