Advances in organocatalysis of the Michael reaction by tertiary Phosphines

Salin, Alexey V.; Shabanov, Andrey A.

doi:10.1080/01614940.2023.2168352

Cited by 6 publications

(10 citation statements)

References 188 publications

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“…Scheme outlines the general mechanism for the phosphine-catalyzed Michael (Pudovik) addition to α-methylene lactones proposed on the basis of kinetic, quantum-chemical, synthetic results presented in this work, and literature data. ,, …”

Section: Resultsmentioning

confidence: 99%

“…Recalling that the generation of phosphonium enolate is the initial step in the reactions of electron-deficient alkenes catalyzed by tertiary phosphines, we anticipated that the stereoelectronic effect would be useful in improving the efficiency of these transformations. Despite the great utility of phosphine-catalyzed reactions, they have limitations associated with substantial erosion in efficiency for substituted alkenes, and long-sustained reaction times, elevated temperatures, highly nucleophilic tertiary phosphines, and increased catalyst loadings are usually needed to achieve reasonable yields of the products, albeit with typically reduced chemoselectivity.…”

Section: Resultsmentioning

confidence: 99%

“…Enolizable acetyl acetone 7f was reactive but delivered complex inseparable reaction mixtures (Table , entries 10 and 11). The chemistry of all other studied reactions was remarkably clean, largely due to the fact that α-methylene lactones are not able to participate in the phosphine-catalyzed Rauhut–Currier dimerization, , which usually competes with the Michael addition to reactive unsubstituted alkenes. All studied reactions were carried out on gram scale to demonstrate the practical utility of the developed protocol.…”

Section: Resultsmentioning

confidence: 99%

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Stereoelectronic Effect in the Reaction of α-Methylene Lactones with Tertiary Phosphines and Its Application in Organocatalysis

et al. 2023

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The kinetic data indicate that the addition of tertiary phosphines to α-methylene lactones in acetic acid is strongly accelerated in comparison to the reactions of related open-chain esters. Six-membered α-methylene-δ-valerolactone exhibited a more pronounced rate increase than five-membered α-methylene-γ-butyrolactone. The use of α-methylene-γ-butyrolactam as a nitrogen analogue of α-methylene-γ-butyrolactone resulted in a total loss of the reaction acceleration. The observed reactivities were rationalized by DFT calculations at the RwB97XD/6-31+G(d,p) level of theory, showing that the intramolecular interaction between phosphonium and enolate oxygen centers provided by the locked s-cis-geometry of the heterocycles plays an important role in the stabilization of intermediate zwitterions. The reactivity is also controlled by the conformational flexibility of the heterocycle. The geometries of five-membered and, especially, six-membered lactone cycles are slightly changed upon the nucleophilic attack of phosphine, leading to the stabilizing stereoelectronic effect by the Ρ···Ο interaction. The addition of phosphine to α-methylene-γ-butyrolactam significantly distorts the initial geometry of the heterocycle, making the nucleophilic attack unfavorable. The application of the stereoelectronic effect to enhance the efficiency of the phosphine-catalyzed Michael and Pudovik reactions of α-methylene lactones was demonstrated.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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Stereoelectronic Effect in the Reaction of α-Methylene Lactones with Tertiary Phosphines and Its Application in Organocatalysis

et al. 2023

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“…Organocatalysis has emerged as a valuable and powerful tool for performing organic reactions [1] and polymerizations [2] in recent years. In this context phosphines have proven to be potent Lewis-base catalysts [3,4] for a variety of reactions [5], including but not limited to Rauhut-Currier [6], Morita-Baylis Hillman [7] and Michael reactions [8,9,10]. In all the mentioned reactions, the first step of the catalytic cycle is the nucleophilic attack of the phosphine on the electrophile, in many cases an electron deficient olefin.…”

Section: Introductionmentioning

confidence: 99%

“…Another example resulting from phosphine addition to α,β-unsaturated aldehydes was published shortly afterwards [32]. Phosphonium carboxylate zwitterions have been obtained by the reaction of phosphines with acrylic acid [8] and ortho-carboxylated aryl phosphines with several Michael acceptors [33].…”

