Phosphorus Ylides Research Articles

Stereoselective synthesis of geminal bromofluoroalkenes by kinetically controlled selective conversion of oxaphosphetane intermediates.

Geminal bromofluoroalkenes are an important subclass of versatile organic interhalide, which can serve as useful synthetic precursors to monofluoroalkenes that are valuable amide group isosteres. Nonetheless, despite the vast advancement of olefination methodologies, the broadly applicable stereoselective synthesis remained elusive for geminal bromofluoroalkenes before our work. In particular, the seemingly straightforward Wittig-type approach with interhalogenated phosphorus ylide has been unsuccessful because of the difficulty in the diastereoselective oxaphosphetane formation. Here, we describe a conceptually distinctive strategy, by which the stereoselectivity is gained via the selective decomposition of the oxaphosphetane intermediates. The suitably identified phosphorus(III) reagent and reaction medium enabled efficient kinetic differentiation, which was supported by nuclear magnetic resonance analysis and density functional theory calculation. Through our method, the highly diastereoselective synthesis of geminal E-bromofluoroalkenes was accomplished in one step. Furthermore, the generality was demonstrated by accommodating a wide range of readily available carbonyl compounds, including ketones and pharmaceutical substrates.

Phosphine-Promoted Synthesis of Naphthoquinones Fused with Cyclopentadienyl Moiety Via Ring Expansion: Synthesis, Reactivity, and Ring Contraction Via [1,5] Sigmatropic Rearrangement.

Phosphine-promoted unprecedented [3 + 2] annulation reactions via ring expansion by using 2-benzylidene-indane-1,3-diones and diynoates for the synthesis of biologically interesting novel naphthoquinones fused with a five-membered ring bearing a phosphorus ylide up to 78% yield are described. Further ring contraction through [1,5] sigmatropic rearrangement to the spiro indan-1,3-diones by mCPBA oxidation was revealed and inferred through oxidation, followed by protonation. The relevant structures were confirmed by single-crystal X-ray diffraction. Electrochemical studies show that the naphthoquinones and lactones with phosphorus ylides could be applied to redox colorimetric materials.

Increasing the Donor Strength of Alkenylphosphines by Twisting the C=C Double Bond

Electron‐rich phosphines play a crucial role in transition metal‐based homogeneous catalysis. While alkyl groups have traditionally been employed to increase the phosphine donor strength, recent studies have shown that zwitterionic functional groups such as phosphorus ylides can result in a further enhancement. Herein we report the concept of twisting a C=C double bond to introduce a zwitterionic substituent by the synthesis and application of N‐heterocyclic olefin phosphines with a sulfonyl substituent (sNHOP). This sulfonyl group enables the twisting of the olefin moiety due to steric and electronic stabilization of the carbanionic center. The resulting zwitterionic structure leads to a significant increase of the donor strength of the sNHOP ligands compared to conventional NHOP systems with a planar N‐heterocyclic olefin moiety. The potential of this new ligand platform for catalysis is demonstrated by its application in the gold‐catalyzed hydroamination and cyclo‐isomerization of alkynes. Here, the ligands outperform the original NHOP ligands suggesting favorable properties for future catalysis applications.

Increasing the Donor Strength of Alkenylphosphines by Twisting the C=C Double Bond.

Electron-rich phosphines play a crucial role in transition metal-based homogeneous catalysis. While alkyl groups have traditionally been employed to increase the phosphine donor strength, recent studies have shown that zwitterionic functional groups such as phosphorus ylides can result in a further enhancement. Herein we report the concept of twisting a C=C double bond to introduce a zwitterionic substituent by the synthesis and application of N-heterocyclic olefin phosphines with a sulfonyl substituent (sNHOP). This sulfonyl group enables the twisting of the olefin moiety due to steric and electronic stabilization of the carbanionic center. The resulting zwitterionic structure leads to a significant increase of the donor strength of the sNHOP ligands compared to conventional NHOP systems with a planar N-heterocyclic olefin moiety. The potential of this new ligand platform for catalysis is demonstrated by its application in the gold-catalyzed hydroamination and cyclo-isomerization of alkynes. Here, the ligands outperform the original NHOP ligands suggesting favorable properties for future catalysis applications.

