Triphenylphosphonium Ylide Research Articles

Recent applications of the Wittig reaction in alkaloid synthesis.

The Wittig reaction is the chemical reaction of an aldehyde or ketone with a triphenyl phosphonium ylide (the Wittig reagent) to afford an alkene and triphenylphosphine oxide. Noteworthy, this reaction results in the synthesis of alkenes in a selective and predictable fashion. Thus, it became as one of the keystone of synthetic organic chemistry, especially in the total synthesis of natural products, where the selectivity of a reaction is paramount of importance. A literature survey disclosed the existence of vast numbers of related reports and comprehensive reviews on the applications of this important name reaction in the total synthesis of natural products. However, the aim of this chapter is to underscore, the applications of the Wittig reaction in the total synthesis of one the most important and prevalent classes of natural products, the alkaloids, especially those showing important and diverse biological activities.

One‐Pot Preparation of C1‐Homologated Aliphatic Nitriles from Aldehydes through a Wittig Reaction under Metal‐Cyanide‐Free Conditions

A one‐pot protocol to obtain C1‐homologated aliphatic nitriles was achieved by treating aromatic and aliphatic aldehydes with the (methoxymethyl)triphenylphosphonium ylide followed by hydrolysis of the resulting methyl vinyl ethers with pTsOH (Ts = para‐toluenesulfonyl) and treatment with molecular iodine and aqueous ammonia under metal cyanide free conditions. Neopentyl‐type nitriles, which could not be obtained by conventional methods that involved conversion of the neopentyl alcohol into a tosylate and treatment with metal cyanide, were successfully obtained by using the present method.

(E)‐Selective Wittig Reactions between a Nonstabilized Phosphonium Ylide Bearing a Phosphastibatriptycene Skeleton and Benzaldehydes

Wittig reactions between benzaldehyde derivatives and a nonstabilized phosphonium ylide bearing a phosphastibatriptycene skeleton, regarded as a tridentate aryl ligand, gave (E)‐alkenes with high selectivity in the presence of both lithium and sodium salts. As previously reported, reactions between a triphenylphosphonium ylide and benzaldehyde derivatives under the same conditions afforded mainly (Z)‐alkenes. Variable‐temperature (VT) 31P{1H} NMR spectra showed two signals, assigned to cis‐ and trans‐1,2‐oxaphosphetanes, which were observed at different temperatures (–80 °C and –40 °C, respectively) in the Wittig reaction between benzaldehyde and the nonstabilized phosphonium ylide bearing the phosphastibatriptycene skeleton, in the presence of both lithium and sodium salts, and showed the existence of equilibrium between these products at –40 °C. On the other hand, this equilibrium was not clearly observed in the reaction between the triphenylphosphonium ylide and benzaldehyde, for which only one signal was detected. The observed intermediates were confirmed to be 1,2‐oxaphosphetanes by deprotonation of the isolated β‐hydroxyalkylphosphonium salts bearing a phosphastibatriptycene skeleton and a triphenylphosphine moiety, respectively. Crossover reactions were conducted in the deprotonations of β‐hydroxyalkylphosphonium salts with TMS2NNa in the presence of p‐chlorobenzaldehyde, resulting in the observation of signals corresponding to 1,2‐oxaphosphetanes containing phenyl and p‐chlorophenyl groups at the 4‐positions, indicating the exchange process between benzaldehyde and p‐chlorobenzaldehyde at –40 °C for the phosphastibatriptycene system and at 0 °C for triphenyl derivatives. These results clearly indicated that stereochemical drift occurred at those temperatures, even in reactions using nonstabilized phosphonium ylides. The stereochemical drift in the phosphastibatriptycene system occurred at a lower temperature than in the case of the triphenyl derivative, thus explaining the (E)‐selective Wittig reactions between the benzaldehyde derivatives and the nonstabilized phosphastibatriptycene‐based phosphonium ylide in the presence of lithium and sodium salts.

