Phosphonate Products Research Articles

CAMDOL-enabled diastereoselective synthesis of α-substituted phosphonates.

Enantiopure α-substituted phosphonic acids are widely utilized as drugs, pesticides, and ligands. Despite numerous synthetic approaches having been investigated, precise construction of P-adjacent chiral tertiary carbon centres by the employment of recoverable chiral auxiliaries is traditional and still one of the most reliable and practical synthetic methodologies so far. Herein, we present a highly diastereoselective synthesis of α-substituted phosphonates via the unique CAMDOL-derived P-substrates by an efficient sequential deprotonation with LiHMDS and alkylation/arylation with RI. A wide range of 30 structurally diverse α-substituted phosphonate products, including the well-known P-analogues of naproxen and ibuprofen, were thus afforded conveniently in up to 92% yields and 99 : 1 diastereomeric ratios. The related chiral phosphonic acid could be easily obtained by simple acidic hydrolysis with fully recovered auxiliary. This CAMDOL-enabled asymmetric synthetic protocol exhibits comparative advantages over known chiral-induction methods with easy accessibility and compatibility of furnishing a variety of C-stereogenic centres in the proximity of the phosphorus atom, including some rare examples.

Environmental-assisted simple synthesis and electrocatalytic performance of Ni-MOF nanorods

It is a tough job for the fabrication of metal phosphonate (MP) products with desired morphologies due to their uncontrolled precipitation reactions between metal ions and phosphonic acids in solution. However, the fabrication of MP nanomaterial with unique controlled morphologies is desired for numerous potential applications due to their exceptional properties. We report the facile and rapid synthesis of very uniform one-dimensional (1-D) nickel phenylphosphonate (NiPP) nanorods without the use of any templates through an inexpensive solution-phase method. For the first time, the formation mechanism of NiPP with 1-D nanostructure is systematically investigated using a series of experiment conditions. The present investigation is extremely important and has never been systematically investigated in the literature. The as-prepared NiPP nanorods are further utilized as electrocatalyst for the oxidation of glucose and methanol.

Electrochemical C\u2013H phosphorylation of arenes in continuous flow suitable for late-stage functionalization

The development of efficient and sustainable methods for carbon-phosphorus bond formation is of great importance due to the wide application of organophosphorus compounds in chemistry, material sciences and biology. Previous C–H phosphorylation reactions under nonelectrochemical or electrochemical conditions require directing groups, transition metal catalysts, or chemical oxidants and suffer from limited scope. Herein we disclose a catalyst- and external oxidant-free, electrochemical C–H phosphorylation reaction of arenes in continuous flow for the synthesis of aryl phosphorus compounds. The C–P bond is formed through the reaction of arenes with anodically generated P-radical cations, a class of reactive intermediates remained unexplored for synthesis despite intensive studies of P-radicals. The high reactivity of the P-radical cations coupled with the mild conditions of the electrosynthesis ensures not only efficient reactions of arenes of diverse electronic properties but also selective late-stage functionalization of complex natural products and bioactive compounds. The synthetic utility of the electrochemical method is further demonstrated by the continuous production of 55.0 grams of one of the phosphonate products.

Facile synthesis of (β-chlorodifluoroethyl)phosphonates via chlorination reaction of difluoroalkyl diazo derivatives with HCl

An efficient chlorination reaction of in situ generated (β-diazo-α,α-difluoroethyl)phosphonates has been achieved with hydrochloric acid as a chlorine source under mild and operationally convenient conditions. The reaction does not need any catalyst and tolerates a wide scope of substrates, which affords the (β-chlorodifluoroethyl)phosphonate products in good to excellent yields. This reaction represents the first example of the halogenation of difluoroalkyl diazo compounds, and also provides an easy way for the synthesis of difluoromethylenephosphonate-containing compounds.

Enantioselective Construction of Tertiary C(sp3)−P Bonds by Thiourea‐based Bifunctional Phosphonium Salt‐catalyzed Hydrophosphonylation of Ketone Compounds

AbstractAsymmetric hydrophosphonylation of carbonyl compounds to generate a variety of optically pure quaternary α‐hydroxy phosphonate molecules is herein described by thiourea‐derived bifunctional phosphonium salt catalysis. This new synthetic protocol has an excellent functional group tolerance, and particularly both aromatic, heteroaromatic and aliphatic α‐ketoesters and 1,2‐diketones were readily transferred into phosphonate products in high yields (up to 99 %) with excellent enantioselectivities (up to 97 % ee). The mechanistic results suggested that both ion pair and hydrogen‐bonding interactions were crucial in asymmetric induction.

