Novel Base‐Free Catalytic Wittig Reaction for the Synthesis of Highly Functionalized Alkenes

A highly efficient catalyst system for base‐free catalytic Wittig reactions has been developed and optimized. Initially, several potential (pre)catalysts as well as different silanes as reducing agents were screened. A system based on a readily available phosphine oxide as precatalyst and trimethoxy silane as reducing agent proved to be optimal. The effect of various Brønsted acidic additives was studied. Subsequently, the reaction conditions were optimized and standard reaction conditions were determined. Under these conditions the scope of this new protocol was evaluated. Nine activated olefins and 33 aldehydes were converted into 42 highly functionalized alkenes. Notably, aromatic, aliphatic as well as heteroaromatic aldehydes could be converted, giving the desired products in isolated yields up to 99 % and with good to excellent E/Z selectivities. These results underline the remarkable efficiency of this protocol considering the complexity of the reaction mixture and the four reaction steps that proceed in parallel in one pot.     

Part I: The Development of the Catalytic Wittig Reaction

We have developed the first catalytic (in phosphane) Wittig reaction (CWR). The utilization of an organosilane was pivotal for success as it allowed for the chemoselective reduction of a phosphane oxide. Protocol optimization evaluated the phosphane oxide precatalyst structure, loading, organosilane, temperature, solvent, and base. These studies demonstrated that to maintain viable catalytic performance it was necessary to employ cyclic phosphane oxide precatalysts of type 1 . Initial substrate studies utilized sodium carbonate as a base, and further experimentation identified N,N‐diisopropylethylamine (DIPEA) as a soluble alternative. The use of DIPEA improved the ease of use, broadened the substrate scope, and decreased the precatalyst loading. The optimized protocols were compatible with alkyl, aryl, and heterocyclic (furyl, indolyl, pyridyl, pyrrolyl, and thienyl) aldehydes to produce both di‐ and trisubstituted olefins in moderate‐to‐high yields (60–96 %) by using a precatalyst loading of 4–10 mol %. Kinetic E/Z selectivity was generally 66:34; complete E selectivity for disubstituted α,β‐unsaturated products was achieved through a phosphane‐mediated isomerization event. The CWR was applied to the synthesis of 54 , a known precursor to the anti‐Alzheimer drug donepezil hydrochloride, on a multigram scale (12.2 g, 74 % yield). In addition, to our knowledge, the described CWR is the only transition‐/heavy‐metal‐free catalytic olefination process, excluding proton‐catalyzed elimination reactions.     

Catalytic Wittig Reactions of Semi‐ and Nonstabilized Ylides Enabled by Ylide Tuning

The first examples of catalytic Wittig reactions with semistabilized and nonstabilized ylides are reported. These reactions were enabled by utilization of a masked base, sodium tert‐butyl carbonate, and/or ylide tuning. The acidity of the ylide‐forming proton was tuned by varying the electron density at the phosphorus center in the precatalyst, thus facilitating the use of relatively mild bases. Steric modification of the precatalyst structure resulted in significant enhancement of E selectivity up to >95:5, E/Z.     

Orthopalladated triarylphosphite complexes as highly efficient catalysts in the Heck reaction

An orthopalladated complex of commercially available tris(2,4-di-tert-butylphenyl)phosphite proves to be an extremely active catalyst in the Heck arylation of alkenes, with turnover numbers of up to 5,750,000 (mol product.mol Pd⁻¹) and turnover frequencies of up to nearly 300,000 (mol product.mol Pd⁻¹.h⁻¹).     

Cu/Fe‐Cocatalyzed Formation of β‐Ketophosphonates by a Domino Knoevenagel–Decarboxylation–Oxyphosphorylation Sequence from Aromatic Aldehydes and H‐Phosphonates

A domino Knoevenagel–decarboxylation–alkene difunctionalization sequence has been developed for the conversion of benzaldehydes into β‐ketophosphonates, catalyzed by a cooperative Cu/Fe system, whereby C?P and C?O bonds are formed simultaneously in a one‐pot reaction. The reaction proceeds in good yields and with a broad substrate scope and environmentally benign conditions.     

Unexpected course of Wittig reaction when using cinnamyl aldehyde as a substrate

When trans-cinnamyl aldehyde was used as a substrate of the Wittig reaction, instead of the olefination product, formation of four products with (E)-1,3-diphenylprop-2-en-1-ol and cinnamyl alcohol was observed being quite unexpected ones. The possible mechanism of this unusual reaction has been considered.     