Stereoselective synthesis of (R)-(−) and (S)-(+)-phoracantholide I from (R)-(+)-γ-valerolactone

A concise total synthesis of (R)-(−)-phoracantholide I 1 and (S)-(+)-phoracantholide I 2 has been developed from (R)-(+)-γ-valerolactone 6. The key steps in the synthesis of these macrolides involved enzymatic reduction of Levulinic ester 4 by asymmetric dehydrogenase, Z-selective Wittig reaction of (4-carboxybutyl)triphenylphosphonium ylide 11 with lactol 7, and cyclization of seco-acid 8 using either a Yamaguchi lactonization protocol or a Mitsunobu protocol to afford (R)-(−)-phoracantholide I and (S)-(+)-phoracantholide I respectively.

ChemInform Abstract: The Use of Methyl 2,2‐Difluoro‐2‐(fluorosulfonyl)acetate as the Difluorocarbene Source to Generate an in situ Source of Difluoromethylene Triphenylphosphonium Ylide.

AbstractThis new Wittig‐type reaction of difluorocarbene (II) with aldehydes or an activated ketone produces 1,1‐difluoroalkenes in good yields.

The use of methyl 2,2-difluoro-2-(fluorosulfonyl)acetate as the difluorocarbene source to generate an in situ source of difluoromethylene triphenylphosphonium ylide

Under moderate conditions in the presence of a demethylating reagent, such as iodide, methyl 2,2,-difluoro-2-(fluorosulfonyl)acetate (MDFA) releases difluorocarbene, which in the presence of triphenylphosphine forms difluoromethylene triphenylphosphonium ylide. When the process is carried out also in the presence of aldehydes or activated ketones, the ensuing in situ Wittig-type reaction of the ylide with the carbonyl reactants produces 1,1-difluoroalkenes in good yield. Density Functional Theory calculations were used to provide new estimates of the energies and structures of singlet and triplet states of CH2:, CHF:, and CF2: carbenes, as well as those of their respective triphenylphosphonium ylides.

Syntheses of (−)-Tatarinoid A, (±)-Tatarinoid B, and (−)-Tatarinoid C

The syntheses of (−)-Tatarinoid A, (±)-Tatarinoid B, and (−)-Tatarinoid C in one to three steps are described herein. (−)-Tatarinoid A and (−)-Tatarinoid C are both constructed in three steps from 1-bromo-2,4,5-trimethoxybenzene in overall yields of 63% and 74%, respectively. The addition of (1-methoxyethyl)triphenylphosphonium ylide to 2,4,5-trimethoxybenzaldehyde provides (±)-Tatarinoid B in one step in 97% yield.

Synthesis, Kinetics and Mechanism of Terpolymerization of Styrene, Vinyl Acetate with Acrylonitrile Initiated by P-Nitrobenzyl Triphenyl Phosphonium Ylide

Synthesis of terpolymers consisting of two electron-donating monomers, viz. styrene and vinyl acetate with one electron-accepting monomer, i.e. acrylonitrile, initiated by p-nitrobenzyl triphenyl phosphonim ylide in dioxane as diluent at 65°C for 150 min has been studied. The kinetic expression is Rpα[I]0.8[Sty] 1.2[VA] 1.4 [AN]1.2. The terpolymer composition was determined by the Kelen-Tüdos method. The values of reactivity ratios using r1 (Sty + VA) = 0.1 and r2 (AN) = 0.005. The overall activation energy is 46 kJ●mol●L–1. The formation of terpolymer is confirmed by the FTIR spectra showing bands at 3030 cm–1, 1598 cm–1, and 2362 cm–1, confirming the presence of phenyl, acetoxy and nitrile group respectively. The terpolymer has been characterized by 1H-Nuclear Magnetic Resonance, 13C-Nuclear Magnetic Resonance. The Differential Scanning Calorimetric curve shows the Tg of the polymer as 149.5°C. A scanning electron microscope confirms the polymer to be phosphorus free. Electron.Spin.Resonance spectra confirms phenyl radical responsible for initiation.

