Pudovik Reaction Research Articles

Continuous Flow Optimisation of the Pudovik Reaction and Phospha-Brook Rearrangement Using DBN

Flow chemistry has shown significant versatility over the last two decades, offering advantages in efficiency, scalability, and sustainability. In this study, the continuous stirred tank reactor (CSTR) was used to optimise the synthesis of α-hydroxyphosphonates via the Pudovik reaction and their subsequent conversion to phosphates through the phospha-Brook rearrangement. The study highlights that using CSTRs allows for better control over reaction parameters, leading to reduced reaction times and improved yields compared to traditional batch methods. The optimised conditions successfully facilitated a range of organophosphates, including electron-rich and electron-poor derivatives, with high efficiency. Additionally, a one-pot tandem process combining the Pudovik reaction and the phospha-Brook rearrangement was developed, reducing reaction times to two hours while maintaining comparable yields. This work demonstrates the potential of CSTRs in flow chemistry for synthesising complex organophosphorus compounds, achieving higher reaction yields and shorter reaction times, highlighting the effectiveness of continuous flow methodologies.

The Addition of α-Hydroxy-benzylphosphonates to Dialkyl Acetyl­enedicarboxylates; Catalytic Hydrogenation of the Adducts

Abstractα-Hydroxy-benzylphosphonates obtained by the Pudovik reaction of substituted benzaldehydes and dialkyl phosphites were added to the triple bond of dialkyl acetylenedicarboxylates. Optimum conditions involved a 24 hours stirring in the presence of 10% diazabicycloundecene in dichloromethane to afford the adducts as a mixture of predominant E- and a minor Z-isomers in 75–90% yields after flash chromatography. The structures of the geometrical isomers were confirmed by NOE- and ROE-measurements. Catalytic hydrogenation of the olefinic moiety of the adducts led to the diastereoisomers of corresponding saturated derivatives.

Synthetic Methods for Azaheterocyclic Phosphonates and Their Biological Activity: An Update 2004-2024.

The increasing importance of azaheterocyclic phosphonates in the agrochemical, synthetic, and medicinal field has provoked an intense search in the development of synthetic routes for obtaining novel members of this family of compounds. This updated review covers methodologies established since 2004, focusing on the synthesis of azaheterocyclic phosphonates, of which the phosphonate moiety is directly substituted onto to the azaheterocyclic structure. Emphasizing recent advances, this review classifies newly developed synthetic approaches according to the ring size and providing information on biological activities whenever available. Furthermore, this review summarizes information on various methods for the formation of C-P bonds, examining sustainable approaches such as the Michaelis-Arbuzov reaction, the Michaelis-Becker reaction, the Pudovik reaction, the Hirao coupling, and the Kabachnik-Fields reaction. After analyzing the biological activities and applications of azaheterocyclic phosphonates investigated in recent years, a predominant focus on the evaluation of these compounds as anticancer agents is evident. Furthermore, emerging applications underline the versatility and potential of these compounds, highlighting the need for continued research on synthetic methods to expand this interesting family.

Synthesis, cytotoxicity and antioxidant activity of new conjugates of N-acetyl-d-glucosamine with α-aminophosphonates

A series of the first conjugates of N-acetyl-d-glucosamine with α-aminophosphonates was synthesized using the Kabachnik-Fields reaction, the Pudovik reaction, a copper(I)-catalyzed azide-alkyne cycloaddition reaction (CuAAC) and evaluated for the in vitro cytotoxicity against human cancer cell lines M − HeLa, HuTu-80, A549, PANC-1, MCF-7, T98G and normal lung fibroblast cells WI-38. The tested conjugates, with exception of compound 21b, considered as a lead compound, were either inactive against the used cancer cells or showed moderate cytotoxicity in the range of IC50 values 33−80 μM. The lead compound 21b, being non cytotoxic against normal human cells WI-38 (IC50 = 90 μM), demonstrated good activity (IC50 = 17 μM) against breast adenocarcinoma cells (MCF-7) which to be 1.5 times higher than the activity of the used reference anticancer drug tamoxifen (IC50 = 25.0 μM). A flexible receptor molecular docking simulation showed that the cytotoxicity of the synthesized conjugates of N-acetyl-d-glucosamine with α-aminophosphonates against breast adenocarcinoma MCF-7 cell line is due to their ability to inhibit EGFR kinase domain. In addition, it was found that conjugates 22a and 22b demonstrated antioxidant activity that was not typical for α-aminophosphonates.