The Aryne-Abramov Reaction as a 1,2-Benzdiyne Platform for the Generation and Solvent-Dependent Trapping of 3-Phosphonyl Benzynes.

Synthetic methodology utilizing two aryne intermediates (i.e., a formal benzdiyne) enables the rapid generation of structurally complex molecules with diverse functionality. This report describes the sequential generation of two ortho-benzyne intermediates for the synthesis of 2,3-disubstituted aryl phosphonates. Aryl phosphonates have proven useful in medicinal chemistry and materials science, and the reported methodology provides a two-step route to functionally dense variants by way of 3-phosphonyl benzyne intermediates. The process begins with regioselective trapping of a 3-trifloxybenzyne intermediate by an O-silyl phosphite in an Abramov-like reaction to bond the strained Csp carbons with phosphorus and silicon. Standard aryne-generating conditions follow to convert the resulting 2-silylphenyl triflate into a 3-phosphonyl benzyne, which readily reacts with numerous aryne trapping reactants to form a variety of 2,3-difunctionalized aryl phosphonate products. DFT computational studies shed light on important mechanistic details and revealed that 3-phosphonyl benzynes are highly polarizable. Specifically, the distortion in the internal bond angles at each of the Csp atoms was strongly influenced by both the electronegativity of the phosphonate ester groups as well as the dielectric of the computational solvation model. These effects were verified experimentally as the regioselectivity of benzyl azide trapping increased with more electronegative esters and/or increasingly polar solvents. Conversely, replacing the conventional solvent, acetonitrile, with nonpolar alternatives provided attenuated or even inverted selectivities. Overall, these studies showcase new reactivity of benzyne intermediates and extend the aryne relay methodology to include organophosphonates. Furthermore, this work demonstrates that the regioselectivity of aryne trapping reactions could be tuned by simply changing the solvent.

Asymmetric Synthesis of Stereogenic Phosphorus P(V) Centers Using Chiral Nucleophilic Catalysis.

Organophosphates have been widely used in agrochemistry, as reagents for organic synthesis, and in biochemistry. Phosphate mimics possessing four unique substituents, and thereby a chirality center, are useful in transition metal catalysis and as nucleotide therapeutics. The catalytic, stereocontrolled synthesis of phosphorus-stereogenic centers is challenging and traditionally depends on a resolution or use of stochiometric auxiliaries. Herein, enantioenriched phosphorus centers have been synthesized using chiral nucleophilic catalysis. Racemic H-phosphinate species were coupled with nucleophilic alcohols under halogenating conditions. Chiral phosphonate products were synthesized in acceptable yields (33–95%) and modest enantioselectivity (up to 62% ee) was observed after identification of an appropriate chiral catalyst and optimization of the solvent, base, and temperature. Nucleophilic catalysis has a tremendous potential to produce enantioenriched phosphate mimics that could be used as prodrugs or chemical biology probes.

New Oomycota Fungicides With Activity Against Phytophthora cinnamomi and Their Potential Use for Managing Avocado Root Rot in California.

Phytophthora root rot (PRR), caused by Phytophthora cinnamomi, is the most destructive disease of avocado worldwide. In the United States, mefenoxam and phosphonate products are currently the only registered fungicides for managing avocado PRR. Four new Oomycota-specific and two registered fungicides, all with different modes of action, were evaluated. Seventy-one isolates of P. cinnamomi from avocado in California, most of them collected between 2009 to 2017, were tested for their in vitro sensitivity to the six fungicides. Baseline sensitivity ranges and mean values (in parentheses) of effective concentrations to inhibit mycelial growth by 50% (EC50) for the new fungicides ethaboxam, fluopicolide, mandipropamid, and oxathiapiprolin were 0.017 to 0.069 μg/ml (0.035), 0.046 to 0.330 μg/ml (0.133), 0.003 to 0.011 μg/ml (0.005), and 0.0002 to 0.0007 μg/ml (0.0004), respectively. In comparison, the EC50 value range (mean) was 0.023 to 0.138 μg/ml (0.061) for mefenoxam and 12.9 to 361.2 μg/ml (81.5) for potassium phosphite. Greenhouse soil inoculation trials with 8-month-old Zutano seedlings and 10-month-old Dusa and PS.54 clonal rootstocks were conducted to assess the efficacy of these fungicides for managing PRR. Mefenoxam and potassium phosphite were effective treatments; however, oxathiapiprolin, fluopicolide, and mandipropamid were more effective. Ethaboxam was effective in reducing PRR on the rootstocks evaluated. Oxathiapiprolin reduced PRR incidence and pathogen population size in the soil by >90%, and plant shoot growth and root dry weight were significantly increased compared with the control; thus, oxathiapiprolin was one of the best treatments overall. The high activity and performance of these new fungicides supports their registrations on avocado for use in rotation and mixture programs, including with previously registered compounds, to reduce the risk of development and spread of resistance in pathogen populations.