Synthesis, Kinetics and Mechanism of Terpolymerization of Styrene, Vinyl Acetate with Acrylonitrile Initiated by P-Nitrobenzyl Triphenyl Phosphonium Ylide

Synthesis, Kinetics and Mechanism of Terpolymerization of Styrene, Vinyl Acetate with Acrylonitrile Initiated by P-Nitrobenzyl Triphenyl Phosphonium Ylide

Free energy landscapes in THF for the wittig reaction of acetaldehyde and triphenylphosphonium ylide

AbstractThe B3P86/6‐31G* mechanistic results for the Wittig reaction of triphenylphosphonium ylide and acetaldehyde, in vacuo and in tetrahydrofuran (THF) in the IEF‐PCM framework, led to distinct behaviors. In particular, only a gauche betaine (Bg) was obtained in the gas phase and the relevant barriers were smaller than those found for a realistic system (a bulky chiral aldehyde (Alagona and Ghio, Theor Chem Acc 2009, 123, 337)). Conversely, in THF, both mechanisms (via oxaphosphetanes (OPs) only and via betaines plus OPs were represented with significant TS1/TSb barriers. Furthermore, an additional gauche betaine, named B′g, was located (Alagona and Ghio, Int J Quant Chem 2010, 110, 765). A number of open questions however called for an answer. The main issues addressed in this study are: (i) Can Bg and B′g proceed to products along different reaction paths on the same hypersurface in THF? (ii) If it is not so, can they interconvert into each other? (iii) Might the reaction proceed via an anti betaine‐type intermediate? (iv) Is it possible to find a pathway leading directly to a transition state along the path to products without passing through an OP intermediate, as suggested on the basis of quantum molecular dynamics simulations on trimethylphosphonium ylide in dimethylsulfoxide (Ziegler et al., J Phys Chem A 2005, 109, 5136)? The answers to these questions depend on the fact that the phenyl groups at the phosphonium ylide are of paramount importance for obtaining a correct reaction behavior. © 2010 Wiley Periodicals, Inc. Int J Quantum Chem 110:2509–2521, 2010

Dependence of the wittig reaction mechanism on the environment and on the substituents at the aldehyde group and at the phosphonium ylide

AbstractThe B3P86/6‐31G* mechanistic results for the Wittig reaction of acetaldehyde, CH3CHO, in vacuo and in tetrahydrofuran (THF) solution in the IEF‐PCM framework, with an unsubstituted trimethylphosphonium or triphenylphosphonium ylide, that is Me3PCH2 or Ph3PCH2, have been compared to those recently obtained at the same levels for the reaction of Ph3PCH2 with a bulky chiral aldehyde, (2S,3R)‐2,4‐dimethyl‐3‐pyrrol‐1‐yl‐pentanal [TCA (DOI: 10.1007/s00214‐009‐0521‐4)], here named sys for short. The two model systems show distinct, but similar, behaviors that however differ from the large system one. In particular, betaine‐type intermediates are not located in vacuo when Me3PCH2 is used, while only a gauche betaine is obtained using Ph3PCH2; the relevant barriers are anyway smaller than those found for sys. Conversely, in THF, the concerted and stepwise mechanisms are both represented and show TS1/TSb barriers, which are negligibly small for sys. Thus, in contrast to assessed literature, models with methyl groups in place of phenyl rings and branched aldehyde chains show a different behavior from realistic systems and prevent inferring general rules from their use, suggesting to resort to Ph3PCH2 whose results in vacuo and in THF are closer to sys. © 2009 Wiley Periodicals, Inc. Int J Quantum Chem, 2010

Stepwise versus concerted mechanisms in the Wittig reaction in vacuo and in THF: the case of 2,4-dimethyl-3-pyrrol-1-yl-pentanal and triphenylphosphonium ylide

The Wittig reaction of the unsubstituted triphenylphosphonium ylide (Ph3PCH2) on an aldehyde with two stereogenic centers ((2S,3R)-2,4-dimethyl-3-pyrrol-1-yl-pentanal) has been investigated with a density functional approach at the B3P86/6-31G* level in vacuo and in tetrahydrofuran (THF) to shed some light on the mechanistic details when bulky chiral substrates are employed in the absence of E/Z selectivity issues. The interest is focused on the reaction intermediates, primarily on those that cannot be observed spectroscopically. Both the concerted mechanism (with a four-center transition state (TS)) and the stepwise one (occurring via a betaine-type zwitterionic intermediate) have been explored, examining the potential energy profiles as well as the free energy ones. The solvent effect in the integral equation formalism-polarizable continuum model (IEF-PCM) framework has also been considered for THF. Interestingly, the early TS found in vacuo for both mechanisms becomes vanishingly small in THF, while the reactant adducts turn out to be somewhat destabilized, with an overall similarity in the relevant profiles.

