Reaction Of Phosphonates Research Articles

Base-Catalyzed Reaction of Isatins and (3-Hydroxyprop-1-yn-1-yl)phosphonates as a Tool for the Synthesis of Spiro-1,3-dioxolane Oxindoles with Anticancer and Anti-Platelet Properties

An approach to the synthesis of phosphoryl substituted spiro-1,3-dioxolane oxindoles was developed from the base-catalyzed reaction of various isatins with (3-hydroxyprop-1-yn-1-yl)phosphonates. It was found that various aryl-substituted and N-functionalized isatins with the formation of appropriate products with high yields and stereoselectivity when using t-BuOLi are able to react. Cytotoxic activity evaluation suggests that the most significant results in relation to the HuTu 80 cell line were shown by N-benzylated spirodioxolanes. 5-Cloro-N-unsubstituted spirooxindoles exhibit antiaggregational activity exceeding the values of acetylsalicylic acid.

Synthesis of Multisubstituted 1,2,3-Triazoles: Regioselective Formation and Reaction Mechanism.

A synthetically useful approach to functionalized triazoles is described via the reaction of β-carbonyl phosphonates and azides. 1,4- and 1,5-disubstituted and 1,4,5-trisubstituted triazoles can be regio- and chemoselectively accessed under mild conditions in good to excellent yields (31 examples, up to 99%). A mechanism is proposed that rationalizes the avoidance of the 4-phosphonate byproducts, which is aligned with crystallographic and experimental evidence.

Enantioselective copper-catalyzed B-H bond insertion reaction of α-diazo phosphonates to access chiral α-boryl phosphonates.

Chiral phosphorus-containing compounds find applications across various fields, including asymmetric catalysis, medicinal chemistry, and materials science. Despite the abundance of reported highly enantioselective methods for synthesizing various chiral phosphorus compounds, the enantioselective synthesis of α-boryl phosphorus compounds still remains an unknown territory. Here, we report a method for the construction of chiral α-boryl phosphates by asymmetric B-H insertion reaction using α-diazo phosphates as carbene precursors, cheap and readily available copper salt as the catalyst and chiral oxazoline as the ligand. This method can directly afford a series of stable α-boryl phosphates with a yield up to 97% and an enantioselectivity up to 98% ee. The operating procedure of this method is straightforward, offering a broad substrate applicability, remarkable tolerance towards various functional groups, and gentle reaction conditions.

Aza-Wittig reaction of (β-diazo-α,α-difluoroethyl)phosphonates with aldehydes for the synthesis of difluoromethylphosphonate-containing arylidene hydrazones

An aza-Wittig reaction of in situ generated difluoroalkyl diazo analog, (β-diazo-α,α-difluoroethyl)phosphonates, with aldehyde under mild conditions has been developed to afford difluoromethylphosphonate-containing arylidene hydrazones up to 99 % yields. The reaction was carried out under mild conditions with a broad substrate scope and was suitable for scale-up application. This reaction provides an efficient method for the facile construction of a series of difluoromethylphosphonate-containing arylidene hydrazones and is also a useful supplement to the transformation of (β-diazo-α,α-difluoroethyl)phosphonates.

Rh‐Catalyzed Hydration/C−F Bond Cleavage of Fluorinated Diazoalkanes Enabling Synthesis of α‐Fluoro‐β‐ketophosphonates

Abstract(β‐Diazo‐α,α‐difluoroethyl)phosphonates have been emerging as useful building blocks in organic synthetic chemistry in recent years, which can be used as diazo analog or masked carbene for the rapid assembly of difluoromethylene phosphonate‐containing compounds. Herein, we elaborate a method for the synthesis of α‐fluoro‐β‐ketophosphonates from hydration/C−F bond cleavage of in situ generated (β‐amino‐α,α‐difluoroethyl)phosphonates via a Rh‐carbene intermediate. Divers (β‐amino‐α,α‐difluoroethyl)phosphonates are tolerated in this reaction affording α‐fluoro‐β‐ketophosphonates in good yields. This reaction used the in situ generated water as the coupling partner, which represents a reaction of (β‐diazo‐α,α‐difluoroethyl)phosphonates and also a method for generating bioactive α‐fluoro‐β‐ketophosphonates.

