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Open AccessArticle

[3+2] Cycloaddition to a Chiral 5-Methylene-1,3-dioxolan-4-one and Pyrolysis of the Spiro Adducts

by R. Alan Aitken, Lynn A. Power and Alexandra M. Z. Slawin

Molecules 2025, 30(6), 1246; https://doi.org/10.3390/molecules30061246 - 10 Mar 2025

Viewed by 1160

The [3+2] cycloaddition chemistry of (2S)-5-methylene-2-t-butyl-1,3-dioxolan-4-one, derived from lactic acid, has been examined, and spiro adducts have been obtained with benzonitrile oxide, acetonitrile oxide, diazomethane and diphenyldiazomethane. The structure and absolute stereochemistry of the benzonitrile oxide adduct has been [...] Read more.

The [3+2] cycloaddition chemistry of (2S)-5-methylene-2-t-butyl-1,3-dioxolan-4-one, derived from lactic acid, has been examined, and spiro adducts have been obtained with benzonitrile oxide, acetonitrile oxide, diazomethane and diphenyldiazomethane. The structure and absolute stereochemistry of the benzonitrile oxide adduct has been confirmed by X-ray diffraction, and all the adducts have been fully characterised by ¹H and ¹³C NMR. Attempted cycloaddition with a nitrile sulfide, a nitrile imine and azides failed. Pyrolysis results in a range of novel gas-phase reactions, with the nitrile oxide adducts giving pivalaldehyde, CO₂, the nitrile and ketene, the diazomethane adduct losing only N₂ to give a cyclopropane-fused dioxolanone, and the diphenylcyclopropane derived from diphenyldiazomethane giving mainly benzophenone in a sequence involving the loss of pivalaldehyde and methyleneketene. Full article

(This article belongs to the Special Issue Advances in Synthesis and Biological Activity of Novel Derivatives Based on Five-Membered Heterocyclic Scaffolds and Their Intermediates—Second Edition)

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5 pages, 809 KB

Open AccessShort Note

(1RS,3SR)-1-(4-Methylbenzyl)-7-phenyl-5-oxa-6-azaspiro[2.4]hept-6-en-4-one

by Gleb D. Titov and Nikolai V. Rostovskii

Molbank 2024, 2024(2), M1799; https://doi.org/10.3390/M1799 - 1 Apr 2024

Cited by 2 | Viewed by 1907

Abstract

The previously unknown cyclopropane spiro-fused with isoxazol-5-one ((1RS,3SR)-1-(4-methylbenzyl)-7-phenyl-5-oxa-6-azaspiro[2.4]hept-6-en-4-one) was synthesized from benzylideneisoxazol-5-one in 34% yield via double methylene transfer from diazomethane. The structure of the compound was established based on ¹H, ¹³C, and 2D NMR spectroscopy and [...] Read more.

The previously unknown cyclopropane spiro-fused with isoxazol-5-one ((1RS,3SR)-1-(4-methylbenzyl)-7-phenyl-5-oxa-6-azaspiro[2.4]hept-6-en-4-one) was synthesized from benzylideneisoxazol-5-one in 34% yield via double methylene transfer from diazomethane. The structure of the compound was established based on ¹H, ¹³C, and 2D NMR spectroscopy and high-resolution mass spectrometry, and confirmed by X-ray diffraction analysis. Full article

(This article belongs to the Section Organic Synthesis and Biosynthesis)

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10 pages, 1287 KB

Open AccessArticle

Synthesis of Spirocyclopropane-Containing 4H-Pyrazolo[1,5-a]indoles via Alkylative Dearomatization and Intramolecular N-Imination of an Indole–O-(Methylsulfonyl)oxime

by Jiann-Jyh Huang, Hung-Chun Liao, Cheng-En Hsu, Yan-Ru Liu, Yi-Fu Chang and Shan-Yen Chou

Molecules 2023, 28(17), 6374; https://doi.org/10.3390/molecules28176374 - 31 Aug 2023

Viewed by 2586

Abstract

In this paper, we report the synthesis of spirocyclopropane-containing 4H-pyrazolo[1,5-a]indoles 6a–e via alkylative dearomatization and intramolecular N-imination of indole–O-(methylsulfonyl)oxime 11. Starting materials tryptophol (7) and 2-bromocyclopetanone (8) were reacted [...] Read more.