Resin-Bound (Succinimid-1-yloxycarbonylmethyl)triphenylphosphonium Ylide - A Synthon for Rapid Access to Diverse Heterocycles under Microwave Heating

The synthesis of a novel and versatile resin-bound (succinimid-1-yloxycarbonylmethyl)triphenylphosphonium ylide is described. The use of this resin to the synthesis of several diverse heterocycles, whilst allowing for ease of workup, is reported.

Inductive and External Electric Field Effects in Pentacoordinated Phosphorus Compounds.

Pentacoordination at phosphorus is associated with a nucleophilic displacement reaction at tetracoordinated phosphorus compounds and shows a great variability in what respects their geometrical and energetic features. By means of a systematic theoretical study on a series of elementary model compounds, we have analyzed the bonding features. The pentacoordinated phosphorus compounds are held together by dative bonds, and the geometry and stability depends on the inductive effects originated by different substitutes at phosphorus. We show also that an external electric field can modify the geometrical features and the reactivity of the nucleophilic substitution reactions. This issue may have great interest in biological reactions involving pentacoordinated phosphorus where the electric field originated by the folded protein could influence the catalytic process. We report also additional calculations on the geometry and NMR spectra on three triphenyl phosphonium ylide derivatives, and our results compare well with the experimental data.

Synthesis and Characterization of Methylmethacrylate-alt-N-vinyl-2-pyrrolidone Initiated by Phosphorus Containing 1,2 Dipolar Compound

Copolymerization of methylmethacrylate (MMA) with 1-vinyl-2-pyrrolidone (N-VP), initiated by p-nitrobenzyl triphenyl phosphonium ylide in dioxane at 60°C for 60 min under inert atmosphere of nitrogen yields alternating copolymer as evidenced by the values of r 1 = 0.01 and r 2 = 0.02. The kinetic expression was Rp ∝ [I]0.75[MMA]1.2[VP]1.2. The overall activation energy is 45.4 kJ/mol. The FTIR bands of OCH3 of MMA at 1725 cm−1 and –C=O of N-VP at 1679 cm−1, confirms the incorporation of both the monomers in the copolymer. The glass transition temperature of the copolymer is 133°C. The GPC data shows the polydispersity index at about 1.5. The ESR spectroscopy confirm phenyl radical responsible for initiation.

Terpene-based semi-interpenetrating polymer networks initiated by p-nitrobenzyl triphenyl phosphonium ylide: synthesis and characterization

A series of semi-interpenetrating polymer networks (IPNs) based on poly(α-terpineol-costyrene) and ethylacrylate cross-linked with divinyl benzene have been synthesized at 80°C for 80 min in dioxane, initiated by p-nitrobenzyl triphenyl phosphonium ylide, under an inert atmosphere of nitrogen. The Fourier transform infrared spectrum attributes structural evidences for IPNs, indicating characteristic frequencies of the ester group of ethyl acrylate at 1727 cm−1 and alcoholic group of α-terpineol at 3390 cm−1. The percentage swelling and average molecular weight between cross-links (m c) are a direct function of α-terpineol-co-styrene and p-nitrobenzyl triphenyl phosphonium ylide and inverse function of ethyl acrylate and divinylbenzene. The semi-IPN system is confirmed by two T g values from the differential scanning calorimetry scan at 15 and 59°C. SEM micrographs show phase separation. The thermogravimetric analysis (TGA) curve shows the IPN to be thermally stable. From the TGA curve the activation energy is calculated using the Coats and Redfern equation to be 23 kJ/mol.