Recent Advances in the Synthesis of Dialkyl (Aryl) α-(Aryl/Heterocyclic/Heteroaryl- α-(Aryl/Heteroarylamino)Phosphonates

Abstract: This review describes recent advances that are commonly applied in the synthesis of dialkyl (aryl) α-aminophosphonates containing heterocyclic compounds. The target structures are divided into three categories, which include α-aminophosphonic acids and their diesters bearing a heterocyclic or heteroaryl system at the α-carbon, nitrogen atom, or both. The synthetic protocols based on the Kabachnik-Fields and Pudovik reactions as the main pathways for the construction of these features, besides other miscellaneous methods. This review may be a useful resource for researchers and it will help them to work in this emerging research area.

Efficient Synthesis of Diethyl, Dialkyl α-Hydroxy-propylenebisphosphonates and Related 5-Phosphonoyl-1,2-oxaphospholane 2-Oxides

AbstractA series of new dialkyl α-diethylphosphonoylethyl-α-hydroxy-ethylphosphonates were prepared using the Pudovik reaction of the corresponding γ-oxophosphonate with dialkyl phosphites performed on the surface of Al2O3/KF. The adducts revealed unexpected reactivity in the attempted O-acylation reaction, and provided the corresponding 5-phosphonoyl-1,2-oxaphospholane 2-oxides. On treatment with Cs2CO3, instead of the expected rearrangement a cyclization reaction leading to the same ring products took place. Three of the phosphonoylethyl-α hydroxy-ethylphosphonates, along with two phosphonoylmethyl analogues revealed significant and selective anticancer effect on A431 cells, and occasionally, on PC-3 and MDA-MB 231 cells.

A Study of the Bisphosphonic Derivatives from the Pudovik Reaction of Dialkyl α-Oxophosphonates and >P(O)H Reagents: X-ray Structure and Bioactivity.

New hydroxy-methylenebisphosphonic derivatives were prepared with different P-functions. The outcome of the reaction of α-oxophosphonates (YC(O)P(O)(OR)2) and dialkyl phosphites or diarylphosphine oxides depended on the Y substituent of the oxo-compound, the nature of the P-reagent and the amount of the diethylamine catalyst. Starting from dimethyl α-oxoethylphosphonate, in the presence of 5% of diethylamine, the corresponding Pudovik adduct was the single product. While using 40% of the catalyst, the rearranged species with the >P(O)-O-CH-P(O)< skeleton was the exclusive component. A similar reaction of α-oxobenzylphosphonate followed the rearrangement protocol. X-ray crystallography revealed not only the spatial structures of the three products, but also an intricate pattern evolving from the interplay of slight chemical differences, solvent inclusion and disorder as well as H-bridge patterns, which invite further investigation. In vitro activity of the compounds was assessed on different tumor cell cultures using end-point-type cell tetrazolium-based measurements. These structure-activity studies revealed a cytostatic effect for four rearranged derivatives containing aromatic units. One of them had a pronounced effect on MDA-MB 231 and Ebc-1 cells, showing IC50 = 37.8 and 25.9 µM, respectively.

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

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.

Enantioselective C−P Bond Formation through C(sp3)−H Functionalization

AbstractAn enantioselective C−P bond formation has been developed through a C(sp3)−H activation in an oxidation step followed by an organocatalyzed hydrophosphonylation protocol. The asymmetric organocatalytic Pudovik reaction has been achieved following a one‐pot strategy, starting from different benzylic and allylic alcohols and dibenzyl phosphite, using MnO2 as the oxidant and a chiral squaramide as organocatalyst. The scope of the reaction provides enantiomerically enriched α‐hydroxy phosphonates with yields from 40% to &gt;95% and enantioselectivities from 64% to &gt;99%. Furthermore, the use of this methodology has been demonstrated to form a tetrasubstituted carbon stereocenter, generating an acetophenone derivative in situ, using diphenyl phosphite. Therefore, this approach represents an asymmetric strategy for constructing chiral C−P bonds, which are of interest to the pharmaceutical industry.

