Stable Ylides Research Articles

Pseudoaromaticity-driven, transition metal detection by squaraine-derived enol phosphonium ylide chemodosimeters.

The addition of PnBu3 to o-substituted dianiline squaraine dyes leads to bench stable ylides. Exposure to a metal analyte in solution, results in PIII abstraction and rapid disruption of the ylide conjugation to promote reversion back to the squaraine dye giving an immediate turn-on colorimetric response. The stoichiometric sensitivity and accessibility of these chemodosimeters constitute effective organic dyes for trace transition metal detection.

Abstract PO-103: Design and synthesis of tetrahydropyridine analogs as selective COX-2 inhibitors and anti-breast cancer agents

Abstract According to the World Health Organization, breast cancer has become the most common cancer globally as of 2021, accounting for 12% of all new annual cancer cases worldwide. In the US, it is estimated that there will be women with an estimated 281,550 new cases of invasive breast cancer and 49,290 non-invasive (in situ) breast cancer in 2021. Female breast cancer has also been rated as the second-highest mortality rate following lung cancer. Hence, there is a dire need for discovering more effective treatment agents. Drug discovery, by way of rational design, has paved the way for the development of novel small molecules as effective anticancer agents. It is known that chronic inflammation has a direct correlation to cancer. Cyclooxygenase-2 (COX-2) has been reported that it is present and overexpressed in many cancers. Thus, it is of great interest to study COX-2 inhibition and its relationship to cancer therapy. Tetrahydropyridines (THPs) are structures that are found in numerous natural products and possess anti-inflammatory, chemotherapeutic, and antioxidant properties. Thus, substituted phenycarbonylamino-5-ethyl-1,2,3,6-tetrahydropyridine analogs have been designed as COX-2 inhibitors in our laboratory. The objective of this project is to utilize computer-aided drug design, including molecular modeling and drug-likeness studies for the basis of drug targeting studies. Molinspiration online software was used for in silico screening of molecular properties and bioactivity prediction scores. For the molecular docking studies, Schrodinger suite software was used to examine the interactions of the THP ligands with the COX-2 enzyme. More than a dozen THP analogs that were synthesized in the lab showed favorable properties aligning well with Lipinski's rule. Most of the analogs reported average to moderate bioactivity scores as enzyme inhibitors. Lastly, the docking studies predicted several interactions with residues within the COX-2 active site, although none of the compounds scored better than the reference drug, Celecoxib. N-(5-ethyl-3,6-dihydropyridin-1(2H)-yl)-2-(trifluoromethyl)benzamide has the best docking score in comparison to Celecoxib. The preliminary data obtained through computer-based investigation showed that appropriate substitutions on the THP molecule would likely produce more effective COX-2 inhibitors. The THP preparation involves a 4-step synthesis. N-amination of 3-Ethylpyridine by the aminating agent, O-mesytelenesulfonylhydroxylamine, and treated with substituted acyl chlorides gives stable pyridinium ylides. These products are purified and reducing them using sodium borohydride gives the target THP compounds. The novel THP analogs will undergo testing as COX-2 inhibitors (arachidonic acid inhibition assay) as well as determining their anti-breast cancer activities using MCF-7 and Ishikawa cell lines assessing their anti-proliferative effects. Citation Format: Shasline Gedeon, Madhavi Gangapuram, Suresh Eyunni, Bereket Mochona, Tiffany Ardley, Kinfe Ken Redda. Design and synthesis of tetrahydropyridine analogs as selective COX-2 inhibitors and anti-breast cancer agents [abstract]. In: Proceedings of the AACR Virtual Conference: 14th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2021 Oct 6-8. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr PO-103.

Strong acid-catalyzed electrophilic ring expansion of oxetanes and sulfoxonium ylides

• Protic acid-catalyzed synthesis of functionalized trans -disubstituted tetrahydrofurans. • Electrophilic ring expansion reaction of sulfoxonium ylides to oxetanes was developed. • A transition metal-free ring expansion reaction of oxetanes to tetrahydrofurans. • Ring expansion of oxetanes to tetrahydrofurans with safe and stable ylides. • Stereospecific synthesis of functionalized trans -2,3-disubstituted tetrahydrofurans. A strong protic acid-catalyzed electrophilic ring expansion of oxetanes into trans -2,3-disubstituted tetrahydrofuran derivatives using sulfoxonium ylides has been developed. This reaction produces functionalized trans -2,3-disubstituted tetrahydrofuran derivatives stereospecifically by using safe and stable sulfoxonium ylides without metal catalysts and the protection of inert gas.