A Planar‐Chiral Palladium Complex Derived from a Weak Oxygen Donor N,N‐Diisopropyl Ferrocenecarboxamide Ligand

AbstractThe reaction of chiral 2‐iodoferrocenecarboxamide, palladium(II) acetate, and triphenylphosphine ligand in acetonitrile has been resulted in the formation of an air‐stable chiral (Sp)‐2‐(N,N‐diisopropyl ferrocenecarboxamide) triphenylphosphine palladium(II) iodide complex. The isolated chiral palladium complex was thoroughly characterized by multi‐nuclear (1H, 13C, 31P) NMR, IR spectroscopy, mass spectrometry, polarimetry, CHN analysis, cyclic voltammetry and single crystal X‐ray crystallography (XRD). The single‐crystal XRD analysis reveals a square planar geometry around the palladium atom with a strong amide oxygen‐Pd bond [2.095(6) Å]. The palladium complex crystallized in the C2‐chiral space group having a Flack parameter value of 0.011(14), which is close to 0 and indicative of the enantiomeric purity of the palladium complex. The electrochemical study reveals a two‐electron redox couple due to the ferrocenyl Fe(II) atom and the palladacyclic Pd(II) center. In differential pulse voltammetry (DPV), two peaks were observed at 450 mV and 590 mV vs. Ag/AgCl. Further, the synthesized chiral palladacyle has also been explored in Suzuki‐Miyaura coupling reaction as a substrate and as a catalyst for Tsuji‐Trost coupling and phosphonation reactions.

Two-Step Substitution Reaction of Phosphonates Carrying a Binaphthyl Group with Grignard Reagents Leading to the Formation of P-Chirogenic Phosphine Oxides

AbstractThe reaction of phosphonates carrying a binaphthyl group with a range of Grignard reagents was complete within two hours at 0 °C to give phosphinates carrying a hydroxybinaphthyl group with high ­efficiency and diastereoselectivity. The resulting phosphinates were further subjected to a substitution reaction with MeMgBr. The reaction at reflux temperature in THF or toluene permitted the formation of P-chirogenic tertiary phosphine oxides with a high enantiomeric ratio. Rare examples of P-chirogenic alkynyl phosphine oxides were also obtained. The sequential one-pot substitution reaction of phosphonates bearing a binaphthyl group with two different Grignard reagents successfully gave the corresponding P-chirogenic phosphine oxides with enantiomeric ratios nearly equal to those of oxides derived from two-step reactions.

Covalent grafting of alkyl chains on laser-treated titanium surfaces through silanization and phosphonation reactions

This work evaluates the efficiency of silanization and phosphonation reactions for the grafting of alkyl chains on the surface of titanium treated by nanosecond laser. The light blue squama-like oxide layers with dominating anatase and rutile were obtained. The silanization using alkoxysilanes with C12 and C18 alkyl chains was attempted in tetrahydrofuran, in pure liquid phase and in vapor phase. The phosphonation with octylphosphonic acid was performed in boiling water solutions. The obtained surfaces were characterized by Raman and X-ray photoelectron spectrometry, scanning electron microscopy and energy dispersive X-ray spectroscopy. Their hydrophobicity was evaluated using static contact angle measurements.The modification in pure liquid silane and in vapor phase allowed obtaining high loadings (6 and 10 at.% Si respectively) of grafted groups and the formation of polycondensed silane layers. The silanization in tetrahydrofuran resulted in partial monolayer coverage. The phosphonation in boiling water solutions allowed obtaining significant P loading (up to 7 at.%) and full monolayer coverage. Both silanization and phosphonation increased the hydrophobicity of laser-treated surfaces. However, the modification with octylphosphonic acid in water solutions is more appropriate since milder conditions of chemical functionalization and lower concentrations of the modifier are necessary to obtain similar organic loading and hydrophobicity.

One‐Pot Reaction of (β‐Amino‐α,α‐difluoroethyl)phosphonates with Trifluoromethylated Ketones via Aza‐Wittig Reagents

AbstractWe report a one‐pot reaction of (β‐amino‐α,α‐difluoroethyl)phosphonates involving aza‐Wittig reagents, in which, difluoromethylphosphonate‐containing diazo and trifluoromethylated ketones assemble to furnish azo‐containing α‐fluorovinylphosphonates. Mechanism studies disclose a pathway, which contains an aza‐Wittig reaction, water addition to hydrazone, and C−F bond cleavage with an aza‐Wittig reagent as a key intermediate. This reaction is conducted at 60 °C affording a series of α‐fluorovinylphosphonate compounds in 42–94% yields and Z‐stereoselectivity. This work opens a vision for the difluoroalkyl‐substituted diazos, and provides a strategy for the synthesis of α‐fluorovinylphosphonate derivatives.magnified image

