Dialkyl Phosphonates Research Articles

Dimephosphone analogs: a pharmacological aspect

We studied some pharmacological properties of dimephosphone P—C and aza analogs, viz., dimethyl (2-methyl-4-oxopent-2-yl)phosphonate, which is one of the first organophosphorus drugs having no anticholinesterase activity. Replacement of two P—O—C fragments in dialkyl (2-methyl-4-oxopent-2-yl)phosphonates with the P—C ones on going to dialkyl-(2-methyl-4-oxopent-2-yl)phosphine oxides results in a dramatic decrease in the acute toxicity of the latter to warmblooded animals. The toxicities of dimephosphone aza analogs and (γ-oxoalkyl)phosphine oxides under study depend on the nature of aza fragment introduced instead of the oxygen atom. Dimephosphone pyridinoylhydrazones were found to exhibit a high antiinflammatory activity, which increases the interest for this type compounds as promising tuberculostatics.

Mechanistic insight into the copper-catalyzed phosphorylation of terminal alkynes: a combined theoretical and experimental study.

The reaction mechanism of copper-catalyzed phosphorylation of terminal alkynes under different conditions has been investigated experimentally and theoretically. The important role of dioxygen has been elucidated, including the formation of η(1)-superoxocopper(II), η(2)-superoxocopper(III), μ-η(2):η(2)-peroxodicopper(II), and bis(μ-oxo)dicopper(III) complexes. More importantly, the proton transfer from the dialkyl phosphonate (in the form of phosphite) to the bridging oxygen atom entails the migration of the deprotonated phosphonate to the terminal alkyne, leading to the formation of a C-P bond with an activation barrier of only 1.8 kcal/mol. In addition, a particularly stable six-centered dicopper(I) species is formed with the migration of both of the Ph2P(O) groups from the copper atoms to the oxygen atoms of the bis(μ-oxo) bridge, explaining the experimental observation that secondary phosphine oxides can be oxidized to the phosphinic acids. Thus, the diphenylphosphine oxide was added to the reaction mixture dropwise to minimize the concentration during the reaction course. Gratifyingly, the coupling product was generated almost quantitatively when the reaction was completed.

Copper-catalyzed synthesis of mixed alkyl aryl phosphonates.

Copper-catalysis allows the direct oxygen-arylation of dialkyl phosphonates with diaryliodonium salts. This novel methodology proceeds with a wide range of phosphonates and phosphoramidates under mild conditions and gives straightforward access to valuable mixed alkyl aryl phosphonates in very good yields and near perfect selectivity.

Self-condensation reactions of acyl phosphonates: synthesis of tertiary $O$-protected $\alpha $-hydroxyphosphonates

The self-condensation reaction of benzoyl dialkyl phosphonates was developed using cyanide ion as catalyst, affording versatile tertiary O-protected a-hydroxy phosphonates in moderate yield.

Study on the Atherton–Todd reaction mechanism

A new mechanism of the Atherton–Todd reaction is discussed. The first step of the reaction between diesters of H-phosphonic acid and carbon tetrachloride in the presence of a base is a salt formation between carbon tetrachloride and the base [amine·Cl]+CCl3−. The trichloromethanide anion [CCl3−] deprotonates dialkyl H-phosphonate to form chloroform and dialkyl phosphonate anion [(RO)2P(O)]−. The latter anion reacts with the chlorine cation to furnish dialkyl chlorophosphate.

McKenna Reaction—Which Oxygen Attacks Bromotrimethylsilane?

The first experimental proof of the course of silylation in the McKenna reaction, one of the most widely used reactions for the synthesis of organophosphorus acids, is presented. The reaction (in acetonitrile) proceeds via an attack of the terminal oxygen from the dialkyl phosphonate on the silicon atom in bromotrimethylsilane. Isotopically enriched diethyl phenylphosphonates (P═(17)O or P═(18)O) were used as the model compounds. The location of the isotopic tracers was detected using (31)P and (17)O NMR spectroscopy.