Ultrasonic Cavitation Facilitates Rapid Synthesis of Trisubstituted Pyrazole Scaffolds through Michael Addition/Domino Cyclization

AbstractA series of aryl/indolyl substituted 4, 5‐dihydro‐1H‐pyrazole derivatives were synthesized via a domino method based on Michael addition mediated cyclization of appropriate chalcones. The chalcones were prepared by Witting reaction in which substituted aromatic aldehydes were treated with stable ylides under eco‐friendly ultrasonic cavitation. The pyrazole scaffolds were obtained in excellent yields within a short span of time.

A short synthesis of 3-enoyltetramic acids employing a new acyl ylide conjugate of Meldrum’s acid

2,2-Dimethyl-5-(triphenylphosphoranylidene)acetyl-1,3-dioxan-4,6-dione (3) is a new activated β-ketoacyl equivalent, readily prepared in quantitative yield by reaction of Meldrum’s acid with the stable ylide Ph3PCCO. Its reaction with α-amino esters affords the corresponding N-(β-ketoacyl)amino ester ylides which, when treated with aldehydes and KOtBu, undergo a simultaneous Wittig olefination cum Dieckmann cyclisation to yield the respective 3-enoyltetramic acids.

Chemistry of Phosphorus Ylides: Part 45 Synthesis of Phosphoranylidene Thietane, Azetidine and Thiazinane Derivatives as Potent Chemo Preventative Agents

Reactions of nucleophilic active phosphacumulenes with iso(thio)cyanate compounds were performed. The reaction products depend on the nature of the reagent, substrate and the condition of the reaction used. New heterocyclic 4-membered or 6-membered sulfur and nitrogen compounds such as phosphoranylidene thietane, azetidine and thiazinane were obtained. On the other hand, the stable phosphonium ylides with the iso(thio)cyanate afforded phosphoranylidene thiocarbamoyl derivatives. Possible reaction mechanisms are considered and the structural assignments are based on compatible analytical and spectroscopic data.

Abstract 3252: Synthesis of N-substituted [Benzoylamino]-3-Ethyl-1,2,3,6-tetrahydropyridines as potential anti-cancer agents

Abstract Chronic inflammation is believed to promote cancer through cellular and genomic damage. Inflammation creates a microenvironment within the tissue that enhances cell proliferation. In 2016, American Cancer Society estimates that 1,685,210 new cancer cases are expected to be diagnosed in the United States. Cyclooxygenase (COX) is an enzyme found to play an essential role in inflammation and converts arachidonic acid to prostaglandin-like molecules. The three isomers of COX are COX-1, COX-2, and COX-3. COX-2 has been found to be up-regulated in inflammation and some cancers, such as breast cancer and prostate cancer. Tetrahydropyridines (THPs) developed by our research group were effective in inhibiting inflammation, COX, and the growth of some breast cancer cells. Previous research has shown that pharmacological activities of the THP derivatives depend greatly on the nature and position of the substituents on the THP ring structure. Here, we present the synthesis of a series of novel THP derivatives. 3-Ethylpyridine is reacted with O-mesitylenesulfonylhydroxylamine (O-MSH) to furnish N-amino-3-ethylpyridinium mesitylenesulfonate. The reaction of N-amino-3-ethylpyridinium mesitylenesulfonate with substituted acid chlorides gives the stable crystalline pyridinium ylides. A sodium borohydride reduction of ylides furnishes the target compounds, N-substituted [benzoylamino]-3-ethyl-1,2,3,6-tetrahydropyridines. Five novel N-substituted [benzoylamino]-3-ethyl-1,2,3,6-tetrahydropyridines were synthesized, purified, and characterized. The evaluation of these compounds cytotoxicity studies on MCF-7 estrogen receptor positive breast cancer cells, MDA-MB-231 estrogen receptor negative breast cancer cell lines, and Ishikawa cells, using the CellTiter-Glo (CTG) luminescent cell viability assay is underway. This research was supported by the National Center for Research Resources and the National Institute of Minority Health and Health Disparities of the National Institutes of Health through Grant Number 8 G12MD007582-28. Citation Format: Elizabeth Henderson, Madhavi Gangapuram, Suresh Eyunni, Kinfe Redda, Tiffany Ardley. Synthesis of N-substituted [Benzoylamino]-3-Ethyl-1,2,3,6-tetrahydropyridines as potential anti-cancer agents [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3252. doi:10.1158/1538-7445.AM2017-3252