The effect of phosphonate rate on control of scab on pecan

Scab, caused by the plant pathogenic fungus Venturia effusa, is the major disease of pecan in the southeastern USA. In widely grown susceptible cultivars, frequent application of fungicides is the only option to control the disease. Unfortunately resistance to some fungicides has developed so management of the chemistries available is critical for the industry. Understanding how rate affects disease control is important to ensure that control is maximized. We compared the effect of different rates of phosphonate products in reducing scab in a total of six field experiments from 2015 to 2018 at two locations in Georgia. Cultivar Desirable was used in four experiments, and cv. Wichita was included in 2 years at one location. Depending on experiment, four rates of ProPhyt® (2.3, 3.5, 5.3 and 7.0 L/Ha), three rates of Rampart® (2.3, 4.7 and 7.0 L/Ha), or two rates of K-phite® 7LP (2.3 and 7.0 L/Ha) were tested. Also depending on experiment, 5 to 10 sprays of phosphonate product were applied. Incidence of scab was invariably high on fruit from the non-treated, control trees and most often high on treated trees. However, treatment with the higher rates of phosphonate product most often significantly or numerically reduced severity of scab compared to the lower rates of the products applied on foliage and fruit. The label-stated weight of the active ingredient (phosphonate) per unit volume is similar in these products and they reduced the severity of scab similarly compared to the control and to each other at comparable rates. We found that applying the higher rates we tested (3.5–7.0 L/Ha) most often controlled scab better when compared to the lowest rate (2.3 L/Ha). In 2015 fruit weight was increased where phosphonate application resulted in reduced disease, but in 2016 the effect was unclear due to a late and mild epidemic of scab likely having limited impact on the fruit size. Regardless of epidemic intensity, higher rates of phosphonate provided more efficacious control. Phosphonate products are a vital chemistry to manage scab for the pecan industry in the southeastern USA and our results demonstrate that higher rates contribute to more efficacious control of this yield-limiting disease.

Synthesis a novel family of phosphonate surfactants and their evaluation as corrosion inhibitors in formation water

Nine phosphonates surfactant were synthesized by two steps. The first step was condensation between acetaldehyde and butyl amine, dodecylamine or hexadecylamine individually to give three corresponding Schiff bases, and then the Schiff base products were added to dibutyl phosphite individually. The second step was reaction of the phosphonate products with polyethylene glycol 400, 600 and 1000 to get on the nine water soluble phosphonate corrosion inhibitors. The products were characterized by FTIR, 1HNMR and 13CNMR spectroscopic techniques. The surface active properties of this phosphonate were calculated and they were evaluated as corrosion inhibitors in formation water formulations using open circuit potential and potentiodynamic polarization. The quantum calculations of the structures were calculated and the data obtained were nearly closed with the experimental data. HMPA1 shows the best results as corrosion inhibitors (efficiency 94%) at lowest concentration 15 ppm. The corrosion inhibition mechanism was discussed on the basis of surface tension measurements and the electronic data.

In Situ Probes of Capture and Decomposition of Chemical Warfare Agent Simulants by Zr-Based Metal Organic Frameworks.