In this paper, we report the synthesis of spirocyclopropane-containing 4H-pyrazolo[1,5-a]indoles 6a–e via alkylative dearomatization and intramolecular N-imination of indole–O-(methylsulfonyl)oxime 11. Starting materials tryptophol (7) and 2-bromocyclopetanone (8) were reacted in the presence of HBF₄·OEt₂, providing 1,2,3,5,6,11-hexahydrocyclopenta[2,3]oxepino[4,5-b]indole (9) in a 63% yield. Compound 9 was reacted with hydroxylamine hydrochloride to afford oxime 10 (65% yield), which was subsequently bis-methanesulfonated to form 11 in a 85% yield. Heating 11 with various alcohols in the presence of N,N-diisopropylethylamine (DIPEA) triggered the alkylative dearomatization and intramolecular N-imination, forming the spirocyclopropane and 4H-pyrazolo[1,5-a]indole structures in the targets 6a–e with 67–84% yields. Full article

(This article belongs to the Special Issue Feature Papers in Organic Chemistry (Volume II))

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6 pages, 579 KB

Open AccessCommunication

Synthesis of 2-[2-(Ethoxymethoxy)phenyl]spiro[cyclopropane-1,2′-indene]-1′,3′-dione

by Olga A. Ivanova, Vitaly V. Shorokhov, Ivan A. Andreev, Nina K. Ratmanova, Victor B. Rybakov, Elena D. Strel’tsova and Igor V. Trushkov

Molbank 2023, 2023(1), M1604; https://doi.org/10.3390/M1604 - 14 Mar 2023

Cited by 1 | Viewed by 3113

Abstract

An 1,3-indanedione-derived donor–acceptor cyclopropane, bearing the ethoxymethyl-protected phenolic group at the ortho-position of the donor aryl substituent, has been synthesized using a reaction sequence involving the Knoevenagel condensation of 1,3-indanedione with the corresponding protected salicylaldehyde followed by the Corey–Chaykovsky cyclopropanation of the [...] Read more.

An 1,3-indanedione-derived donor–acceptor cyclopropane, bearing the ethoxymethyl-protected phenolic group at the ortho-position of the donor aryl substituent, has been synthesized using a reaction sequence involving the Knoevenagel condensation of 1,3-indanedione with the corresponding protected salicylaldehyde followed by the Corey–Chaykovsky cyclopropanation of the obtained adduct with dimethylsulfoxonium methylide. The structure of the synthesized cyclopropane was unambiguously proved by single-crystal X-ray diffraction data. Full article

(This article belongs to the Section Organic Synthesis and Biosynthesis)

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16 pages, 1912 KB

Open AccessArticle

Palladium Catalyzed Ring-Opening of Diazabicylic Olefins with 4-Halo-1,3-Dicarbonyl Compounds: Accessing 3(2H)-Furanone-Appended Cyclopentenes

by Vishnu K. Omanakuttan, Alisha Valsan, Henning Hopf and Jubi John

Organics 2023, 4(1), 70-85; https://doi.org/10.3390/org4010006 - 13 Feb 2023

Viewed by 2719

Abstract

We have realized a Pd-catalyzed ring-opening of diazabicyclic olefins with 4-halo-1,3-dicarbonyl compounds. This reaction resulted in the formation of 3(2H)-furanone-appended hydrazino cyclopentenes. The reaction proceeds via the formation of a π-allylpalladium intermediate which is attacked by the active methylene species, and [...] Read more.

