Phosphorus Ylides Research Articles

Direct Stereodivergent Olefination of Carbonyl Compounds with Sulfur Ylides.

The reactivity of phosphorus and sulfur ylides toward carbonyl compounds constitutes a well-known dichotomy that is a common educational device in organic chemistry—the former gives olefins, while the latter gives epoxides. Herein, we report a stereodivergent carbonyl olefination that challenges this dichotomy, showcasing thiouronium ylides as valuable olefination reagents. With this method, aldehydes are converted to Z-alkenes with high stereoselectivity and broad substrate scope, while N-tosylimines provide a similarly proficient entry to E-alkenes. In-depth computational and experimental studies clarified the mechanistic details of this unusual reactivity.

Insights into the anticancer activity of chiral alkylidene-β-lactams and alkylidene-γ-lactams: Synthesis and biological investigation

Chiral alkylidene-β-lactams and alkylidene-γ-lactams were synthesized and screened for their in vitro activity against four human cancer cell lines (melanoma, esophageal, lung and fibrosarcoma carcinoma). Alkylidene-β-lactams were synthesized via Wittig reaction of diverse phosphorus ylides with benzhydryl 6‐oxopenicillanate, derived from 6-aminopenicillanic acid. Moreover, novel chiral alkylidene-γ-lactams were synthesized through a multistep strategy starting from a chiral substrate (d-penicillamine). The in vitro assays allowed the identification of four compounds with IC50 values < 10 μM for A375 cell line, and three compounds with IC50 values < 10 μM for OE19 cell line. The effect of the most promising compounds on cell death mechanism, reactive oxygen species generation as well as the evaluation of their ability to act as MMP-9 inhibitors were studied. The reported results unveil the potential of alkylidene-β-lactams as anticancer agents.

Integration of C-Acylation in the Solid-Phase Synthesis of Peptides and Peptidomimetics Employing Meldrum’s Acid, Phosphorus, and Sulfur Ylides

AbstractThe modification of native peptides to peptidomimetics is an important goal in medicinal chemistry and requires, in many cases, the integration of C-acylation steps involving amino acids with classical peptide synthesis. Many classical C-acylation protocols involving Claisen condensations and the use of ylides are not compatible with peptide synthesis, mostly due to the requirements for strong bases leading to epimerization or deprotection of peptides. Meldrum’s acid as well as several specific phosphorus and sulfur ylides, however, are acidic enough to provide reactive C-nucleophiles under mildly basic conditions tolerated during peptide synthesis. This review provides an overview of peptide-compatible C-acylations using Meldrum’s acid and phosphorus and sulfur ylides, and their application in the medicinal chemistry of peptides.1 Introduction2 C-Acylation of Meldrum’s Acid2.1 C-Acylation of Meldrum’s Acid on Solid Phase3 Ylides as Substrates for C-Acylation3.1 C-Acylation of Phosphorus Ylides in Solution Phase3.2 C-Acylation of Solid-Supported Phosphorus Ylides3.3 C-Acylation of Sulfur Ylides3.4 C-Acylation of Solid-Supported Sulfur Ylides4 Miscellaneous Ylides as Acyl Anion Equivalents5 Summary

Mechanochemical synthesis of half‐sandwich iridium/rhodium complexes with 8‐hydroxyquinoline derivatives ligands

AbstractMechanochemistry provides a rapid, efficient route to half‐sandwich iridium and rhodium complexes from [MCp*(μ‐Cl)Cl]2 (M = Ir, Rh) and 8‐hydroxyquinoline‐2‐carbaldehyde without the need for Schlenk manipulation, inert gas protection, or dry solvents. Furthermore, post‐synthetic modification of the half‐sandwich metal complexes has been carried out via a mechanochemical Wittig reaction between half‐sandwich metal complex and phosphorus ylide. All complexes were fully characterized by 1H and 13C NMR spectra, infrared spectroscopy, mass spectrometry, and single‐crystal X‐ray diffraction method. The half‐sandwich rhodium complexes exhibited high catalytic activity towards the amide synthesis between aldehyde and hydroxylamine hydrochloride (NH2OH·HCl) with a broad functional group tolerance.

Phosphorus ylides of cage-opened sulphide [60]fullerene derivatives.

