Trialkyl Phosphites Research Articles

Photoredox Catalytic Phosphite-Mediated Deoxygenation of α-Diketones Enables Wolff Rearrangement and Staudinger Synthesis of β-Lactams.

A novel visible-light-driven catalytic activation of C=O bonds by exploiting the photoredox chemistry of 1,3,2-dioxaphospholes, readily accessible from α-diketones and trialkyl phosphites, is reported. This mild and environmentally friendly strategy provides an unprecedented and efficient access to the Wolff rearrangement reaction which traditionally entails α-diazoketones as precursors. The resulting ketenes could be precisely trapped by alcohols/thiols to give α-aryl (thio)acetates and by imines to afford the valuable β-lactams in up to 99 % yields.

Copper‐Phosphine Mediated Oxidative Phosphorylation of Aromatic Amines and P(OR)3 under Aerobic Conditions

AbstractA copper‐phosphine system (Cu(OAc)2 and t‐Bu3P⋅HBF4) was used to synthesize α‐aminophosphonates and phosphoramides from various aromatic amines and trialkyl phosphites under oxygen atmosphere. With this Cu−P system, α‐aminophosphonates containing C−P bonds were generated from N,N‐dimethylanilines or N‐methylanilines and trialkyl phosphites; phosphoramidates containing N−P bonds were produced from N‐benzylanilines and trialkyl phosphites. This strategy provided a convenient and efficient method for the synthesis of phosphorous compounds. The compounds containing phosphoryl group attracted extensive attention due to their biological activities and wide applications.[1,2] The α‐aminophosphonates have been applied in medicine and agriculture such as anticancer drugs, antibiotics, antibacterial agents, and enzyme inhibitors.[1] And phosphoramides could be served as antibiotics, prodrugs, flame retardants, and ligands.[2]

Electrochemically driven synthesis of phosphorothioates from trialkyl phosphites and aryl thiols

A facile and elegant protocol for synthesis of phosphorothioates from trialkyl phosphites and aryl thiols via indirect electrochemical oxidation mediated by KI has been successfully developed. KI as a redox mediator, enabled the reaction of trialkyl phosphites and aryl thiols effectively at low potential. Cyclic voltammetry and in situ FTIR were applied to investigate the electrocatalytic activity of KI for the cross-coupling of trialkyl phosphites with aryl thiols. A variety of phosphorothioates were obtained in good to excellent yields under the optimal conditions. This strategy provided an expedient access to construct P–S bond with good functional group compatibility and a broad substrate scope.

Synthesis of α-Aminophosphonates and Related Derivatives; the Last Decade of the Kabachnik-Fields Reaction.

The Kabachnik–Fields reaction, comprising the condensation of an amine, oxo compound and a P-reagent (generally a >P(O)H species or trialkyl phosphite), still attracts interest due to the challenging synthetic procedures and the potential biological activity of the resulting α-aminophosphonic derivatives. Following the success of the first part (Molecules 2012, 17, 12821), here we summarize the synthetic developments in this field accumulated in the last decade. The procedures compiled include catalytic accomplishments as well as catalyst-free and/or solvent-free “greener” protocols. The products embrace α-aminophosphonates, α-aminophosphinates, and α-aminophosphine oxides along with different bis derivatives from the double phospha-Mannich approach. The newer developments of the aza-Pudovik reactions are also included.

Direct Synthesis of ortho-Halogenated Arylphosphonates via a Three-Component Reaction Involving Arynes.

A three-component reaction involving arynes, trialkyl phosphites, and halides has been achieved under mild reaction conditions. This transformation provides a direct synthetic approach to ortho-halogenated arylphosphonates, which could be rapidly converted to diversely ortho-functionalized arylphosphorus compounds.