PREPARATION OF PYRIMIDINE DERIVATIVES THROUGH THREE-COMPONENT REACTIONS OF DIALKYL (2-OXO-3,3,3-TRIFLUOROPROPYL)PHOSPHONATES

Methods are proposed for the preparation of fluorophosphorus-containing pyrimidines through three-component reactions of dialkyl (3,3,3-trifluoro-2-oxopropyl)phosphonates. Cyclocondensation of these phosphonates with urea and aryl aldehydes gave 6-aryl-4-hydroxy-2-oxo-4-trifluoromethylhexahydropyrimidin-5-ylphosphonates and reaction with urea and trialkyl orthoformates led to 4-alkoxy-2-oxo-4-trifluoromethyl-1,2,3,4-tetrahydropyrimidin-5-ylphosphonates. Authors: V. M. Timoshenko, Yu. N. Markitanov, and Yu. G. Shermolovich. English translation in Chemistry of Heterocyclic Compounds , 2011, 47 (8), pp 977-982 http://link.springer.com/article/10.1007/s10593-011-0863-4

ChemInform Abstract: Palladacycle‐Catalyzed Phosphonation of Aryl Halides in Neat Water.

AbstractCyclopalladated ferrocenylimines are found to be efficient catalysts for the phosphonation of aryl halides with dialkyl phosphonates.

Natural Sesquiterpene Lactones as Renewable Chemical Materials for New Medicinal Products

<p>Literature data and own research results on the technology for isolating natural sesquiterpene lactones such as arglabin, alantolactone, artemisinin, grosheimin, isoalantolactone, parthenolide, santonin and potential possibilities of their use as renewable material for obtaining new compounds as well as biologically active derivatives are generalized in this review. Sesquiterpene lactones from plants are promising sources for the development and practical application of new original medical products possessing antitumor, anti-inflammatory, antimalarial, antiulcer, antiviral and immune-stimulating action. The technology for isolating sesquiterpene lactones is based on the extraction of raw plant material by different organic solvents with the subsequent chromatographic purification. The effective and environmentally safe technology for isolation and purification of sesquiterpene lactone arglabin from <em>Artemisia glabella</em> Kar. et Kir. by the СО<sub>2</sub>-extraction method is developed. Thereat, it was experimentally determined that the method for isolating arglabin from CO<sub>2</sub> extract of <em>Artemisia glabella</em> Kar. et Kir. using centrifugal partition chromatography is effective for preparative isolation of the active substance and its manufacturing application. It is practically important to obtain water-soluble derivatives of biologically active sesquiterpene lactones and also to use the nanotechnology achievements for directed transportation of a molecule of the medicine in the human body thereby reducing toxicity of an active component. Promising direction is chemical modification of molecules in sesquiterpene lactones which are renewable material for obtaining new derivatives, thanks to which it becomes possible to solve two problems at the same time. Firstly, these researches help to obtain derivatives with higher biological activity or improved physical and chemical properties. Secondly, these researches enable us to disclose the mechanism of action of different medicines within the framework of “structure-activity” correlation. The article presents the literature data and own results on chemical modification of sesquiterpene lactones of alantolactone, arglabin, artemisinin, grosheimin, isoalantolactone, parthenolide and santonin. Various reactions on functional groups of these molecules were used to obtain a number of new derivatives of sesquiterpene lactones containing haloid-, pyrazole-, triazole-, amino-, dialkylamino-, hydroxy-, dialkyl phosphonate- and cyclopropane groups, which have shown high physiological activity.</p>

FeCl3‐Mediated Arylation of α‐Hydroxyphosphonates with Unactivated Arenes: Pseudo‐Umpolung in Allylic Phosphonates

AbstractAn FeCl3‐mediated regio‐ and stereoselective Friedel–Crafts‐type arylation of α‐hydroxy phosphonates with unactivated arenes has been developed in which the unstable allylphosphonate cations generated are stabilized by extended conjugation. The approach provides a simple, efficient and economic approach to highly demanding stereoselective γ‐aryl‐substituted vinylphosphonates and dialkyl (diarylmethyl)phosphonates with good regioselectivity. These reactions proceed under mild conditions and proceed in the absence of any additional solvent.