We have realized a Pd-catalyzed ring-opening of diazabicyclic olefins with 4-halo-1,3-dicarbonyl compounds. This reaction resulted in the formation of 3(2H)-furanone-appended hydrazino cyclopentenes. The reaction proceeds via the formation of a π-allylpalladium intermediate which is attacked by the active methylene species, and an intramolecular nucleophilic substitution in the 4-halo-1,3-dicarbonyl moiety furnishes the 3(2H)-furanone-substituted cyclopentene. We could extend this methodology to cyclopropane-appended spirotricyclic olefin for synthesizing 3(2H)-furanone-substituted spiro[2.4]hept-5-ene. Full article

(This article belongs to the Collection Advanced Research Papers in Organics)

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18 pages, 7961 KB

Open AccessArticle

The Solubility Studies and the Complexation Mechanism Investigations of Biologically Active Spiro[cyclopropane-1,3′-oxindoles] with β-Cyclodextrins

by Anna A. Kravtsova, Anna A. Skuredina, Alexander S. Malyshev, Irina M. Le-Deygen, Elena V. Kudryashova and Ekaterina M. Budynina

Pharmaceutics 2023, 15(1), 228; https://doi.org/10.3390/pharmaceutics15010228 - 9 Jan 2023

Cited by 7 | Viewed by 4169

Abstract

In this work, we first improved the aqueous solubility of biologically active spiro[cyclopropane-1,3′-oxindoles] (SCOs) via their complexation with different β-cyclodextrins (β-CDs) and proposed a possible mechanism of the complex formation. β-CDs significantly increased the water solubility of SCOs (up to fourfold). Moreover, the [...] Read more.

In this work, we first improved the aqueous solubility of biologically active spiro[cyclopropane-1,3′-oxindoles] (SCOs) via their complexation with different β-cyclodextrins (β-CDs) and proposed a possible mechanism of the complex formation. β-CDs significantly increased the water solubility of SCOs (up to fourfold). Moreover, the nature of the substituents in the β-CDs influenced the solubility of the guest molecule (MβCD > SBEβCD > HPβCD). Complexation preferably occurred via the inclusion of aromatic moieties of SCOs into the hydrophobic cavity of β-CDs by the numerous van der Waals contacts and formed stable supramolecular systems. The phase solubility technique and optical microscopy were used to determine the dissociation constants of the complexes (K_c~10² M⁻¹) and reveal a significant decrease in the size of the formed crystals. FTIR-ATR microscopy, PXRD, and ¹H-¹H ROESY NMR measurements, as well as molecular modeling studies, were carried out to elucidate the host–guest interaction mechanism of the complexation. Additionally, in vitro experiments were carried out and revealed enhancements in the antibacterial activity of SCOs due to their complexation with β-CDs. Full article

(This article belongs to the Special Issue Applications of Crystal Engineering in Drug Delivery)

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14 pages, 1988 KB

Open AccessArticle

Synthesis of New Spiro-Cyclopropanes Prepared by Non-Stabilized Diazoalkane Exhibiting an Extremely High Insecticidal Activity

by Naoufel Ben Hamadi and Ahlem Guesmi

Molecules 2022, 27(8), 2470; https://doi.org/10.3390/molecules27082470 - 12 Apr 2022

Cited by 5 | Viewed by 3949

Abstract

The synthesis of new insecticidal gem-dimethyspiro-cyclopropanes derived from pyrrolidine-2,3-dione have been described, and their biological effect against different insect species has been evaluated. The presented results demonstrate the excellent insecticidal activity of cyclopropane 5c against Aedes aegypti and Musca domestica. Cyclopropane [...] Read more.