Efficient generation of novel phosphorus ylides via chemoselective and chemospecific reactions utilizing 2-(arylamino)-2-thioxoacetamide and methyl benzoylglycinates as precursors with activated acetylenic compounds

A chemospecific and chemoselective procedure has been developed for the efficient synthesis of novel phosphorus compounds, achieving moderate to excellent yields. This method involves the reaction of 2-(arylamino)-2-thioxoacetamide and methyl benzoylglycinate precursors with PPh3 in the presence of activated acetylenic esters. Notably, the reaction exhibits superior selectivity toward the NH2 group in 2-(arylamino)-2-thioxoacetamide, rather than the NH group. Moreover, when methyl benzoylglycinates are employed as a precursor, the reaction yields two distinct families of ylides, each with its own unique percentage yield.

Diversity-oriented synthesis of chromone inden-1-one-fused cyclopentadienylides and C-acylated chromone adducts via allylic phosphorus ylides.

An organophosphine-controlled diversity-oriented synthesis of chromone inden-1-one-fused cyclopentadienylides and C-acylated 2-((chromone-3-yl)methylene)-indandiones is reported. Key attributes of the methodology are the in situ generation of an allylic P-ylide and subsequent regio- and chemoselective intramolecular cyclization reactions that preferentially result in the aforementioned chromone adducts.

Synthesis of Functionalized Furans: Three‐Component Reactions Involving Ketene Dithioacetals, Acetylenes, and Phosphines to Generate Phosphorus Ylides or N‐Acyliminophosphoranes

AbstractSynthesis of new polysubstituted furans incorporating reactive phosphorus ylides or N‐acyliminophosphoranes was achieved by the heterocyclization of flexible α‐acyl ketene dithioacetals. This one‐pot tandem reaction was initiated by acyl‐directed desulfurative Sonogashira coupling, followed by 1,6‐addition of phosphine to the in situ‐generated enynone and subsequent 5‐exo‐dig cyclization, as well as phosphoranation. The selectivity toward the two products, i. e. α‐phosphorus ylides vs. α‐N‐acyliminophosphoranes‐substituted furans, was determined by both electron‐deficient acetylenes and copper salts.

Photocatalytic carbyne reactivity of phosphorus ylides for three-component formal cycloaddition reactions

Photocatalytic carbyne reactivity of phosphorus ylides for three-component formal cycloaddition reactions

Groups 9 and 10 Complexes of C–Donor Ligands Derived from Pyridinium-Stabilized Phosphorus Ylides

Groups 9 and 10 Complexes of C–Donor Ligands Derived from Pyridinium-Stabilized Phosphorus Ylides

More than just Alkene Construction – Re‐Using Wittig Reactions/Reagents in Biomacromolecular Labeling, Imaging, Sequencing and Modification

AbstractClassical organic chemical reactions are essential for modern synthetic chemistry and offer valuable insights for chemical biology research. The pioneering bioorthogonal chemistry, based on the Staudinger reaction, is a prime example. However, the biocompatibility of classic “name” reactions like the Wittig reaction is still not fully explored. This versatile reaction efficiently converts carbonyl groups into olefins using phosphorus ylides, making it valuable in synthetic chemistry. Despite being in the early stages of development, the Wittig reaction and its reagents have various applications in peptide, protein, DNA, and RNA research. However, they have limitations such as low activity and efficiency, requiring organic solvents. Future directions may include developing Wittig reagents with improved biostability, simplifying the method, and creating multi‐labeling methods. Improving light‐activated Wittig reactions and interdisciplinary integration can further advance bioorthogonal chemistry. As technology advances, the Wittig reaction is poised to make greater contributions to molecular biology, cell biology, and biochemical modification research.

Enantioselective Potassium-Catalyzed Wittig Olefinations.

We report asymmetric potassium-isothiourea-boronate-catalyzed Wittig olefinations of 4-substituted cyclohexanones with non-stabilized phosphorus ylides to afford highly enantioenriched axially chiral alkenes. The optimal catalyst features an unusual macrocyclic amide-potassium-boronate chelate. Kinetic and spectroscopic analyses are consistent with a Lewis acid mechanism for the catalytic olefination that results in the formation of the oxaphosphetane adduct under cryogenic conditions. Thermal fragmentation of the oxaphosphetane to the alkene product occurs after the reaction is complete. Computational studies indicate that cycloaddition proceeds via a stepwise mechanism involving enantiodetermining polar 1,2-addition to afford an intermediate potassium betaine complex.

Isolation of a Cyclic Trinuclear Gold(I) Complex with Metalated Phosphorus Ylides: Synthesis and Structural Properties.