Zr-based metal organic frameworks (MOFs) have been recently shown to be among the fastest catalysts of nerve-agent hydrolysis in solution. We report a detailed study of the adsorption and decomposition of a nerve-agent simulant, dimethyl methylphosphonate (DMMP), on UiO-66, UiO-67, MOF-808, and NU-1000 using synchrotron-based X-ray powder diffraction, X-ray absorption, and infrared spectroscopy, which reveals key aspects of the reaction mechanism. The diffraction measurements indicate that all four MOFs adsorb DMMP (introduced at atmospheric pressures through a flow of helium or air) within the pore space. In addition, the combination of X-ray absorption and infrared spectra suggests direct coordination of DMMP to the Zr6 cores of all MOFs, which ultimately leads to decomposition to phosphonate products. These experimental probes into the mechanism of adsorption and decomposition of chemical warfare agent simulants on Zr-based MOFs open new opportunities in rational design of new and superior decontamination materials.

Trapping hemiacetals with phosphono substituted palladium π-allyl complexes for the synthesis of substituted cyclic ethers

Oxidation of hydroxy substituted phosphono allylic carbonates gave the aldehyde substituted phosphonates in good yield. Stereospecific palladium (0)-catalyzed cyclization in the presence of methanol or water gave acetal tetrahydrofuran and tetrahydropyran vinyl phosphonate products derived from hemiacetal trapping. The tetrahydrofuran acetals undergo Lewis acid catalyzed addition of nucleophiles to give diastereoisomeric mixtures of substituted tetrahydrofurans.

Synthesis of Some New Triphenylphosphanylidenes, Alkylphosphonates, and Heterocycles of Pyrazole Derivatives and Their Antimicrobial Activity

The reaction of 5(4H)-pyrazolone with phosphorus ylides afforded new triphenylphosphanylidene alkanone derivatives. Moreover, its benzylidene derivative reacted with Wittig–Horner reagents to give the corresponding dialkoxyphosphoryl, alkyl phosphonate, and heterocyclic products. Treatment of pyrazole-4-carbaldehyde with Wittig–Horner reagents and trialkyl phosphites gave the respective alkyl phosphonate adducts. Mechanisms accounting for the formation of the new products are discussed. The biological activity of some of the newly synthesized compounds was also examined.

Carbodiimides – key mediators in the synthesis of novel cytotoxic and analgesic/antiinflammatory motifs based on α-amino-, enaminophosphonates, and azaphosphones

Based on the prediction results (PASS program), a new series of α-aminophosphonate derivatives and azaphosphones was synthesized and evaluated as antitumor agents against breast-, cervical-, liver, and colon cancer diseases. The analgesic/antiinflammatory properties of the new phosphorylated pyrazoles were also investigated. The study demonstrated an efficient site selective method for making condensation products of phosphonate derivatives in high yields from carbodiimides and different types of HE reagents (74–78%) as well as dialkyl phosphites (54–65%) and hexaalkyltriamidophosphites (80–85%). Their antitumor properties against four carcinoma cell lines representing human-liver (HEPG2), -colon (HCT116), -breast (MCF7), and -cervix (HeLa) were investigated. The results showed that at least two out of the five tested phosphonates exhibited remarkable antitumor activity (IC50: 4.15–6.95 μM mL−1) when compared to the standard drugs (IC50: 5.7–9.3 μM mL−1). Nevertheless, four phosphonate products showed an analgesic capacity >80%, when compared to aspirin (73%) at the same dose of 100 mg kg−1. Furthermore, QSAR results indicated that the fused azaphosphones, thiazolopyrimidine- and pyridine-α-aminophosphonate derivatives (6 of 11 tested compounds), possess inflammatory inhibitory potency (99–117%) when compared to the standard drug (100%) after 360 min.

Use of Phosphonate to Manage Foliar Potato Late Blight in Developing Countries.

Twenty phosphonate products found in the agrochemical market in Ecuador and Peru were evaluated in bioassays for the control of foliar potato late blight, caused by Phytophthora infestans. Eight phosphonate products were evaluated in 16 field experiments done in Peru, Ecuador, Kenya, and Nepal. A meta-analysis across locations involving 71 combinations of potato genotype by site and year demonstrated a significant relationship between phosphonate application rate and efficacy for controlling late blight on potato foliage. The meta-analysis revealed that phosphonate rates of approximately 2.5 g a.i./liter provided efficacy similar to that of the conventional contact fungicides mancozeb and chlorothalonil used at similar rates. At rates higher than 2.5 g a.i./liter, the efficacy of phosphonate was superior to the contact fungicides. Overall, late blight control by phosphonate appeared relatively stable in field experiments across locations. An analysis of field experiments and 64 combinations of potato genotype by site and year showed no correlation between the susceptibility level of potato genotypes and efficacy of phosphonates. The cost of both phosphonate compounds and contact fungicides varied greatly among the countries of the field study; however, in Kenya, control with phosphonate was clearly less expensive than with mancozeb.