Electrochemical Oxidation of [1-X-12-I-CB11Me10-] Anions: Formation of Borenium Ylides [12-Dehydro-1-X-CB11Me10] and Iodonium Ylide Anions [{12-(1-X-CB11Me10-)}2I+

Cyclic voltammograms of 12-iodinated icosahedral carborane anions [1-X-12-I-CB11Me10-] (X = H, CH3, C2H5, C3H7, C4H9, C6H13, and COOCH3) show two one-electron anodic oxidation peaks at the Pt electrode in liquid SO2. Oddly, the first is irreversible and the second partially reversible. Mass spectrometry of the principal anionic product of preparative anodic oxidation of [1-H-12-I-CB11Me11-], identical with the anionic product of its reaction with [Et3Si-H-SiEt3]+ and/or Et3Si+, allows it to be identified as the iodonium ylide anion [{12-(1-H-CB11Me10-)}2I+]. Its reversible oxidation to a neutral ylide radical [{12-(1-H-CB11Me10•)}{12-(1-H-CB11Me10-)}I+] is responsible for the second peak. A DFT geometry optimization suggests that both the ylide anion and the ylide radical are very crowded and have an unusually large C-I-C valence angle of ∼132°; they are the first compounds with two bulky highly methylated CB11 cages attached to the same atom. Molecular iodine is another product of the electrolysis. We propose an electrode mechanism in which initial one-electron oxidation of [1-X-12-I-CB11Me10-] is followed by a transfer of an iodine atom from the B-I bond to SO2 to yield a weakly bound radical ISO2• which disproportionates into SO2 and I2. The other product is the borenium ylide [12-dehydro-1-X-CB11Me10], which has a strongly Lewis acidic naked vertex in position 12 that rapidly adds to another [1-X-12-I-CB11Me10-] anion to form the observed stable ylide anion [{12-(1-X-CB11Me10-)}2I+]. In acetonitrile, where it presumably exists as a solvent adduct, [12-dehydro-1-X-CB11Me10] has been trapped with H2O and, to a small extent, with MeOH, but not with several other potential trapping agents.

Chemical methods for the conversion of Prednisolone to 11-β-hydroxy-1,4-androstadiene-3,17-dione

Several microbial transformations of steroids to 17-keto cortisones through side chain cleavage have been presented in the literature; however, yields and product selectivity in these methods were low. In the present study, some new methods have been identified for the side chain cleavage of prednisolone (1) to form 11- β-hydroxy-1,4-androstadiene-3,17-dione (11- β-hydroxy ADD). Prednisolone upon reaction with zinc chloride in dry THF results in the formation of cleavage product in good yield (76%). 11- β-hydroxy ADD (2) has been formed in moderate yield (60%) under the Reformatsky reaction conditions by reacting with zincate. While performing the Wittig reaction using stable ylides, again results in the formation of compound 2 in good yield (56%). Side chain cleavage of prednisolone was confirmed from the physical and analytical data and similar when compared with the literature reports. A few chemical methods were investigated for the side chain cleavage of prednisolone in order to obtain 11-β-hydroxy-1,4-androstadiene-3,17-dione. Among these methods, ZnCl2 mediated transformation gives the best results with 76% yield.

ChemInform Abstract: A Simple Approach to Pyrrolylimidazole Derivatives by Azirine Ring Expansion with Imidazolium Ylides.