Visible‐Light‐Induced C‐P‐Bond Formation Using Reduced Graphene Oxide Decorated with Copper Oxide/Zinc Oxide (rGO/CuO/ZnO) as Ternary Recyclable Nanophotocatalyst

AbstractThe reduced graphene oxide and copper oxide loaded on zinc oxide (rGO/CuO/ZnO) was successfully synthesized, fully characterized, and applied as a highly efficient reusable nano photocatalyst for the synthesis of aryl phosphonate derivatives starting from trialkyl phosphites and arylhydrazines in the presence of visible light radiation at room temperature in the air atmosphere under eco‐friendly and very mild reaction conditions without using base, oxidant, additive or ligand. Moreover, this strategy is the first report of the use of rGO/CuO/ZnO ternary nanocomposite as heterogeneous photocatalyst in organic synthesis.

Photoinduced transition-metal and external photosensitizer free cross-coupling of aryl triflates with trialkyl phosphites.

Photoinduced phosphonation of aryl triflates with trialkyl phosphites via a tandem single-electron-transfer, C-O bond cleavage and Arbuzov rearrangement process in the absence of transition-metal and external photosensitizer is reported herein. The protocol features good functional group compatibility and mild reaction conditions, providing various aryl phosphates in good to high yields. Furthermore, this strategy allows the late-stage phosphonation of complex and biologically active compounds.

Catalytic phosphonylation of C=X electrophiles

A method for the catalytic phosphonylation of C = X electrophiles has been developed. Pyridinium perchlorate is an effective catalyst for the phosphonylation reaction of trialkyl phosphites with various electrophiles C = X (X = O, S, N). The reaction leads to the formation of corresponding α-substituted phosphonates in high yields. The reaction leading to the formation of bisphosphonates represents the highest interest. It was found that the nucleo philic attack of triethyl phosphite on the electron-deficient carbon of the C = X group leads to the formation of beta ine, which reacts with pyridinium perchlorate to form alkoxyphosphonium perchlorate and pyridine. Quasiphosphonium salt is unstable and decomposes to form phosphonate, alkene, and perchloric acid, which reacts with pyridine to regenerate pyridinium perchlorate. The intermediate formed from the pyridinium halide decomposes to form alkyl halide. The general strategy of the proposed method for introducing phosphonate groups into a polyprenyl mole cule consisted in the sequential treatment of hydroxyl-containing a compound with the Swern reagent with the con version of the C—OH group into a carbonyl one. Subsequent phosphonylation of the carbonyl-containing interme diate with the reagent (EtO)3P/[PyH] + ClO 4– leads to the formation of hydroxyalkylbisphosphonate. The synthe sized prenyl bisphosphonates have a pronounced biological activity. These include, for example, enolpyruvylshikimate-3- phosphate synthase (EPSP), farnesyl protein transferase (FPTase), as well as HIV protease, which are of interest as potential biologically active substances.

Adsorption and Reaction of Trimethyl and Triethyl Phosphite on Fe3O4 by Density Functional Theory

First-principle density functional theory (DFT) calculations are used to calculate the most stable structures and heats of adsorption of trimethyl and triethyl phosphites on an Fe3O4 surface in order to understand their behavior as lubricant additives. Previous surface science studies of phosphate and phosphite esters on iron oxide surface have shown that they react by sequentially desorbing the corresponding alcohol and aldehyde in equimolar amounts. This implies that the reactions are limited by the rate of alkoxide removal, followed by a rapid reaction to form the alcohol and aldehyde. It is found that the trialkyl phosphites, dialkyl phosphite, and monoalkyl phosphite all adsorb with the phosphorus atoms bound to surface Fe3+ ions, with the alkoxy groups close to parallel to the surface. The heat of adsorption increases as the alkoxide groups are removed. The postulate that the rate-limiting step in the decomposition of the phosphate esters is the sequential removal of the alkoxide group is tested by plotting the experimental activation energy obtained from temperature-programed desorption experiments versus the corresponding heats of adsorption calculated by DFT. A linear dependence shows that the reaction obeys the so-called Evans–Polanyi relation, thereby confirming the above postulate. The slope of the plot is close to unity and thus implies that the structure of the transition state of the reaction resembles the product.