Crystal engineering in confined spaces. A novel method to grow crystalline metal phosphonates in alginate gel systems

In this paper we report a crystal growth method for metal phosphonate frameworks in alginate gels. It consists of a metal-containing alginate gel, in which a solution of phosphonate ligand is slowly diffused. Crystals of metal phosphonate products are formed inside the gel. We have applied this for a variety of metal ions (alkaline-earth metals, transition metals and lanthanides) and a number of polyphosphonic acid and mixed carboxy/phosphonic acid ligands.

Synthetic and mechanistic aspects of halo-F-methylphosphonates

The synthesis of a variety of new halo-F-methylphosphonates has been achieved by a Michaelis–Arbuzov type reaction between a halo-F-methane and a trialkyl phosphite. This synthesis has proved to be of wide scope and utility for the high yield preparation of a number of heretofore unknown compounds. The 1H, 19F, 13C and 31P NMR spectroscopic properties are reported in detail. The mechanism for the formation of bromodifluoromethylphosphonates has been shown to proceed through the intermediacy of difluorocarbene:CF 2. The phosphonate products have been shown to react with a wide variety of reagents. Fluoride and alkoxide ions react by attack at phosphorus with cleavage of the carbon–phosphorus bond and formation of [:CF 2] from the bromodifluoromethylphosphonates and the CFBr 2 − anion from the dibromofluoromethylphosphonates. Iodide ion and tertiary phosphines react by attack at the ester carbon to give stable phosphonate salts. Hydrolysis of the phosphonate esters with 50% aqueous HCl gives the expected phosphonic acids. Trimethylsilyl bromide attacks phosphoryl oxygen to afford the bis(trimethylsilyl) esters.

Design and synthesis of non-steroidal diclofenac derivatives as anti-inflammatory drugs

In the course of our studies directed towards the discovery of novel non-steroidal anti-inflammatory agents (NSAIDs), which are expected to have improved drug efficacy and better toxicity profile than diclofenac, we have synthesized new derivatives of diclofenac phosphonates. These phosphonate analogs were efficiently prepared from commercially available 2-hydroxymethylaniline in three steps. The 2-hydroxymethylaniline was converted to the azide in reasonable yield. Click chemistry with a variety of alkynes followed by Arbuzov reaction resulted in a series of triazole based phosphonate products. Our inhibitors are designed to reduce the gastrointestinal bleeding caused by diclofenac by substituting the carboxylic acid group with the phosphonate group and in addition replacing with the triazole ring would allow the flexibility to explore the importance of both hydrophilicity and hydrophobicity of the ring at the active site.

Diastereoselective and enantioselective synthesis of tertiary alpha-hydroxy phosphonates through hydrogen-bond catalysis.

Hydrogen-bond activation by a diol promotes enantioselective Mukaiyama aldol reactions of acyl phosphonates. This mild and general method gives α-hydroxy phosphonate products having two chiral centers, one tertiary and one quaternary, formed with high diastereo- and enantioselectivity.

Enantioselective Friedel−Crafts Alkylations Catalyzed by Bis(oxazolinyl)pyridine−Scandium(III) Triflate Complexes

The enantioselective Friedel-Crafts addition of a variety of indoles catalyzed by bis(oxazolinyl)pyridine-scandium(III) triflate complexes (Sc(III)-pybox) was accomplished utilizing a series of beta-substituted alpha,beta-unsaturated phosphonates and alpha,beta-unsaturated 2-acyl imidazoles. The acyl phosphonate products were efficiently transformed into esters and amides, whereas the acyl imidazole adducts were converted to a broader spectrum of functionalities such as esters, amides, carboxylic acids, ketones, and aldehydes. The sense of stereoinduction and level of enantioselectivity were found to be functions of the size of the substrate employed, the substitution on the ligand, and the catalyst loading. Molecular modeling of the catalyst with the bound substrates was performed based on the crystal structures of the catalyst complexes and the sense of stereoinduction observed in the addition reaction. Nonlinear effects over a range of catalyst concentrations implicate a mononuclear complex as the active catalyst.