Enantioselective Construction of Amino Carboxylic‐Phosphonic Acid Derivatives Enabled by Chiral Amino Thiourea‐Catalyzed Decarboxylative Mannich Reaction

AbstractAn asymmetric decarboxylative Mannich reaction of phosphonate sultam‐ketimines with malonic acid half esters is developed enabled by saccharide‐derived bifunctional amino thiourea catalysis. This protocol provides access to a broad range of α‐amino‐β‐carboxylic phosphonates featuring the N,P‐containing tetrasubstituted stereocenters with 78–99% ee. Further synthetic derivatizations could allow the introduction of amide, alcohol, and azetidine scaffolds to the core structures.magnified image

Synthesis of α-CF3-substituted γ,δ-didehydro lysine derivatives

An efficient and selective access to novel α-CF3-substituted γ,δ-didehydro lysine derivatives and their phosphorus analogues has been developed via the Cu-catalyzed Mannich reaction of α-amino α-propargyl α-trifluoromethyl carboxylates or phosphonates with different secondary amines and paraformaldehyde.

Covalent Grafting of Alkyl Chains on Laser-Treated Titanium Surfaces Through Silanization and Phosphonation Reactions

Covalent Grafting of Alkyl Chains on Laser-Treated Titanium Surfaces Through Silanization and Phosphonation Reactions

Structural modification and biological activity studies of tagitinin C and its derivatives

The Michael addition reaction of amines, phosphonates and thiols to Tagitinin C containing in its structure an α-methylene-γ-lactone motif and two α,β-unsaturated ketone systems has been described. 27 Tagitinin C derivatives were synthesized and isolated in good to excellent yield (up to 99% yield) under mild reaction conditions. The biological activity of Tagitinin C and its derivatives were evaluated against three human cancer cell lines (breast human cancer cells MCF-7, breast human cancer cells multi-resistant to drugs MCF7-MDR, pancreas cancer cells MiaPaCa-2) and on normal cell line (HEK-293) as control. We showed that the biological activity of Tagitinin C derivatives is remained. These compounds presented an enhanced water solubility that could improve their bioavailability and their pharmacological profiles.

Synthesis of 1,3-Aminoalcohols and Spirocyclic Azetidines via Tandem Hydroxymethylation and Aminomethylation Reaction of β-Keto Phosphonates with N-Nosyl-O-(2-bromoethyl)hydroxylamine

An unprecedented tandem α-hydroxymethylation and α-aminomethylation reaction of aromatic cyclic β-keto phosphonates with N-nosyl-O-(2-bromoethyl)hydroxylamine in the presence of DBU base has been developed, affording a range of 1,3-aminoalcohols in good yields. The resultant products could be flexibly transformed into the spirocyclic and bispirocyclic azetidines via one step of Mitsunobu reaction. Mechanistic study revealed that hydroxylamine in situ generated the formaldehyde and nosylamide, which in turn triggered the sequential Horner-Wadsworth-Emmons, Michael, and aldol reactions.

1,3-Dipolar cycloaddition reactions of acyl phosphonates with nitrile oxides: synthesis of phosphonate-containing dioxazole derivatives

New phosphonate-containing five-membered heterocyclic dioxazole derivatives are synthesized via 1,3-dipolar cycloaddition reactions of nitrile oxides used as dipole with acyl phosphonates under basic conditions. Herein, acyl phosphonates take part in the cyclization process as a dipolarophile to afford the related dioxazole compounds in moderate-to-good yields (49–84%). Substituted aryl nitrile oxides and aroyl phosphonates were employed in the 1,3-dipolar cycloaddition reactions where triethylamine was the effective tertiary base. Alkyl version of acyl phosphonate also afforded the expected cycloadduct, that is, dimethyl 5-isopropyl-3-phenyl-1,4,2-dioxazol-5-yl-5-phosphonate. Diethyl/dimethyl 3,5-aryl-1,4,2-dioxazol-5-yl-5-phosphonate derivatives are fully characterized by using 1H NMR, 13C NMR, 31P-NMR, and FT along with high-resolution mass spectroscopy.

Achieving Site-Selectivity for C-H Activation Processes Based on Distance and Geometry: A Carpenter's Approach.