AbstractThe formed pyrrolyl imidazolium bromides are reacted to imidazolium ylides, which are a new type of stable ylides, in the presence of KOH and ultrasound irradiation.

ChemInform Abstract: Synthesis of Photochromic Bis‐1,3‐diazabicyclo[3.1.0]hex‐3‐ene Derivatives Having a Bisindole Linkage.

AbstractNew photochromic bis‐1,3‐diazabicyclo[3.1.0]hex‐3‐ene derivatives (III) (6 examples) are synthesized which form deeply colored, relatively stable ylides under UV irradiation.

Abstract 2229: Synthesis of heterocyclic compounds as anticancer agents.

Abstract Cancer is a very complex disease, linked with different initiating causes, cofactors and promoters, and several types of cellular damages. There is a strong correlation between chronic inflammatory conditions in a particular organ and cancer specific to that organ. The longer the inflammation persists, the higher the risk of associated carcinogenesis. Drug discovery process has changed dramatically over the past decade as there is an increasing demand to obtain more drug candidates and decrease attrition during drug development. Chromone scaffold [(4H)-1-benzopyran-4-one] has been recognized as a pharmacophore of a large number of bioactive molecules of either natural or synthetic origin. Until now, numerous biological effects such as anti-inflammatory, antitumoral, and antimicrobial activities especially in popular medicine, have been attributed to this benzo-γ-pyrone nucleus. Compounds of this type also possess inhibition properties towards different enzymes such as oxidoreductases, kinases, tyrosinases, lipoxygenases and cyclooxygenases. Chemotherapeutic agents like tetrahydropyridine (THP) analogs exhibit diverse biological activities like analgesic and anti-inflammatory effects. Our earlier research results indicated that some of the THP derivatives showed COX-2 inhibition and anti-inflammatory activities on rat paw edema assay studies. Incorporation of THP moiety might enhance biological activity of the chromone derivatives. Herein, we report the synthesis of substituted N-(5,6-dihydropyridin-1-(2H)-yl)-4-oxo-4H-chromene-2-carboxamide as anticancer and anti-inflammatory agents. The starting material 4-oxo-4H-chromene-2-carbonyl chloride was obtained by the reaction of 4-oxo-4H-chromene-2-carboxylic acid, dissolved in 1,2-dichloroethane and SOCl2 containing few drops of DMF under reflux for 4h. The crude acid chloride obtained by removing the excess of SOCl2 and solvent under vaccum, was used immediately for next step. Reaction of the acid chloride with substituted N-amino pyridinium salt in anhydrous tetrahydrofuran gave stable ylides. This was followed by reduction with sodim borohydride in absolute ethanol, which furnished the target compound. These compounds were evaluated for their cytotoxic effects on MCF-7 ER positive breast cancer cells, MDA-MB ER receptor negative breast cancer cells, and Ishikawa cell line using the CellTiter-Glo (CTG) luminescent cell viability assay. N-(4-tert-butyl-5,6-dihydropyridin-1(2H)-yl)-6-chloro-7-methyl-4-oxo-4H-chromene-2-carboxamide showed the cytotoxicity with an IC50 values of 73.28 μM on MDA-MB-231 cell lines. This research was supported by the National Center for Research Resources and the National Institute of Minority Health and Health Disparities of the National Institutes of Health through Grant Number 8 G12MD007582-28. Citation Format: Kinfe Ken Redda, Madhavi Gangapuram, Mohammad A. Ghaffari, Suresh Eyunni, Nelly Mateeva, Bereket Mochona. Synthesis of heterocyclic compounds as anticancer agents. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2229. doi:10.1158/1538-7445.AM2013-2229

ChemInform Abstract: Synthesis of New Stable Phosphorus Ylides and 1,4‐Diionic Organophosphorus Compound from a Reaction Between Hexamethyl Phosphorous Triamide and Dimethyl Acetylenedicarboxylate in the Presence of CH‐Acids.