(Eta2-alkyne)methyl(dioxo)rhenium complexes as aldehyde-olefination catalysts

Complexes CH3ReO2L (L = 2-butyne, 3-hexyne, diphenylacetylene) are catalysts for the olefination of aldehydes, using 4-nitrobenzaldehyde (4-nba) as the standard aldehyde and ethyldiazoacetate (eda) as the diazo compound. Spectroscopic studies including in situ 31P, 17O, 13C, and 1H NMR spectroscopy are used to elucidate the mechanism and the nature of the active species. One of the key steps of the mechanism is the rapid formation of phosphazine at the beginning of the cycle and its subsequent reaction with the metal dioxide complex to form the catalytically active carbene species.     

Cycloruthenated complexes as homogeneous catalysts for atom-transfer radical additions

Various cycloruthenated complexes were used as homogeneous catalysts for the atom-transfer radical addition of polyhalogenated compounds to several olefinic substrates. Yields obtained through conventional or microwave heating could reach high values (up to 98% with CBrCl₃ and 88% with CCl₄).     

Polymer fibers as carriers for homogeneous catalysts

This paper describes a polymer fiber-based approach for the immobilization of homogeneous catalysts. The goal is to generate products that are free of catalysts which would be of great importance for the development of optoelectronic or pharmaceutical compounds. Electrospinning was employed to prepare the non-woven fiber assembly composed of polystyrene. The homogeneous catalyst scandium triflate was immobilized on the polystyrene fibers during electrospinning and on corresponding core shell fibers using a fiber template approach. An imino aldol and an aza-Diels-Alder model reaction were carried out with each fibrous catalytic system. This resulted in the immobilization of homogeneous catalysts in a polymer environment without loss of their catalytic activity and may even be enhanced when compared with reactions carried out in homogeneous solutions.     

Bis(β‐enaminoketonato) vanadium (III or IV) complexes as catalysts for olefin polymerization

Bis(β‐enaminoketonato) vanadium(III) complexes ( 2a–c ) [O(R₁)C?C(H)_xC(R₂)?NC₆H₅]₂VCl(THF) and the corresponding vanadium(IV) complexes ( 3a–c ) [O(R₁)C?C(H)_xC(R₂)? NC₆H₅]₂VO (R₁ = ? (CH₂)₄? , R₂ = H, x = 0, a ; R₁ = ? C₆H₅, R₂ = H, x = 1, b ; R₁ = ? C₆H₅, R₂ = ? C₆H₅, x = 1, c ) have been synthesized from VCl₃(THF)₃ and VOCl₂(THF)₂, respectively, by treating with 2.0 equivalent β‐enaminoketonato ligands in tetrahydrofuran. Structures of 2b and 3a–c were further confirmed by X‐ray crystallographic analysis. The complexes were investigated as the catalysts for ethylene polymerization in the presence of Et₂AlCl. Complexes 2a–c and 3a–c exhibited high catalytic activities (up to 23.76 kg of PE/mmol_V h bar), and afforded polymers with unimodal molecular weight distributions at 70 °C indicating the good thermal stability. The catalytic behaviors were influenced not only by the oxidation state of the catalyst precursors but also by the ligand structures. Complexes 2a–c and 3a–c were also effective catalyst precursors for ethylene/1‐hexene copolymerization. The influence of polymerization parameters such as reaction temperature, Al/V molar ratio and hexene feed concentration on the ethylene/hexene copolymerization behaviors have bee also investigated in detail. In addition, the agents such as AlMe₃, AlⁱBu₃, MeMgBr, MgCl₂, and ZnEt₂ were applied to control the molecular weight and molecular weight distribution modal. © 2010 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 48: 3062–3072, 2010     

Domino hydroformylation-Wittig olefination-hydrogenation

Rhodium-catalyzed hydroformylation in the presence of stabilized phosphorus ylides initiates a domino hydroformylation-Wittig olefination process. When mono-substituted acceptor-stabilized phosphorus ylides were employed, a hydrogenation step succeeds the Wittig olefination to give a domino hydroformylation-Wittig olefination hydrogenation process. For the hydroformylation key step both, linear regioselective hydroformylation of terminal alkenes based on catalyst control as well as diastereoselective hydroformylation based on ortho-diphenylphosphanylbenzoate (o-DPPB)-directed active substrate control could be employed.