Free‐radical polymerization of styrene with p‐nitrobenzyl triphenyl phosphonium ylide as an initiator

AbstractThe free‐radical polymerization of styrene with p‐nitrobenzyl triphenyl phosphonium ylide as an initiator in dioxane at 80 ± 1 °C in a dilatometer under a nitrogen atmosphere for 150 min resulted in a syndiotactic polymer, as evidenced by IR, 1H NMR, and 13C NMR spectroscopy. A 1H NMR spectrum showed methylene protons as triplets; 13C NMR signals of the phenyl ipso carbons were used for the determination of the tacticity. The system followed ideal kinetics. Gel permeation chromatography data were used evaluate the weight‐average molecular weight. The overall activation energy was 47 kJ/mol. Electron spin resonance spectroscopy confirmed the initiation by the phenyl radical obtained by the dissociation of the ylide and the free‐radical mode of polymerization. Differential scanning calorimetry studies showed the glass‐transition temperature of the polymer to be 342 K. © 2005 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 43: 6524–6533, 2005

Free Radical Polymerisation of Methylmethacrylate Using p-nitrobenzyltriphenyl Phosphonium Ylide as Novel Initiator

p-nitrobenzyl triphenyl phosphonium ylide initiated radical polymerisation of MMA in 1-4 dioxane at 65 ± 1°C for 2 h under a nitrogen blanket, follows ideal kinetics with bimolecular termination. The overall activation energy and average value of kp2/kt are 75.7 kJ mol and 1.14 × 102 l mol−1 s−1. FTIR Spectroscopy confirms a band of 1,729 cm−1 of the ester group. 1H NMR and 13C NMR confirms methoxy protons at 3.8 δ ppm and 52 δ ppm, respectively. E.S.R studies confirm a free radical mode of polymerisation. TGDTA analysis confirms the atactic nature of polymer and its thermal stability up to 120°C. Ylide dissociates to give a phenyl radical which is responsible for polymerisation.

Substituent effect on the transition from ionic to covalent bonding in triphenylphosphonium ylide derivatives: reactivity of 3-methyl-2,2,2-triphenyl-2H-cyclohepta[d][1,2λ5]oxaphosphole with heterocumulenes

X-Ray crystal analysis of 3-methyl-2,2,2-triphenyl-2H-cyclohepta[d][1,2λ5]oxaphosphole [and the triphenylphosphonium ylide] 1a and its parent compound 1b has been carried out. The 31P and 13C NMR spectral studies of 1a,b and their derivatives 1c,d, and the correlation of their chemical shifts with P1–O1 bond lengths obtained by X-ray analyses for 1a–d were investigated to clarify that compounds 1a–d exist as resonance hybrids of a P–O bonding oxaphosphole structure (structure A) and a phosphonium ylide structure (structures B and C). The contribution of the structure A decreases gradually in the order of 1a > 1c > 1b > 1d in the solid state. On the basis of a linear correlation between P1–O1 bond lengths and θsum (the sum of bond angles between the equatorial bonds), it is clarified that an increase of the P1–O1 bonding character causes change in the configuration of the phosphorus atom from a tetrahedral to a trigonal bipyramidal arrangement. In connection with these studies, inspection of the structure of a related compound, 2,2,2-triphenyl-6,11-methano-2H-cycloundeca[d][1,2λ5]oxaphosphole structure 2, was also carried out. With a view to clarifying the reactivity of 1a in connection with a contribution of canonical structures A, B, and C, compound 1a was allowed to react with phenyl isocyanate, diphenylcarbodiimide, and phenyl isothiocyanate to give heteroazulenes. The reaction pathways depending on the contribution of canonical structures A, B, and C are discussed.

Stereoselective Synthesis of Racemic and Optically ActiveE-Vinyl andE-Dienyl Sulfoxides via Wittig Reaction of α-Sulfinyl Phosphonium Ylides

A series of α-sulfinyl phosphonium ylides have been obtained in the reaction of phosphonium mono- and diylides with sulfinic acid esters. The use of (−)-(S)-menthyl p-toluenesulfinate in this reaction afforded the corresponding (S)-((p-tolylsulfinyl)methyl)triphenylphosphonium ylide. The Wittig reaction of these ylides with saturated and unsaturated aldehydes resulted in the formation of racemic and optically active (+)-(R)-vinyl and dienyl sulfoxides with the E-geometry. The synthesis of (+)-(R)-((p-tolylsulfinyl)methyl)triphenylphosphonium iodide as a precursor of the optically active ylide has also been described.