A simple and efficient one-pot three-component reaction between hexamethyl phosphorous triamide and dimethyl acetylenedicarboxylate (DMAD) in the presence of CH-acids, such as acetylacetone, 1,3-indandione, dibenzoylmethane, anthrone, and N,N-dimethylbarbituric acid, has been studied. In all cases, new and stable phosphorus ylides are obtained in excellent yields. These stable ylides exist in solution as a mixture of two geometrical isomers as a result of restricted rotation around the carbon–carbon partial double bond, resulting from conjugation of the ylide moiety with the adjacent carbonyl group. From the reaction of N,N-dimethylbarbituric acid with DMAD in the presence of hexamethyl phosphorous triamide, a 1,4-diionic organophosphorus compound is obtained. © 2012 Wiley Periodicals, Inc. Heteroatom Chem 24:84–89, 2013; View this article online at wileyonlinelibrary.com. DOI 10.1002/hc.21067

AIM analysis, synthetic, kinetic and mechanistic investigations of the reaction between triphenylphosphine and dialkyl acetylenedicarboxylate in the presence of 3-methoxythiophenol

Triphenylphosphine reacts with dialkyl acetylenedicarboxylates in the presence of 3-methoxythiophenol to generate stable phosphorus ylides. These stable ylides exist in solution as a mixture of two geometrical isomers as a result of restricted rotation around the carbon–carbon partial double bond resulting from conjugation of the ylide moiety with the adjacent carbonyl group. Quantum mechanical calculations were employed to check the stability of the two geometrical isomers in phosphorous ylide by natural population analysis (NPA), atoms in molecules (AIM) methods and CHelpG keyword. To determine the kinetic parameters and mechanistic investigation of the reaction, they were monitored by UV spectrophotometry. The second order fits were automatically drawn, and the value of the second order rate constants (k 2) were automatically calculated using standard equations. At the temperature range studied, the dependence of the second order rate constant (ln k 2) on reciprocal temperature was in good agreement with the Arrhenius equation. This provided the relevant plots to calculate the activation energy of all the reactions. Furthermore, useful information was obtained from studies of the effect of solvent, structure of reactions (different alkyl groups within the dialkyl acetylenedicarboxylates), and also concentration of reactants on the rate of reaction. The proposed mechanism was confirmed according to the obtained experimental results, and a steady state approximation. The first (k 2) and third (k 3) steps of the reactions were recognized as the rate determining and fast steps, respectively on the basis of experimental data. Also, the activation parameters involving ΔG# , ΔS# and ΔH# were obtained for all the reactions. Triphenylphosphine reacts with dialkyl acetylenedicarboxylates in the presence of 3-methoxythiophenol to generate stable phosphorus ylides. Quantum mechanical calculations were employed to check the stability of the two geometrical isomers of phosphorous ylides.

Synthesis of New Stable Phosphorus Ylides and 1,4‐Diionic Organophosphorus Compound from a Reaction between Hexamethyl Phosphorous Triamide and Dimethyl Acetylenedicarboxylate in the Presence of CH‐Acids

ABSTRACTA simple and efficient one‐pot three‐component reaction between hexamethyl phosphorous triamide and dimethyl acetylenedicarboxylate (DMAD) in the presence of CH‐acids, such as acetylacetone, 1,3‐indandione, dibenzoylmethane, anthrone, and N,N‐dimethylbarbituric acid, has been studied. In all cases, new and stable phosphorus ylides are obtained in excellent yields. These stable ylides exist in solution as a mixture of two geometrical isomers as a result of restricted rotation around the carbon–carbon partial double bond, resulting from conjugation of the ylide moiety with the adjacent carbonyl group. From the reaction of N,N‐dimethylbarbituric acid with DMAD in the presence of hexamethyl phosphorous triamide, a 1,4‐diionic organophosphorus compound is obtained. © 2012 Wiley Periodicals, Inc. Heteroatom Chem 24:84–89, 2013; View this article online at wileyonlinelibrary.com. DOI 10.1002/hc.21067

A Novel Strategy for the Synthesis of 3-(N-Heteryl)pyrrole Derivatives

A flexible approach to unknown 1-(1H-pyrrol-3-yl)pyridinium salts with selective control of the substitution patterns, by the reaction of pyridinium ylides with 2H-azirines, is disclosed. 3-(Pyridinium-1-yl)pyrrolides, a new type of stable ylide, were prepared from these salts in high yields by treatment with base. Atmospheric-pressure hydrogenation of the ylides with Adams' catalyst lead to 1-(pyrrol-3-yl)piperidines in good yields.