The partial structural change in cage-opened C60 derivatives by replacing a carbonyl group with a sulphide moiety significantly lowers the chemical stability of the corresponding phosphorus ylides. Thus they readily undergo in situ hydrolysis to give an α-methylene carbonyl compound. Owing to the elevated LUMO level, the near-infrared absorption band was hypsochromically shifted from λedge 880 to 800 nm.

A neutral, acyclic, borataalkene-like ligand for group 11 metals: L- and Z-type ligands side by side.

The overall neutral α-borylated phosphorus ylide Ph3PC(Me)BEt2 behaves like a polar borataalkene and can act as acyclic, ambiphilic π-type ligand with L- and Z-type functionalities side by side. In the complexes [MX{η2-Ph3PC(Me)BEt2}] (M = Cu, (Ag), Au; X = Cl, NTf2), the bonding is dominated by the highly nucleophilic ylidic carbon atom (L-type ligand). The Lewis acidic boron atom furnishes nonetheless a small but significant bonding contribution (Z-type ligand).

Catalytic comparison of Pd-C60 complex and its non-fullerene form bearing phosphorus ylide in C[sbnd]C coupling reactions

The new fullerene-based Pd complex [(η2‐C60) Pd(Y)2] (1) and its non-fullerene form [(Y)PdCl2] (2) bearing unsymmetrical phosphorus ylide [Ph2P(CH2)2PPh2 = C(H)C(O)C6H4-p-CH3] (Y) were prepared through dissolving Y in related solvent in the presence of [C60Pd]n polymer or PdCl2(cod) (cod = 1,5-cyclooctadiene), respectively. The synthesized compounds were characterized using NMR (1H, 13C, and 31P), IR, UV–Visible, XRD, EDX, TGA/DTG/DTA, and SEM/TEM techniques. The crystal structure of compound Y was also obtained by X-ray analysis. The data proved that fullerene (C60) and two ylides were coordinated to Pd(0) center in complex 1 through [6,6] bond and two free phosphorus atoms, respectively. Also, the reaction of the unsymmetric phosphorus ylide Y with PdCl2(cod) led to the PC chelated complex 2. Finally, the catalytic properties of synthesized complexes were studied on Suzuki-Miyaura and Mizoroki-Heck CC coupling reactions. By comparing catalytic properties of complexes, it was found that complex 1 including fullerene nanoparticle has more promising activity in CC coupling reactions.

One-pot synthesis of stable phosphorus ylides by three-component reaction between arylglyoxals, phosphines and barbituric or Meldrum’s acid

One-pot synthesis of stable phosphorus ylides by three-component reaction between arylglyoxals, phosphines and barbituric or Meldrum’s acid

Cover Feature: Accessing Cationic α‐Silylated and α‐Germylated Phosphorus Ylides (Chem. Eur. J. 1/2022)

Competition for the lone pair: Our paper describes efforts to access cationic α-silylated (and α-germylated) phosphorus ylides of the general formula [R3PC(R)SiR2]+. One inherent feature of these molecules is that the silyl and phosphonyl entities compete for the lone pair of electrons. The ambivalent nature of the possible resonance structures is reflected in the coloured segmentation of the cover feature. The two “competitors” are illustrated as sportspersons, and both resonance structures are represented depending on where the ball of positive change is. More information can be found in the Research Article by F. Breher et al. (DOI: 10.1002/chem.202103974).

Carbodiphosphorane-Catalyzed Hydroboration of Ketones and Imines

We report the use of a cyclic carbodiphosphorane catalyst for ketone and imine hydroboration reactions. Ketone hydroboration reactions are particularly rapid, typically reaching completion within 15 min using a 1 mol % catalyst loading at 25 °C. To our knowledge, this represents the first use of a carbodiphosphorane as an organocatalyst. The carbodiphosphorane exhibited superior catalytic activity in comparison to other neutral carbon nucleophiles tested, including an N-heterocyclic carbene, an N-heterocyclic olefin, and phosphorus ylides.

Accessing Cationic α-Silylated and α-Germylated Phosphorus Ylides.