A Novel Phosphonates Synthesized from Schiff's Base Indenoquinoxaline Derivatives and its Biological Activity

AbstractIn this study we made of reaction of 11H‐indeno[1,2‐b]quinoxalin‐11‐one with hydrazine hydrate and phenyl hydrazine to afford the corresponding hydrazineylidenes 3 a, b in good yield.A series of a novel Schiff's bases of isatin and aldehydes were synthesized by condensation of them with 11‐hydrazineylidene‐11H‐indeno[1,2‐b]quinoxaline. A number of aminophosphonates were synthesized by reaction of imines with dialkyl phosphites according to Pudovik reaction. The chemical structures of the synthesized compounds were confirmed by means spectroscopic evidences. The cytotoxic activity of ten derivatives were investigated in the liver cancer cell line HepG‐2 and the breast cancer cell line MCF‐7.Compounds 7 a, b showed higher cytotoxicity towards the liver cancer cell line HepG‐2 and compound 10 a gave higher cytotoxicity towards the breast cancer cell line (MCF7) most than the reference drug (Doxorubicin). From the above‐mentioned results it may be concluded that compounds containing bis‐aminophosphonate exhibit better activity than the aminophosphonate. The molecular docking studies of phosphonates and bisphosphonates were investigated.

Optimized Synthesis and Cytotoxic Activity of α-Aminophosphonates Against a Multidrug Resistant Uterine Sarcoma Cell Line

Background: α-Aminophosphonates are potentially biologically active species. Objective: We wished to compare the synthetic methods and evaluate the effect of the α- aminophosphonates on sarcoma cell lines. Methods: We investigated microwave-assisted Kabachnik–Fields and Pudovik reactions, as well as substitutions, and applied in vitro cytotoxicity screening. Results: The Kabachnik–Fields condensation and the Pudovik reaction were found to be the most suitable regarding efficiency. Surprisingly, the multidrug resistant (MDR) uterine sarcoma (Mes-Sa/Dx5) cell line was the most susceptible to the aminophosphonates tested. Conclusions: α-Aminophosphonates may indeed display anticancer effect. Substituents in the para position of the phenyl ring have an impact on the activity: the 4-Me and 4-Cl derivatives were more toxic to all cell lines as compared to the 4-H and 4-MeO species.

Lewis acid-catalyzed Pudovik reaction-phospha-Brook rearrangement sequence to access phosphoric esters.

Herein, we report a Lewis acid-catalyzed Pudovik reaction–phospha-Brook rearrangement sequence between diarylphosphonates or -phosphinates and α-pyridinealdehydes to access valuable phosphoric ester compounds. This transformation provides an extended substrate scope that is complementary to similar previously reported base-catalyzed transformations.

Design and Synthesis of New α-hydroxy β-fluoro/β-trifluoromethyl and Unsaturated Phosphonates from Carbohydrate-Derived Building Blocks via Pudovik and Horner-Wadsworth-Emmons Reactions.

Herein, we present the application of fluorinated carbohydrate-derived building blocks for α-hydroxy β-fluoro/β-trifluoromethyl and unsaturated phosphonates synthesis. Pudovik and Horner–Wadsworth–Emmons reactions were applied to achieve this goal. The proposed pathway of the key reactions is supported by the experimental results, as well as quantum chemical calculations. The structure of the products was established by spectroscopic (1D, 2D NMR) and spectrometric (MS) techniques. Based on our data received, we claim that the progress of the Pudovik and HWE reactions is significantly influenced by the acidic protons present in the molecules as assessed by pKa values of the reagent.

Ultrasound-Promoted Solvent-Free Synthesis of Some New &amp;alpha;-Aminophosphonates as Prospective Antioxidants

To achieve an efficient synthesis of some novel α-aminophosphonates via Pudovik reaction; ultrasonic irradiation has been adopted. Major benefits of this method is eco-friendly, free of catalyst, high yielding, uncomplicated work-up procedure, short reaction time and solvent free condition. Spectral characterization and elemental analysis of the synthesized samples was carried out. In vitro antioxidant activity of the synthesized a-aminophosphonates compounds was screened by DPPH•, O2•− and NO• scavenging methods. Good to moderate activities were shown by most of the compounds while compared with the standards.

Convenient Hydrophosphorylation of Dibenzo[b,f][1,4]oxa‐/thiazepines by Acid Catalysis

AbstractA protocol for the acid‐catalyzed synthesis of phosphorylated dihydrodibenzoxa‐/thiazepine derivatives from dibenzo[b,f][1,4]oxa‐/thiazepines has been established. The reaction appears compatible with a range of functional groups in both the dibenzo[b,f][1,4]oxa‐/thiazepine, H‐phosphonate and especially diarylphosphine oxide phosphorylation partners, affording moderate to excellent yields of the corresponding products. The present method further expands the utility of Pudovik reaction.