Synthesis of 15‐, 16‐, and 17‐Membered Bis‐C‐Pivot Macrocycles Consisting of N2O2 Donor‐Type Crown Ethers and Dialkyl Phosphonates

ABSTRACTBis‐C‐pivot macrocycles containing aminophosphonate functions (5–10) have been synthesized and characterized by elemental analysis, FTIR, MS, 1D 1H, 13C and 31P NMR, and 2D HETCOR techniques. The phosphorylation reaction of dibenzo‐bis‐imino crown ethers (1–4) with dimethyl and diethyl phosphite used here has the potential to provide bis‐C‐pivot macrocycles (5–10), which possess two stereogenic C‐centers giving rise to diastereoisomers (meso and racemic). Detailed spectral assignments for the meso and racemic forms of the compounds are reported on the basis of chemical shifts, signal intensities, spin–spin coupling constants, and splitting patterns. The bis‐C‐pivot macrocycles (5–10) may serve as a potential new class of supramolecular host molecules.

Supported monocationic copper(II) complexes obtained by coordination with dialkylphosphonate groups on styrene–divinylbenzene copolymer as catalysts for oxidation of organic compounds

New catalysts were synthesized by immobilization of neutral and monocationic copper complexes Cu(hfac)2 (hfac−=hexafluoroacetylacetonato ligand) and [Cu(acac)(tmen)]NO3 (acac−=acetylacetonato ligand, tmen=N,N,N′,N′-tetramethyl-ethylendiamine) on styrene–divinylbenzene copolymer functionalized with four different dialkyl phosphonate moieties typified by PPO(OR)2 (with R=CH3, C2H5, iC3H7, and nC4H9). The formation of P(O)(OR)2 phosphonates groups has been confirmed by the FT-IR spectra. Thermogravimetric analysis results reveal that the thermal stability of polymer support depend on the functional group attached. The complexes were anchored by coordination interaction between the copper(II) ion and the phosphonate oxygen atom on each of the four functionalized supports and the strength of the PO⋯Cun+ coordination interaction was influenced by the nature of the R group. The effect of functionalized supports on the structure and catalytic activity of Cu(hfac)2 and [Cu(acac)(tmen)]+ mononuclear species was determined in oxidation of several organic compounds (anisole, cyclohexene, toluene, styrene, phenol) with hydrogen peroxide. The catalytic activity results show that the activity and selectivity of Cu(II) complexes depends on the equilibrium between steric factor and inductive electron-releasing effect. The best selectivity was obtained in oxidation of anisole, phenol and styrene for all the catalysts. The main products were for 2-methoxyphenol, catechol and benzaldehyde, respectively.

ChemInform Abstract: Mild and Efficient Esterification of Alkylphosphonic Acids Using Polymer‐Bound Triphenylphosphine.

AbstractA convenient procedure is developed for the synthesis of dialkyl phosphonates from alkylphosphonic acids and primary alcohols under mild conditions.

ChemInform Abstract: Preparation of Pyrimidine Derivatives Through Three‐Component Reactions of Dialkyl (2‐Oxo‐3,3,3‐trifluoropropyl)phosphonates.

Methods are proposed for the preparation of fluorophosphorus-containing pyrimidines through three- component reactions of dialkyl (3,3,3-trifluoro-2-oxopropyl)phosphonates. Cyclocondensation of these phosphonates with urea and aryl aldehydes gave 6-aryl-4-hydroxy-2-oxo-4-trifluoromethylhexa-hydropyrimidin-5-ylphosphonates and reaction with urea and trialkyl orthoformates led to 4-alkoxy-2-oxo-4-trifluoromethyl-1,2,3,4-tetrahydropyrimidin-5-ylphosphonates.

ChemInform Abstract: Direct Oxidative Phosphonylation of Amines under Metal‐Free Conditions.

