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Open AccessCommunication

An Alternative Method for Preparing Methyl 2-Ferrocenyl-2-oxo-acetate

by Pascal Pigeon and Hugo Hapel

Molbank 2025, 2025(2), M2009; https://doi.org/10.3390/M2009 - 21 May 2025

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Because of the continuous interest in ferrocene chemistry, there is a sustained demand for various ferrocenic building blocks, especially small molecules with useful chemical functional groups, sometimes containing multiple groups. Our interest in ferrocene ketoesters (ω-ferrocenyl-ω-ketoesters) was motivated by the synthesis of esters and subsequently alcohols of ferrociphenols. However, from a bibliographic survey, only one publication dated from 1964 reports the two-step synthesis (six-step synthesis from ferrocene) of methyl 2-ferrocenyl-2-oxoacetate, the simplest member of this family of compounds, with no further developments since. We hypothesized that a simpler method might exist, such as the Friedel–Crafts method. By focusing on our experiments to use aluminum trichloride as the catalyst, we managed to achieve the synthesis of FcCOCOOMe in a single step, albeit with a very low yield, regardless of reaction time, temperature, amount of aluminum chloride and reagents concentration. Nevertheless, considering the time saved, simplicity, and the use of less hazardous and less expensive reagents, this method offers certain advantages for synthesizing this building block. Full article

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

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7 pages, 1278 KB

Open AccessShort Note

Ethyl 4-Ene-4-ferrocenyl-5,5-bis-(4-hydroxyphenyl)-pentanoate

by Jérémy Forté and Pascal Pigeon

Molbank 2025, 2025(1), M1980; https://doi.org/10.3390/M1980 - 13 Mar 2025

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Abstract

The ferrociphenol family is a group of molecules in which a ferrocenyl moiety is connected to at least one 4-hydroxyphenyl group through a C-C double bond. Among them, ferrocidiphenols in which the double bond is substituted by two gem 4-hydroxyphenyl groups have been largely studied, demonstrating interesting anticancer properties. The fourth available position of the double bond could be substituted by a simple ethyl group (1a) inherited from Tamoxifen, but also by ethyl or methyl acetate, propionate, butanoate, pentanoate (1b-g), hydroxyethyl or hydroxypropyl (1h–i). Ethyl 4-ene-4-ferrocenyl-5,5-bis-(4-hydroxyphenyl)-pentanoate 1e shows an IC₅₀ on the MDA-MB-231 breast cancer cell line very close to that of 1a. These compounds were synthesized in moderate to good yields by McMurry coupling reaction from the corresponding ketones. Ethyl 4-ene-4-ferrocenyl-5,5-bis-(4-hydroxyphenyl)-pentanoate (1e) was fully characterized by ¹H NMR (including COSY), ¹³C NMR (including DEPT135), low resolution mass spectrometry, HRMS, infrared spectroscopy, elemental analysis, and X-ray diffraction (XRD). The data of already published crystal structures of five structurally related ferrocidiphenols are also included for comparison purposes. Full article

(This article belongs to the Section Structure Determination)

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7 pages, 1507 KB

Open AccessShort Note

1,1-Bis(4-hydroxyphenyl)-2-ferrocenylbutane

by Jérémy Forté, Patrick Herson and Pascal Pigeon

Molbank 2024, 2024(4), M1932; https://doi.org/10.3390/M1932 - 6 Dec 2024

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Abstract

Ferrociphenols are anticancer organometallic molecules bearing a ferrocene group linked, at least, to one para-phenol moiety via a double bond. Up to the present, their biological activity has been thought to be linked to their oxidation within cells to form a reactive quinone-methide metabolite with the participation of this central double bond. To prove this assertion, the alkenyl entity of ferrociphenol 1a (1,1-bis-(4-hydroxyphenyl)-2-ferrocenylbut-1-ene) was reduced by triethylsilane in an acidic medium to obtain the alkyl counterpart 1,1-bis(4-hydrophenyl)-2-ferrocenylbutane. 1,1-bis(4-hydrophenyl)-2-ferrocenylbutane was fully characterized by ¹H NMR (including COSY), ¹³C NMR, HRMS, IR, elemental analysis and X-ray diffraction (XRD). Although missing the central double bond, this compound remains biologically active, opening the way to a new family of anticancer ferrocene-containing molecules. Full article

(This article belongs to the Section Structure Determination)

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16 pages, 2240 KB

Open AccessArticle

Unravelling the Role of Uncommon Hydrogen Bonds in Cyclodextrin Ferrociphenol Supramolecular Complexes: A Computational Modelling and Experimental Study

by Pascal Pigeon, Feten Najlaoui, Michael James McGlinchey, Juan Sanz García, Gérard Jaouen and Stéphane Gibaud