The synthesis and full characterization of α‐silylated (α‐SiCPs; 1–7) and α‐germylated (α‐GeCPs; 11–13) phosphorus ylides bearing one chloride substituent R3PC(R1)E(Cl)R2 2 (R=Ph; R1=Me, Et, Ph; R2=Me, Et, iPr, Mes; E=Si, Ge) is presented. The molecular structures were determined by X‐ray diffraction studies. The title compounds were applied in halide abstraction studies in order to access cationic species. The reaction of Ph3PC(Me)Si(Cl)Me2 (1) with Na[B(C6F5)4] furnished the dimeric phosphonium‐like dication [Ph3PC(Me)SiMe2]2[B(C6F5)4]2 (8). The highly reactive, mesityl‐ or iPr‐substituted cationic species [Ph3PC(Me)SiMes2][B(C6F5)4] (9) and [Ph3PC(Et)SiiPr2][B(C6F5)4] (10) could be characterized by NMR spectroscopy. Carrying out the halide abstraction reaction in the sterically demanding ether iPr2O afforded the protonated α‐SiCP [Ph3PCH(Et)Si(Cl)iPr2][B(C6F5)4] (6 dec) by sodium‐mediated basic ether decomposition, whereas successfully synthesized [Ph3PC(Et)SiiPr2][B(C6F5)4] (10) readily cleaves the F−C bond in fluorobenzene. Thus, the ambiphilic character of α‐SiCPs is clearly demonstrated. The less reactive germanium analogue [Ph3PC(Me)GeMes2][B{3,5‐(CF3)2C6H3}4] (14) was obtained by treating 11 with Na[B{3,5‐(CF3)2C6H3}4] and fully characterized including by X‐ray diffraction analysis. Structural parameters indicate a strong CYlide−Ge interaction with high double bond character, and consequently the C−E (E=Si, Ge) bonds in 9, 10 and 14 were analyzed with NBO and AIM methods.

Nucleophilicity and CO2 fixation ability of phosphorus, nitrogen and sulfur ylides: insights on stereoelectronic factors from DFT study

Nucleophilicity and CO2 fixation ability of phosphorus, nitrogen and sulfur ylides: insights on stereoelectronic factors from DFT study

A series of nanoscaled Pt(0)‐phosphorus ylide complexes based on [60]fullerene: Synthesis, characterization, and in vitro biological assessments

AbstractHerein, A type of Pt(0) complexes based on fullerene C60 including phosphorus ylides as monodentate ligands, [(η2‐C60)Pt(Y1–4)2] (Y1 = PPh3CHC(O)C6H4‐p‐NO2, Y2 = PPh3CHC(O)C6H4‐p‐CH3, Y3 = (p‐tolyl)3P‐CHC(O)C6H4‐p‐NO2, Y4 = (p‐tolyl)3P‐CHC(O)C6H4‐p‐CH3), were synthesized via adding of related monodentate phosphorus ylide to toluene solution of C60 and Pt (dba)2 (dba = dibenzylideneacetone). The structures were identified using IR, NMR (1H, 13C, and 31P), UV–visible, ESI‐MS, and EDX spectroscopies, thermal curve TGA, and electron microscopic images (scanning electron microscopy, SEM, and transmission electron microscopy, TEM). The molecular structure of complexes clearly shows that two ylidic ligands in a cis configuration and two hexagons of C60 in the junction[6,6] coordinate to Pt(0) metal center. These complexes were treated as biological agents in antibacterial, antioxidant, and anticancer assessments. Three Gram‐negative (Escherichia coli, Salmonella typhimurium, and Shigella dysenteriae) and three Gram‐positive bacteria (Bacillus subtilis, Bacillus cereus, and Staphylococcus aureus) were used for antibacterial investigation. The activities of complexes against cancer cells were also tested using AGS (gastric carcinoma), A549 (non‐small lung carcinoma), and MCF‐7 (breast carcinoma) cell lines. All biological studies on synthesized nanocomplexes showed promising effects in comparison with standards.

Synthesis and characterization of mononuclear oxime-based palladacycles incorporating phosphorus ylides: application as a catalyst in Suzuki cross coupling reactions and their biological activities

The synthesis of mononuclear oxime-based palladacycles of the type [Pd{C,N-C6H4{C(Me)=NOH}-2}(Ph2PCH2CH2PPh2C(H)C(O)C6H4X)]ClO4(X = Cl (1), Br (2), NO2 (3), OCH3 (4)) is reported from the reactions of [Pd{C,N-C6H4{C(Me)=NOH}-2}(μ-Cl)]2 with phosphorus ylides in dichloromethane under reflux. The obtained compounds were characterized by FT-IR, NMR (1H, 13C{H} and 31P{H}) spectroscopic methods and elemental analysis. Splitting of the chloride bridge formed four new mononuclear oxime-based palladacycles incorporating bidentate phosphorus ylides (1-4). These palladacycles were applied for Suzuki-Miyaura cross-coupling reactions under aerobic conditions in EtOH/H2O solvent. Upon optimizing the reaction conditions, complex 3 was highly efficient to catalyze the cross-coupling of aryl halides with phenylboronic acids at a 0.44 mol % palladium loading. Also, the cytotoxic effects of 1-4 were evaluated by an MTT assay in three human carcinoma cell lines: HT29, A549, and 1321N1. The results indicate that these compounds had toxic effects and 4 has greater toxic activity with respect to the other complexes in all three cell lines. Thus, these compounds can be considered as efficient catalysts in cross-coupling reactions and as a cytotoxic agent.