The synthesis of new insecticidal gem-dimethyspiro-cyclopropanes derived from pyrrolidine-2,3-dione have been described, and their biological effect against different insect species has been evaluated. The presented results demonstrate the excellent insecticidal activity of cyclopropane 5c against Aedes aegypti and Musca domestica. Cyclopropane 5c showed the quickest knockdown and the best killing against Aedes aegypti and Musca domestica compared to trans-chrysanthemic acid and pyrethrin. The biological results of the high insecticidal activity were confirmed by the results of docking. This is evident in the binding affinity obtained for cyclopropane 5c, indicating good binding with an important active amino acid residue of the 5FT3 protein. Full article

(This article belongs to the Special Issue Organic Synthesis in Drug Discovery)

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16 pages, 3066 KB

Open AccessArticle

Synthesis of Novel C/D Ring Modified Bile Acids

by Roselis A. Landaeta Aponte, Andreas Luxenburger, Scott A. Cameron, Alex Weymouth-Wilson, Richard H. Furneaux, Lawrence D. Harris and Benjamin J. Compton

Molecules 2022, 27(7), 2364; https://doi.org/10.3390/molecules27072364 - 6 Apr 2022

Cited by 3 | Viewed by 3597

Abstract

Bile acid receptors have been identified as important targets for the development of new therapeutics to treat various metabolic and inflammatory diseases. The synthesis of new bile acid analogues can help elucidate structure–activity relationships and define compounds that activate these receptors selectively. Towards [...] Read more.

Bile acid receptors have been identified as important targets for the development of new therapeutics to treat various metabolic and inflammatory diseases. The synthesis of new bile acid analogues can help elucidate structure–activity relationships and define compounds that activate these receptors selectively. Towards this, access to large quantities of a chenodeoxycholic acid derivative bearing a C-12 methyl and a C-13 to C-14 double bond provided an interesting scaffold to investigate the chemical manipulation of the C/D ring junction in bile acids. The reactivity of this alkene substrate with various zinc carbenoid species showed that those generated using the Furukawa methodology achieved selective α-cyclopropanation, whereas those generated using the Shi methodology reacted in an unexpected manner giving rise to a rearranged skeleton whereby the C ring has undergone contraction to form a novel spiro–furan ring system. Further derivatization of the cyclopropanated steroid included O-7 oxidation and epimerization to afford new bile acid derivatives for biological evaluation. Full article

(This article belongs to the Special Issue Organic Synthesis in Drug Discovery)

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21 pages, 2200 KB

Open AccessArticle

Attempted Synthesis of Vinca Alkaloids Condensed with Three-Membered Rings

by András Keglevich, Szabolcs Mayer, Réka Pápai, Áron Szigetvári, Zsuzsanna Sánta, Miklós Dékány, Csaba Szántay, Péter Keglevich and László Hazai

Molecules 2018, 23(10), 2574; https://doi.org/10.3390/molecules23102574 - 9 Oct 2018

Cited by 11 | Viewed by 5842

Abstract

Our successful work for the synthesis of cyclopropanated vinblastine and its derivatives by the Simmons–Smith reaction was followed to build up further three-membered rings into the 14,15-position of the vindoline part of the dimer alkaloid. Halogenated 14,15-cyclopropanovindoline was prepared by reactions with iodoform [...] Read more.

Our successful work for the synthesis of cyclopropanated vinblastine and its derivatives by the Simmons–Smith reaction was followed to build up further three-membered rings into the 14,15-position of the vindoline part of the dimer alkaloid. Halogenated 14,15-cyclopropanovindoline was prepared by reactions with iodoform and bromoform, respectively, in the presence of diethylzinc. Reactions of dichlorocarbene with vindoline resulted in the 10-formyl derivative. Unexpectedly, in the case of the dimer alkaloids vinblastine and vincristine, the rearranged products containing an oxirane ring in the catharanthine part were isolated from the reactions. The attempted epoxidation of vindoline and catharanthine also led to anomalous rearranged products. In the epoxidation reaction of vindoline, an o-quinonoid derivative was obtained, in the course of the epoxidation of catharanthine, a hydroxyindolenine type product and a spiro derivative formed by ring contraction reaction, were isolated. The coupling reaction of vindoline and the spiro derivative obtained in the epoxidation of catharanthine did not result in a bisindole alkaloid. Instead, two surprising vindoline trimers were discovered and characterized by NMR spectroscopy and mass spectrometry. Full article