Section: Introductionmentioning

confidence: 99%

Using the phospha-Michael reaction for making phosphonium phenolate zwitterions

Steiner,

Schmallegger,

Donner

et al. 2023

Preprint

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The reactions of 2,4-di-tert-butyl-6-(diphenylphosphino)phenol and various Michael acceptors (acrylonitrile, acrylamide, methyl vinyl ketone, several acrylates, methyl vinyl sulfone) yield the respective phosphonium phenolate zwitterions at room temperature. Nine different zwitterions were synthesized and fully characterized. Zwitterions with the poor Michael acceptors methyl methacrylate and methyl crotonate formed, but could not be isolated in pure form. The solid-state structures of two phosphonium phenolate molecules were determined by single-crystal X-ray crystallography. The bonding situation in the solid state together with NMR data suggests an important contribution of an ylidic resonance structure in these molecules. The phosphonium phenolates are characterized by UV-Vis absorptions peaking around 360 nm and exhibit a negative solvatochromism. An analysis of the kinetics of the zwitterion formation was performed for three Michael acceptors (acrylonitrile, methyl acrylate and acrylamide) in two different solvents (chloroform and methanol). Results revealed the proton transfer step necessary to stabilize the initially formed carbanion as the rate determining step. A preorganization of the carbonyl bearing Michael acceptors allowed for reasonable fast direct proton transfer from the phenol in aprotic solvents. In contrast, acrylonitrile not capable of forming a similar preorganization, is hardly reactive in chloroform solution, while in methanol the corresponding phosphonium phenolate is formed.

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Phosphine‐Catalyzed Synthesis and Cytotoxic Evaluation of Michael Adducts of the Sesquiterpene Lactone Arglabin

Salin,

Shabanov,

Khayarov

et al. 2024

ChemMedChem

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A general method for chemo‐ and diastereoselective modification of anticancer natural product arglabin with nitrogen‐ and carbon‐centered pronucleophiles under the influence of nucleophilic phosphine catalysts was developed. The locked s‐cis‐geometry of α‐methylene‐γ‐butyrolactone moiety of arglabin favors for the additional stabilization of zwitterionic intermediate by electrostatic interaction between phosphonium and enolate oxygen centers, leading to the unprecedentedly efficient phosphine‐catalyzed Michael additions to this sesquiterpene lactone. Using n‐Bu3P as the catalyst, pyrazole, phthalimide, 2‐oxazolidinone, 4‐quinazolinone, uracil, thymine, cytosine, and adenine adducts of arglabin were obtained. The n‐Bu3P‐catalyzed reaction of arglabin with active methylene compounds resulted in the predominant formation of bisadducts bearing a new quaternary carbon center. All synthesized Michael adducts and previously obtained phosphorylated arglabin derivatives were evaluated in vitro against eleven cancer and two normal cell lines, and the results were compared to those of natural arglabin and its dimethylamino hydrochloride salt currently used as anticancer drugs. 2‐Oxazolidinone, uracil, diethyl malonate, dibenzyl phosphonate, and diethyl cyanomethylphosphonate derivatives of arglabin exhibited more potent antiproliferative activity towards several cancer cell lines and lower cytotoxicity towards normal cell lines in comparison to the reference compounds, indicating the feasibility of the developed methodology for the design of novel anticancer drugs with better therapeutic potential.

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Advances in organocatalysis of the Michael reaction by tertiary Phosphines

Cited by 6 publications

References 188 publications

Stereoelectronic Effect in the Reaction of α-Methylene Lactones with Tertiary Phosphines and Its Application in Organocatalysis

Stereoelectronic Effect in the Reaction of α-Methylene Lactones with Tertiary Phosphines and Its Application in Organocatalysis

Using the phospha-Michael reaction for making phosphonium phenolate zwitterions

Phosphine‐Catalyzed Synthesis and Cytotoxic Evaluation of Michael Adducts of the Sesquiterpene Lactone Arglabin

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