ChemInform Abstract: Synthesis and Dynamic 1H NMR Study Around the Carbon—Carbon Double Bond in the New Stable Phosphorus Ylides Derived from the Reaction Between Hexamethyl Phosphorous Triamide and Dimethyl Acetylenedicarboxylate in the Presence of NH‐Heterocyclic Compounds.

New and stable phosphorous ylides are obtained from a simple and efficient one-pot three-component reaction between hexamethyl phosphorous triamide and dimethyl acetylenedicarboxylate in the presence of NH-heterocyclic compounds in excellent yields at an ambient temperature. These stable ylides exist in solution as a mixture of two geometrical isomers as a result of the restricted rotation around the carbon–carbon partial double bond resulting from the conjugation of the ylide moiety with the adjacent carbonyl group. Dynamic effects are observed in the 1H NMR spectra that are attributed to the restricted rotation around the carbon–carbon double bond. The experimental rotational energy barrier (Δ G#) and other activation parameters on the basis of the 1H NMR study for the rotational interchangeable process of major and minor isomers in ylides 4a–dare reported. © 2011 Wiley Periodicals, Inc. Heteroatom Chem 23:131–137, 2012; View this article online at wileyonlinelibrary.com. DOI 10.1002/hc.20761

Synthesis and Dynamic NMR Study of New Stable Ylides Derived from the Reaction of Triphenylphosphine, Dialkyl Acetylenedicarboxylates, and 5-ACYL Meldrum’s Acid

Triphenylphosphine and dialkyl acetylenedicarboxylate react smoothly in the presence of 5-acyl Meldrum's acid in dichloromethane at room temperature and lead to synthesis of new stable ylide derivatives of dimethyl (5-acetyl-2,2-dimethyl-4,6-dioxo-1,3-dioxane-5-yl)-3-(triphenyl-λ5-phosphanylidene) succinate. Dynamic NMR study results of rotamers are reported and compared with the previous-related reports.

An Efficient One-Pot Synthesis of 2,3-Dialkyl-1,1-Diethyl-1-(Acetylamino)-3-(1,1,1-Triphenylphosphanilidene)-1,1,2,3-Propanetetracarboxylates and Their Temperature-Dependent NMR Spectra

Stable crystalline phosphorus ylides of 1,1-diethyl 2,3-dimethyl 1-(acetylamino)-3-(1,1,1-triphenylphosphanilidine)-1,1,2,3-propanetetracarboxylates were obtained in excellent yields from the 1:1:1 addition reaction between triphenylphosphine and dialkyl acetylenedicarboxylates in the presence of diethyl acetamidomalonate as a CH-acid. These stable ylides exist in solution as a mixture of two geometrical isomers (E and Z) as a result of restricted rotation around the carbon–carbon partial double bond resulting from conjugation of the ylide moiety with the adjacent carbonyl group on the nuclear magnetic resonance (NMR) time scale at ambient temperature. The dynamic effects in the ylide moieties were investigated by 1H NMR spectra. Supplemental materials are available for this article. Go to the publisher's online edition of Phosphorus, Sulfur, and Silicon and the Related Elements to view the free supplemental file.

Inter- and intramolecular reactions of 1-deoxy-1-thio-1,6-anhydrosugars with α-diazoesters: synthesis of the tagetitoxin core by photochemical ylide rearrangement

The one-carbon ring expansion of 1-deoxy-1-thio-1,6-anhydrosugars, mediated by metal carbenes and proceeding through the intermediacy of sulfur ylides, has been proposed as a route for the synthesis of the tagetitoxin skeleton. Intermolecular reactions of such thioanhydrosugars with diazoesters afford a range of undesired products derived from the initially formed ylide, whereas use of an intramolecular process generates stable ylides which can be converted to the tagetitoxin skeleton by photo-Stevens rearrangement. Computational studies using density functional theory indicate that the photochemical rearrangement likely proceeds through a homolysis-recombination pathway.