The first chiral and luminescent cyclic trinuclear gold(I) complex, [{AuCH(PPh2Me)(Ph2P)}3]3+, has been isolated with metalated phosphorus ylides (PY). This complex was initially obtained through the reaction of either mononuclear [C6F5SAuCH(PPh2Me)(Ph2P)]OTf or dinuclear [C6F5S{AuCH(PPh2Me)(Ph2P)}2](OTf)2 thiolate-gold-phosphane complexes in the presence of NaH, followed by the abstraction of the thiopyridine moiety employing either AgOTf or [Cu(CH3CN)4]PF6. Our quest for a more efficient synthesis route led to the development of a streamlined one-pot synthesis method, employing Ag(acac) as both a halogen abstractor and a base, offering a quicker and more direct path to this intriguing trimer. Comprehensive computational studies have unveiled the luminescent characteristics of this complex, which can be attributed to phosphorescence. These emissions originate from ligand-to-metal (LMCT) and metal-centered (MC) charge transfer excited states. Furthermore, the structural analysis via X-ray crystallography corroborated the formation of a trimeric species, featuring three monomers with the [AuCH(PPh2Me)(Ph2P)] motif. Each monomer exhibits a single chiral center, leading to four possible absolute configurations (RRR, RRS, RSR, and SRR). NMR and X-ray spectroscopy have provided valuable insights, establishing that the former configuration (RRR) is disfavored due to steric hindrance, while the three remaining configurations can interconvert, arising from the structural arrangement of the metallacycle and inherent symmetry operations.

Methylation of Phenyl Rings in Ester-Stabilized Phosphorus Ylides Vastly Enhances Their Protonophoric Activity.

We have recently discovered that ester-stabilized phosphorus ylides, resulting from deprotonation of a phosphonium salt such as [Ph3PCH2COOR], can transfer protons across artificial and biological membranes. To create more effective cationic protonophores, we synthesized similar phosphonium salts with one ((heptyloxycarbonylmethyl)(p-tolyl)bromide) or two ((butyloxycarbonylmethyl)(3,5-xylyl)osphonium bromide) methyl substituents in the phenyl groups. The methylation enormously augmented both protonophoric activity of the ylides on planar bilayer lipid membrane (BLM) and uncoupling of mammalian mitochondria, which correlated with strongly accelerated flip-flop of their cationic precursors across the BLM.

An efficient access to tetrahydropyrrolo[2,1-a]isoquinoline derivatives based on phosphoranylidene succinimide

A simple and convenient synthesis of new isoquinolinone derivatives based on N-(homoveratryl)succinimide phosphorus ylide and natural aldehydes is suggested. The final formation of the tetrahydropyrrolo[2,1-a]isoquinoline framework occurs via the Pictet–Spengler cyclization.

Reactivity of Nickel Complexes Bearing P(C=X)P Ligands (X = O, N) Toward Diazoalkanes: Evidence for Phosphorus Ylide Intermediates.

Nickel carbenes are attracting attention for the development of more sustainable catalysts, among others, for cyclopropanation. Intramolecular trapping of a nickel carbene intermediate with an olefin incorporated in a P(C=C)P Ni pincer complex had previously allowed the isolation of a nickelacyclobutane intermediate and a detailed characterization of its reactivity. Herein, we report the reactivity of related nickel pincer complexes bearing a ketone P(C=O)P or an imine P(C=N)P with diazoalkanes as the carbene precursor. The observed reactivity suggests, in both cases, the reaction of the transient nickel carbene with one of the phosphine arms to form phosphorus ylides that subsequently react with the unsaturated backbone. Density functional theory (DFT) calculations are used to shed light on the mechanisms of these reactions.

Quo Vadis CO2 Activation: Catalytic Reduction of CO2 to Methanol Using Aluminum and Gallium/Carbon-based Ambiphiles.

We report on so-called "hidden FLPs" (FLP: frustrated Lewis pair) consisting of a phosphorus ylide featuring a group 13 fragment in the ortho position of a phenyl ring scaffold to form five-membered ring structures. Although the formation of the Lewis acid/base adducts was observed in the solid state, most of the title compounds readily react with carbon dioxide to provide stable insertion products. Strikingly, 0.3-3.0 mol% of the reported aluminum and gallium/carbon-based ambiphiles catalyze the reduction of CO2 to methanol with satisfactory high selectivity and yields using pinacol borane as stoichiometric reduction equivalent. Comprehensive computational studies provided valuable mechanistic insights and shed more light on activity differences.

