Graphene Oxide Catalyzed Synthesis of Fused Chromeno Spiro Pyrrolidine Oxindoles via Tandem Decarboxylation and 1,3-Dipolar Cycloaddition

A short and efficient multicomponent sequence for synthesizing fused novel polyheterocyclic chromeno spiro-pyrrolidine oxindoles via 1,3-dipolar cycloaddition reaction mediated by reactive azomethine ylides catalyzed by the Graphene Oxide (GO) is reported herein. This approach was utilized for synthesizing fused polyheterocyclic spiro-pyrrolothiazole and spiro-pyrrole oxindoles with yields ranging from good to excellent. A heterogeneous GO catalyst with an ultra-low catalytic loading of 0.05 wt% could proficiently catalyze the reaction without the formation of any side products and can also be visualized by the formation of solid mass in the reaction flask. The methodology is green in nature and the products were isolated by simple filtration without the use of any chromatographic techniques.

Azomethine Ylide Cycloaddition of 1,3- dienyl esters: Highly regio- and diastereoselective synthesis of functionalized pyrrolidinochromenes

An efficient protocol for the synthesis of tricyclic pyrolidinochromenes has been developed via an intramolecular 1,3-dipolar cycloaddition of azomethine ylides generated in situ from 1,3- dienyl ester tethered O-hydroxyarylaldehyde and...

Highly Efficient and Diastereoselective Construction of Substituted Pyrrolidines Bearing A Quaternary Carbon Center via 1,3-Dipolar [3 + 2] Cycloaddition

A general approach to substituted pyrrolidines via [3 + 2] 1,3-dipolar cycloaddition between nonstabilized azomethine ylides and cyanosulfones was developed. The efficient method provides a series of substituted pyrrolidines bearing a quaternary carbon center in high yields (up to 98%) excellent diastereoselectivities (up to >25:1 dr) under ambient reaction conditions.

An Approach to the Synthesis of a Hepatitis C Virus Inhibitor through a Proline-Catalyzed 1,3-Dipolar Cycloaddition Using Acrolein

An efficient and easy protocol for performing 1,3-dipolar cycloaddition using azomethine ylides and acrolein is presented. The reaction catalyzed by d-proline allows the synthesis of C-3 unsubstituted pyrrolidines. The application of this methodology to the synthesis of an advanced intermediate in the preparation of a Hepatitis C virus inhibitor is presented. Final attempts to complete the synthesis of the target inhibitor results in the preparation of its C-4 epimer in good overall yield.

An Experimental and Theoretical Study of the 1,3-Dipolar Cycloaddition of Alloxan-Derived Azomethine Ylides to Cyclopropenes

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, various 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) have been 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.

Stereoselective Synthesis of the Di-Spirooxindole Analogs Based Oxindole and Cyclohexanone Moieties as Potential Anticancer Agents

A new series of di-spirooxindole analogs, engrafted with oxindole and cyclohexanone moieties, were synthesized. Initially, azomethine ylides were generated via reaction of the substituted isatins 3a–f (isatin, 3a, 6-chloroisatin, 3b, 5-fluoroisatin, 3c, 5-nitroisatin, 3d, 5-methoxyisatin, 3e, and 5-methylisatin, 3f, and (2S)-octahydro-1H-indole-2-carboxylic acid 2, in situ azomethine ylides reacted with the cyclohexanone based-chalcone 1a–f to afford the target di-spirooxindole compounds 4a–n. This one-pot method provided diverse structurally complex molecules, with biologically relevant spirocycles in a good yields. All synthesized di-spirooxindole analogs, engrafted with oxindole and cyclohexanone moieties, were evaluated for their anticancer activity against four cancer cell lines, including prostate PC3, cervical HeLa, and breast (MCF-7, and MDA-MB231) cancer cell lines. The cytotoxicity of these di-spirooxindole analogs was also examined against human fibroblast BJ cell lines, and they appeared to be non-cytotoxic. Compound 4b was identified as the most active member of this series against prostate cancer cell line PC3 (IC50 = 3.7 ± 1.0 µM). The cyclohexanone engrafted di-spirooxindole analogs 4a and 4l (IC50 = 7.1 ± 0.2, and 7.2 ± 0.5 µM, respectively) were active against HeLa cancer cells, whereas NO2 substituted isatin ring and meta-fluoro-substituted (2E,6E)-2,6-dibenzylidenecyclohexanone containing 4i (IC50 = 7.63 ± 0.08 µM) appeared to be a promising agent against the triple negative breast cancer MDA-MB231 cell line. To explore the plausible mechanism of anticancer activity of di-spirooxindole analogs, molecular docking studies were investigated which suggested that spirooxindole analogs potentially inhibit the activity of MDM2.

Synthesis of polysubstituted spiropyrrolidines using 2-acetylfuran, 2-acetylthiophene, and 2-acetylpyrrole

A series of novel spirooxindoles have been synthesized through three-component 1,3-dipolar cycloaddition of azomethine ylides generated in situ by the decarboxylative condensation of isatin and sarcosine with the dipolarophile 3-phenyl-1-(heteroaryl -2-yl)prop-2-en-1- one, synthesized by the Knoevenagel reaction using 2-acetylfuran, 2-acetylpyrrole, 2-acetylthiophene and substituted benzaldehydes. These compounds are used for the first time as dipolarophiles. This method has the advantages of mild reaction conditions, high atom economy, excellent yields, and high regio- and stereo-selectivity. The reaction was carried out by mixing equimolar amounts of enone and isatin, as well as a slight excess of sarcosine in isopropyl alcohol when heated to 60–70°C. Among the enones with various heterocyclic substituents, it is most convenient to use compounds containing a pyrrole fragment as dipolarophiles, since the products are obtained in a short amount of time in good yields. The use of enones obtained from 2-acetylthiophene leads to an increase in the reaction time, and from 2-acetylfuran - to a significant resinification of the reaction mixture. The structures of the compounds obtained were proved using a combination of 1H, 13C NMR spectroscopy data, as well as two-dimensional NMR experiments of heteronuclear correlation, HSQC and HMBC. Based on the data obtained, a mechanism for the formation of products has been proposed.