Int. J. Mol. Sci. 2023, 24(15), 12288; https://doi.org/10.3390/ijms241512288 - 31 Jul 2023

Cited by 2 | Viewed by 1903

Abstract

We sought to determine the cyclodextrins (CDs) best suited to solubilize a patented succinimido-ferrocidiphenol (SuccFerr), a compound from the ferrociphenol family having powerful anticancer activity but low water solubility. Phase solubility experiments and computational modelling were carried out on various CDs. For the latter, several CD-SuccFerr complexes were built starting from combinations of one or two CD(s) where the methylation of CD oxygen atoms was systematically changed to end up with a database of ca. 13 k models. Modelling and phase solubility experiments seem to indicate the predominance of supramolecular assemblies of SuccFerr with two CDs and the superiority of randomly methylated β-cyclodextrins (RAMEβCDs). In addition, modelling shows that there are several competing combinations of inserted moieties of SuccFerr. Furthermore, the models show that ferrocene can contribute to high stabilization by making atypical hydrogen bonds between Fe and the hydroxyl groups of CDs (single bond with one OH or clamp with two OH of the same glucose unit). Full article

(This article belongs to the Special Issue Cyclodextrins: Properties and Applications)

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15 pages, 3017 KB

Open AccessArticle

Synthesis, Electrochemical and Fluorescence Properties of the First Fluorescent Member of the Ferrocifen Family and of Its Oxidized Derivatives

by Charles Fayolle, Pascal Pigeon, Nathalie Fischer-Durand, Michèle Salmain, Olivier Buriez, Anne Vessières and Eric Labbé

Molecules 2022, 27(19), 6690; https://doi.org/10.3390/molecules27196690 - 8 Oct 2022

Cited by 2 | Viewed by 2387

Abstract

The first fluorescent ferrociphenol derivative (P797) has been synthesized via McMurry cross-coupling followed by copper-catalyzed [3 + 2] azide-alkyne cycloaddition of the fluorescent group coumarin. Cyclic voltammograms of P797 exhibit either a monoelectronic oxidation wave ascribed to the ferrocene Fe(II) → Fe(III) conversion or a three-electron oxidation process in the presence of a base, leading to a Fe(III) quinone methide adduct. This general sequence is consistent with those previously described for non-fluorescent ferrociphenols. Furthermore, the fluorescence properties of P797 and its oxidized intermediates appear to strongly depend on the redox state of the ferrocene group. Indeed, electrochemical generation of Fe(III) (ferrocenium) states markedly increases the fluorescence emission intensity. In contrast, the emission of the Fe(II) (ferrocene) states is partially quenched by photoinduced electron transfer (PET) from the Fe(II) donor to the coumarin acceptor and by concentration-dependent self-quenching. Owing to its switchable fluorescence properties, complex P797 could represent an innovative and useful tool to study the biodistribution and the redox state of ferrocifens in cancer cells. Full article

(This article belongs to the Special Issue Electrochemistry and Organometallic Catalysis: Themed Issue in Honor of the Great Contribution of Prof. Dr. Christian Amatore and Prof. Dr. Anny Jutand)

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26 pages, 2021 KB

Open AccessArticle

α-Hydroxylactams as Efficient Entries to Diversely Functionalized Ferrociphenols: Synthesis and Antiproliferative Activity Studies

by Pascal Pigeon, Marie Gaschard, Mohamed Othman, Michèle Salmain and Gérard Jaouen

Molecules 2022, 27(14), 4549; https://doi.org/10.3390/molecules27144549 - 16 Jul 2022

Cited by 6 | Viewed by 2565

Abstract

The [ferrocene-ene-phenol] motif has been identified as the pharmacophore responsible for the anticancer activity of the family of ferrocene-based molecules coined ferrocifens, owing to its unique redox properties. The addition of imide entities to the historical ferrociphenol scaffold tremendously enhanced the cytotoxic activity of a large panel of cancer cell cultures and preliminary studies showed that the reduction of one of the carbonyl groups of the imide groups to the corresponding α-hydroxylactams only slightly affected the antiproliferative activity. As a continuation to these studies, we took advantage of the facile conversion of α-hydroxylactams to highly electrophilic N-acyliminium ions to graft various substituents to the imide motif of phthalimido ferrocidiphenol. Cell viability studies showed that the newly synthesized compounds showed diverse cytotoxic activities on two breast cancer cell lines, while only one compound was significantly less active on the non-tumorigenic cell line hTERT-RPE1. Full article

(This article belongs to the Special Issue Anticancer Compounds with Different Biological Targets)

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