Tetraalkyl Hydroxymethylene-bisphosphonate and Dialkyl 1-Diphenylphosphinoyl-1-hydroxy-ethylphosphonate Derivatives by the Pudovik Reaction and Their Rearranged Products.

The reaction of diethyl α-oxoethylphosphonate and diethyl oxobenzylphosphonate with diethyl phosphite, dimethyl phosphite, and diphenylphosphine oxide affords, depending on the substrates and conditions (nature and quantity of the amine catalyst, temperature, and solvent), the Pudovik adduct and/or the corresponding >P(O)–CH–O–P(O)< product formed by rearrangement. The nature of the substituent on the central carbon atom (a methyl or phenyl group) influences the inclination for the rearrangement. The asymmetric products (either adducts or rearranged species) with different P(O)Y functions (Y = RO or Ph) exhibit interesting NMR features.

Novel and durable flame-retardant modification based on the Schiff base and Pudovik reaction for wool fabric

Durable and formaldehyde-free flame-retardant (FR) modification of wool fabric using phosphorous compounds is of great interest. In this study, Schiff base imine groups were firstly introduced onto wool fiber through aldehyde-amine condensation between p-hydroxybenzaldehyde and wool fiber. Then, an efficient and durable FR wool fabric was fabricated by incorporating diethyl phosphite (DEP) into a Schiff base intermediate via the Pudovik reaction. The potential reaction mechanism among p-hydroxybenzaldehyde, DEP and wool fiber was explored. The thermal stability, smoke generation ability, FR ability and washing durability of the modified wool fabric were studied. The FR modification significantly increased the thermal resistance of wool fabric and suppressed smoke generation by half. The wool fabric modified by 20 g/L DEP was able to self-extinguish during the burning test, suggesting the higher FR efficiency of the DEP-incorporated Schiff base system. The modified wool fabric still self-extinguished after 20 commercial launderings, which is attributed to the covalent grafting of DEP onto wool fiber. Char residue analyses revealed the condensed charring FR mechanism of the DEP-incorporated Schiff base system on wool. This work provides a novel approach to prepare efficient and durable FR functional wool fabric via the Schiff base reaction and Pudovik reaction among p-hydroxybenzaldehyde, DEP and wool fiber.

Synthesis of β‐Chloro‐α‐hydroxyphosphonates through Triethylamine‐Catalyzed Pudovik Reaction

AbstractVersatile β‐chloro‐α‐hydroxyphosphonates were synthesized in high yields from α‐chloroketones and phosphites based on the efficient control of competitive Pudovik/Arbuzov/Perkow reactions. Triethylamine was found most efficient to catalyze the Pudovik reaction regioselectively under mild solvent‐free conditions. Aliphatic, aromatic, cyclic α‐chloroketones and phosphonites/phosphinites were also applicable to this practical column‐free procedure.

Enantioseparation of P-Stereogenic Secondary Phosphine Oxides and Their Stereospecific Transformation to Various Tertiary Phosphine Oxides and a Thiophosphinate.

Secondary phosphine oxides incorporating various aryl and alkyl groups were synthesized in racemic form, and these products formed the library reported in this study. TADDOL derivatives were used to obtain the optical resolution of these P-stereogenic secondary phosphine oxides. The developed resolution method showed a good scope under the optimized reaction conditions, as 9 out of 14 derivatives could be prepared with an enantiomeric excess (ee) ≥ 79% and 5 of these derivatives were practically enantiopure >P(O)H compounds (ee ≥ 98%). The scalability of this resolution method was also demonstrated. Noncovalent interactions responsible for the formation of diasteromeric complexes were elucidated by single-crystal XRD measurements. (S)-(2-Methylphenyl)phenylphosphine oxide was transformed to a variety of P-stereogenic tertiary phosphine oxides and a thiophosphinate in stereospecific Michaelis–Becker, Hirao, or Pudovik reactions.

Green synthesis of α-hydroxy phosphonates containing unsaturated organochalcogenyl moiety

A simple and efficient protocol for the chemoselective synthesis ofα-hydroxy phosphonates containing unsaturated alkoxy/phenoxy or organosulfanyl moiety has been developed. This approach was performed by Pudovik reaction from readily available organochalcogenyl enals and dialkyl phosphites in a solvent-free system, using 0.25 equiv. CaO as a catalyst at room temperature, which provided the target phosphonates in high yields.