(This article belongs to the Special Issue Advances in Plant Alkaloid Research)

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18 pages, 2243 KB

Open AccessArticle

Diastereoselective Synthesis of Spirocyclopropanes under Mild Conditions via Formal [2 + 1] Cycloadditions Using 2,3-Dioxo-4-benzylidene-pyrrolidines

by Yi Li, Qing-Zhu Li, Li Huang, Hong Liang, Kai-Chuan Yang, Hai-Jun Leng, Yue Liu, Xu-Dong Shen, Xiao-Jun Gou and Jun-Long Li

Molecules 2017, 22(2), 328; https://doi.org/10.3390/molecules22020328 - 22 Feb 2017

Cited by 12 | Viewed by 7718

Abstract

A highly diastereoselective cyclopropanation of cyclic enones with sulfur ylides was developed under catalyst-free conditions, producing multifunctional spirocyclopropanes in generally excellent yields (up to 99% yield and >99:1 d.r.). The asymmetric version of this method was realized by using an easily available chiral [...] Read more.

A highly diastereoselective cyclopropanation of cyclic enones with sulfur ylides was developed under catalyst-free conditions, producing multifunctional spirocyclopropanes in generally excellent yields (up to 99% yield and >99:1 d.r.). The asymmetric version of this method was realized by using an easily available chiral sulfur ylide, affording products with moderate to good stereoselectivity. Full article

(This article belongs to the Collection Heterocyclic Compounds)

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12 pages, 302 KB

Open AccessArticle

A Study of Palladium Catalyzed Intra/Intermolecular Cascade Cross Coupling/Cyclizations Involving Bicyclopropylidene

by Aydin Demircan

Molecules 2014, 19(5), 6058-6069; https://doi.org/10.3390/molecules19056058 - 13 May 2014

Cited by 3 | Viewed by 6371

Abstract

The compounds [3-(2-Bromocyclohex-2-enyloxy)prop-1-ynyl]-tert-butyl-dimethylsilane 3, [4-(2-bromocyclohex-2-en-1-yloxy)but-2-yn-1-yloxy]tert-butyldimethylsilane 5 and dimethyl 2-(2-bromocyclohex-2-enyl)-2-(3-(tert-butyldimethylsilanyl)prop-2-ynyl)malonate 9 were prepared and subjected to palladium-catalyzed intra-intermolecular cascade cross couplings incorporating bicyclopropylidene 10 under two types of conditions. In the presence of Pd(OAc)₂, PPh [...] Read more.

The compounds [3-(2-Bromocyclohex-2-enyloxy)prop-1-ynyl]-tert-butyl-dimethylsilane 3, [4-(2-bromocyclohex-2-en-1-yloxy)but-2-yn-1-yloxy]tert-butyldimethylsilane 5 and dimethyl 2-(2-bromocyclohex-2-enyl)-2-(3-(tert-butyldimethylsilanyl)prop-2-ynyl)malonate 9 were prepared and subjected to palladium-catalyzed intra-intermolecular cascade cross couplings incorporating bicyclopropylidene 10 under two types of conditions. In the presence of Pd(OAc)₂, PPh₃ and K₂CO₃ in acetonitrile at 80 °C, the products were indene analogues, cross-conjugated tetraenes 11, 12 and 13, respectively. The corresponding spirocyclopropanated tricycle 16 in dimethylformamide at 110 °C was obtained, albeit in low yield (24%), and observed as an equimolar mixture of diastereomers, whereas 14, 15 were not fully isolated. Full article

(This article belongs to the Section Organic Chemistry)

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