Carbodiimide and Isocyanate Hydroboration by a Cyclic Carbodiphosphorane Catalyst.

We report hydroboration of carbodiimide and isocyanate substrates catalyzed by a cyclic carbodiphosphorane catalyst. The cyclic carbodiphosphorane outperformed the other Lewis basic carbon species tested, including other zerovalent carbon compounds, phosphorus ylides, an N-heterocyclic carbene, and an N-heterocyclic olefin. Hydroborations of seven carbodiimides and nine isocyanates were performed at room temperature to form N-boryl formamidine and N-boryl formamide products. Intermolecular competition experiments demonstrated the selective hydroboration of alkyl isocyanates over carbodiimide and ketone substrates. DFT calculations support a proposed mechanism involving activation of pinacolborane by the carbodiphosphorane catalyst, followed by hydride transfer and B-N bond formation.

Unveiling the Antifouling Potential of Stabilized Poly(phosphorus ylides).

Zwitterionic polymers have emerged as highly attractive building blocks for antifouling coatings in biomedical applications. Notably, these polymers offer effective alternatives to the widely used poly(ethylene glycol) (PEG), which has raised concerns regarding its immunotoxicity and the development of PEG-specific antibodies. Polymeric ylides, a largely overlooked class of zwitterionic polymers, have been reported as effective antifouling scaffolds. However, the reported subclasses, poly(sulfur ylides) and N-oxides, lack structural diversity and chemical variability. In this study, we present the synthesis and characterization of polymeric phosphorus ylides as an unexplored class of poly(ylides) with significantly increased structural diversity, which is of high value when designing future ylide-based antifouling materials. Our findings demonstrate that, owing to their low dipole moments and hydration layers, these polymeric phosphorus ylides significantly reduce bacterial attachment. Furthermore, we observe selective toxicity toward bacteria rather than mammalian cells. The bactericidal nature of poly(phosphorus ylides), coupled with their expanded chemical space, provides a distinct advantage over existing materials, including zwitterionic polymers from betaine scaffolds. We anticipate that these unexplored structures will broaden the scope of antifouling applications for poly(ylides).

Wittig Synthesis, Optical Properties and Electrochemical Behaviors of Some Conjugated Derivatives of 4-Pyrones

The novel hetero-stilbene derivatives were synthesized by the Wittig reaction between 2-formyl-4-pyrones and polysubstituted imidazole-based phosphonium salts in the presence of a base. The optical properties of the products were investigated via UV–Vis absorption and fluorescent emission spectroscopy in dilute ethanol solution. Electrochemical properties were also studied by the cyclic voltammetry in CH2Cl2 solutions. The phosphorus ylides obtained from α-halocarbonyls were also condensed with 2-formyl-4-pyrone to give two electrochemically inactive and non-emitting products.

Synthesis, characterization, and theoretical studies on ylidic complexes of mercury(II) as antioxidant agents

Herein we describe the synthesis of a library of new mercury complexes, including some dimers and polymeric species. Initially, a phosphonium salt, [PPh3CH2C(O)C6H4–m-OCH3]Br (S), was synthesized from triphenylphosphine (PPh3) and BrCH2C(O)C6H4-m-OCH3 in acetone. We then reacted this phosphonium salt with an appropriate base to acquire a new phosphorus ylide monodentate, PPh3=C(H)C(O)C6H4-m-OCH3 (Y). Finally, we treated the synthesized ligand with mercury halides in dry CH3OH to form C-coordinated complexes of the form [HgX(PPh3C(H)C(O)C6H4-m-OCH3) (μ-X)]2 [X = Cl (1), Br (2), I (3)], [(PPh3=C(H)C(O)C6H4-m-OCH3)Hg(NO3)2]n (4). We characterized these compounds using CHN analysis, FT-IR, NMR (1H, 13C and 31P) and density functional theory. We elucidated the structure of 2 by single-crystal X-ray diffraction. The results establish that 1, 2 and 3 have dimeric structures, while a polymeric structure is suggested for 4. The antioxidant activity of all compounds in DMSO was assessed using a DPPH free radical scavenging method. Also, the nature of metal-ligand (C→Hg) bonding in 1, 2 and 3 have been investigated using natural bond orbital (NBO) and energy-decomposition analyses (EDA).