AgOTf/I2-Mediated Cyclization/Cross-Coupling/Isomerization of Enynones with Phosphorus Ylides: An Expedient Route to Stereoselective Synthesis of (E)-2-Alkenylfurans.

Ag(I)-catalyzed cascade reactions involving enynone cyclization and cross-coupling with phosphorus ylides have been achieved for the first time. Subsequent treatment of the reaction mixture with I2 afforded the corresponding (E)-α-alkenylfurans in 73-95% yields with excellent stereoselectively. A reasonable mechanism has been proposed.

Synthesis of Difluoroalkylated Heteroarenes via Difluorocarbene

A diversity-oriented and C2-selective synthesis of difluoroalkyl-substituted heteroarenes from three fragments, N-methoxyazinium salts, difluorocarbene, and electrophilic or radical reagents, is described. The reaction proceeds via the addition of difluorinated phosphorus ylide to in situ methylated heteroarene N-oxides, leading to phosphonium salts, which can undergo further transformations under basic or photoinduced conditions.

Phosphine-Catalyzed Cross-Coupling of Benzyl Halides and Fumarates.

A phosphine-catalyzed olefinic cross-coupling between benzyl halides and fumarates is described, which affords trisubstituted alkenes in good yields and excellent E-selectivity under metal-free conditions. Mechanistic studies suggest a catalytic cycle involving phosphorus ylide formation, Michael addition, water-assisted hydrogen transfer, and phosphine elimination.

Reactions on a 1,2-Dicarbonyl Moiety of a Fullerene Skeleton.

A 1,2-dicarbonyl moiety on a cage-opened fullerene skeleton is one of suitable building blocks for the further derivatization. Herein, we discuss the chemical transformation of a 1,2-dicarbonyl compound into β-oxo-phosphorus ylide, acid anhydride, and α-methylene carbonyl derivatives. Despite possessing a sterically small methylene unit in the last one, the release of an encapsulated water molecule was significantly supressed whereas the β-oxo-phosphorus ylide bearing three bulky p-tolyl groups on the P-atom enabled the faster insertion/release dynamics, implying the flexibility of the phosphonium substituent. The replacement of the carbonyl group with phosphorus ylide and methylene units largely varied electrochemical properties of the fullerene skeleton, likely arising from the anionic charge delocalized over the entire molecule and removal of an electron-withdrawable carbonyl group, respectively.

Phosphine-Catalyzed Chemoselective Reduction/Elimination/Wittig Sequence for Synthesis of Functionalized 3-Alkenyl Benzofurans.

An efficient protocol for the construction of functionalized 3-alkenyl benzofurans is demonstrated under metal-free conditions using catalytic amount of phosphine proceeding an intramolecular Wittig reaction. This one-pot reaction initiated by the phospha-Michael addition of phosphine to O-acylated nitrostyrene, in which phosphine was in-situ-generated from the chemoselective reduction of phosphine oxide with PhSiH3, would provide the phosphorus ylide to result in the aforementioned multifunctionalized benzofuran via O-acylation/nitrous acid elimination/Wittig reaction.

A Phosphine-Mediated Dearomative Skeletal Rearrangement of Dianiline Squaraine Dyes.

A phosphorus(III)-mediated dearomatization of ortho-substituted dianiline squaraine dyes results in an unusual skeletal rearrangement to provide exotic, highly conjugated benzofuranone and oxindole scaffolds bearing a C3 side chain comprised of a linear conflagration of an enol, a phosphorus ylide, and 2,4-disubstituted aniline. Employing experimental and computational analysis, a mechanistic evaluation revealed a striking dependence on the acidity of the aniline ortho substituent. Notably, the rearrangement adducts underwent rapid and complete reversion to the parent squaraine in the presence of a Brønsted acid.