AbstractA method for the regioselective α‐phosphonylation of N‐arylated tetrahydroisoquinolines allows the use of diphenyl and dialkyl phosphonates.

Preparation of pyrimidine derivatives through three-component reactions of dialkyl (2-oxo-3,3,3-trifluoropropyl)phosphonates

Methods are proposed for the preparation of fluorophosphorus-containing pyrimidines through three- component reactions of dialkyl (3,3,3-trifluoro-2-oxopropyl)phosphonates. Cyclocondensation of these phosphonates with urea and aryl aldehydes gave 6-aryl-4-hydroxy-2-oxo-4-trifluoromethylhexa-hydropyrimidin-5-ylphosphonates and reaction with urea and trialkyl orthoformates led to 4-alkoxy-2-oxo-4-trifluoromethyl-1,2,3,4-tetrahydropyrimidin-5-ylphosphonates.

ChemInform Abstract: Synthesis of Phosphonylated and Thiolated Indenones by Manganese(III)‐Mediated Addition of Phosphorus‐ and Sulfur‐Centered Radicals to 1,3‐Diarylpropynones.

Phosphorus- or sulfur-centered radicals generated from the reaction of manganese (III) acetate with dialkyl phosphonates or arylthiols undergo selective additions to conjugated alkynes followed by cyclization and rearomatization to afford 2-phosphonyl- or 2-thioaryl-substituted indenones in fair to good yields.

Syntheses, spectroscopic properties and stereochemistry of bis-C-pivot macrocycles with two dialkyl phosphonate groups

Bis-C-pivot macrocycles containing dimethyl ( 1a, 2a) or diethyl phosphonate ( 1b, 2b) groups have been prepared by adding dimethyl or diethyl phosphite to two –CH N bonds in corresponding dibenzo-bis-imino crown ethers ( 1 and 2). Bis-C-pivot macrocycles possess two equivalent stereogenic centres giving rise to diastereoisomers ( meso and racemate). The structures were characterized by elemental analysis, FTIR, MS, TGA, DSC and NMR measurements. 1H, 13C and 31P NMR assignments were made for the isolated meso form of compounds 2a and 2b and for the meso and racemic forms of compounds 1a and 1b by analysis of chemical shifts, signal intensities and splitting patterns and the DEPT and 2D HETCOR NMR techniques. Thermal analysis and 1H NMR showed that the crystallised form of compound 1a contained an equimolar amount of water of crystallisation.

Synthesis of Phosphonylated and Thiolated Indenones by Manganese(III)‐Mediated Addition of Phosphorus‐ and Sulfur‐Centered Radicals to 1,3‐Diarylpropynones

AbstractPhosphorus‐ or sulfur‐centered radicals generated from the reaction of manganese(III) acetate with dialkyl phosphonates or arylthiols undergo selective additions to conjugated alkynes followed by cyclization and rearomatization to afford 2‐phosphonyl‐ or 2‐thioaryl‐substituted indenones in fair to good yields.

Efficient synthesis and biological properties of the 2′-trifluoromethyl analogues of acyclic nucleosides and acyclic nucleoside phosphonates

Efficient and optimized procedure for the preparation of several acyclic nucleosides and acyclic nucleoside phosphonates substituted at the C-2′ position of the aliphatic part by the trifluoromethyl group is described. Trifluoromethyloxirane was found to be an excellent reagent for the introduction of the 1,1,1-trifluoropropan-2-ol moiety. Surprisingly, the next reaction of these 1,1,1-trifluoropropan-2-ols with the reagent for the introduction of the methylphosphonic residue afforded the desired phosphonates in very high yields and finally a novel simple and scalable procedure for the isolation of free phosphonic acids, after the reaction of dialkyl phosphonates with bromotrimethylsilane, was developed. Prepared compounds were evaluated for their biological properties, but none of the prepared phosphonic acids or acyclic nucleosides exhibits any antiviral, antiproliferative or anti-toxin activities.