The ability to differentiate between highly similar C-H bonds in a given molecule remains a fundamental challenge in organic chemistry. In particular, the lack of sufficient steric and electronic differences between C-H bonds located distal to functional groups has prevented the development of site-selective catalysts with broad scope. An emerging approach to circumvent this obstacle is to utilize the distance between a target C-H bond and a coordinating functional group, along with the geometry of the cyclic transition state in directed C-H activation, as core molecular recognition parameters to differentiate between multiple C-H bonds. In this Perspective, we discuss the advent and recent advances of this concept. We cover a wide range of transition-metal-catalyzed, template-directed remote C-H activation reactions of alcohols, carboxylic acids, sulfonates, phosphonates, and amines. Additionally, we review eminent examples which take advantage of non-covalent interactions to achieve regiocontrol. Continued advancement of this distance- and geometry-based differentiation approach for regioselective remote C-H functionalization reactions may lead to the ultimate realization of molecular editing: the freedom to modify organic molecules at any site, in any order.

Assembling Homometallic Sb6 and Heterometallic Ti4Sb2 Oxo Clusters.

Isolation and structural characterization of novel organoantimony(V)-based oxo clusters are reported. (RSb)4(OH)4(t-BuPO3)6 and (RSb)2(O)(t-BuPO3H)6 independently in the presence of pyridine under solvothermal conditions afford the hexanuclear organoantimonate clusters [(RSb)6(μ3-O)2(μ2-O)6(t-BuPO3)4], where R = p-i-PrC6H4 (1), p-ClC6H4 (2). Further, reaction of organostibonate phosphonate with Ti(OiPr)4 in the presence of pyridine under solvothermal conditions afforded the mixed-metal titanium stibonate hexanuclear clusters [(RSb)2Ti4(μ3-O)2(μ2-O)2(t-BuPO3)4(μ-OCH3)4(OCH3)4], where R = p-i-PrC6H4 (3), p-ClC6H4 (4). Band gap measurements were performed on 1-4. They reveal a remarkable reduction in the band gap on moving from the heavier main-group-based oxo cages (1 and 2) to the titanium-incorporated oxo cages (3 and 4).

Synthesis of Functionalized Novel α‐Amino‐β‐alkoxyphosphonates through Regioselective Ring Opening of Aziridine‐2‐phosphonates

AbstractAziridines are highly useful compounds as building blocks for the synthesis of important organic compounds. Amino acid synthesis by aziridine ring opening reaction is a good example to the use of aziridines. Although this reaction is studied by many groups, the synthesis of amino phosphonic acids is less explored. In this study, we have carried out the ring opening reaction of aziridinyl phosphonates with a variety of alcohols including the more functional propargylic and allylic alcohols. These reactions provided functionalized α‐amino‐β‐alkoxyphosphonates in 40–91 % yield.

Synthesis, Characterization and Evaluation of Cytotoxic Activities of Novel Aziridinyl Phosphonic Acid Derivatives.

New aziridine 2-phosphonic acids were prepared by monohydrolysis of the aziridine 2-phosphonates that were obtained by the modified Gabriel-Cromwell reaction of vinyl phosphonate or α-tosylvinyl phosphonate with a primary amine or a chiral amine. The cellular cytotoxicity of these compounds was tested against the HCT-116 colorectal cancer cell lines and the CCD-18Co normal colon fibroblast lines using the MTT assay. Three of the synthesized phosphonic acid derivatives 2e (ethyl hydrogen {(2S)-1-[(1S)-1-(naphthalen-2-yl)ethyl]aziridin-2-yl}phosphonate), 2h (ethyl hydrogen (1-benzylaziridin-2-yl)phosphonate), and 2i (ethyl hydrogen (1-cyclohexylaziridin-2-yl)phosphonate) showed higher cytotoxicity than the reference cancer treatment agent etoposide. Cell death was through a robust induction of apoptosis even more effectively than etoposide, a well-known apoptosis inducing agent.

Synthesis of (4-nitro-1H-indol-6-yl)- and (4-amino-1H-indol-6-yl)phosphonic acid derivatives

A convenient methodology for the synthesis of previously unreported (1H-indol-6-yl)phosphonic acid derivatives has been described. Reaction of (4-methyl-3,5-dinitrophenyl)phosphonates with dimethylformamide dimethyl acetal leads to the respective enamines that can be readily converted into indoles by the Batcho–Leimgruber synthetic protocol. Proper choice of reducing agent for the reductive cyclization of intermediate enamines allows to selectively obtain (4-nitro-1H-indol-6-yl)- and (4-amino-1H-indol-6-yl)phosphonates.