Solvent and catalyst-free synthesis, corrosion protection, thermodynamic, MDS and DFT calculation of two environmentally friendly inhibitors: Bis-phosphonic acids

Solvent and catalyst-free synthesis of two bis-phosphonic acids were realized adopting one-pot reaction of 2,6-bis (hydroxymethyl)-4-methoxyphenol or 4-chloro- 2,6-bis (hydroxymethyl) phenol with trialkyl phosphite. Their structures were confirmed by 1H, 13C, 31P NMR and IR spectroscopies. The molecular structures have been optimized using DFT, and the related calculated vibrational frequencies and NMR shift confirm the proposed structures. Chemical and electrochemical tests evaluated the inhibitive capabilities on the XC48 steel corrosion against 1 M HCl. The weight loss (chemical one) shows that the adsorption on the XC48 steel surface obeys to Langmuir isotherm, while the polarization measurements suggest that the inhibition process is mixt, the results of Electrochemical Impedance Spectroscopy (EIS) prove an increase of the inhibition efficiency with the increase of inhibitor concentrations. The surface topographies were analyzed by the Atomic Force Microscopy (AFM). The Density Functional Theory (DFT) with B3LYP as correlation function and 6-31G (p, d) as basis sets were used to determine some theoretical physic-chemical parameters affecting the corrosion inhibition and on the other hand the DFT develop the Frontier Molecular Orbitals (FMOs) and the Molecular Electrostatic Potentials (MEP) and through a discussion was made about their relationship with the inhibition of the corrosion. At the end, Molecular Dynamics Simulations (MDS) based on Monte-Carlo calculations were accomplished to simulate the interface configuration between the inhibitor molecules and Fe (110)/H2O.

Synthesis of Novel Coumarin Derivatives Bearing Phosphor Ester Motifs and Evaluation of their Antioxidant Activities

phosphoramidate, phosphoranylidenetriazene, and azaphosphole derivatives can be respectively formed when the substituted azidocoumarin 1 reacted with trialkylphosphites (TAP), dialkylphosphonates (DAP), and tris(dialkylamino)phosphines. The known triazinedione was revealed to be a side product in the reactions of carbaldehyde 1 with TAP and tris(dialkylamino)-phosphines. In the same context, when the starting coumarin 16 was allowed to react with P (III) reagents, chromen phosphoramidates and chromen phosphoric triamide derivatives were obtained via Staudinger reaction. Contrary to that pathway, phosphoranylidenetriazen chromen derivative could be isolated and identified when coumarin 16 was allowed to react with tris(diethylamino)-phosphine. The antioxidant activities of 6-newly products were evaluated. The results showed that two from the six screened compounds exhibited good antioxidant activities.

Reaction of Lawesson’s Reagent with Triethylphosphite

Previously, It has been reported that the reaction of L.R. with Di and Tri alkyl phosphites afforded the thioproducts. Here in, we have reacted Lawesson’s reagent (L.R.,1) with triethylphosphite 2 in refluxing acetonitrile to give three phosphonate derivatives 3, 4 and 5 respectively. Structures of the later products were confirmed by analytical and spectroscopic evidences.

Reaction of barbituric/thiobarbituric acid with phosphines or phosphites and dialkyl acetylenedicarboxylates for synthesis of phosphorus zwitterions or phosphonate derivatives

A three-component reaction between barbituric/thiobarbituric acid, phosphines, and dialkyl acetylenedicarboxylates in dry acetonitrile led to the formation of barbiturate/thiobarbiturate-functionalized stable zwitterionic salts in a one-pot process. When trialkyl phosphites were used instead of phosphines, barbiturate/thiobarbiturate-functionalized phosphonates were obtained in good yields.

Regioselective O/C phosphorylation of α-chloroketones: a general method for the synthesis of enol phosphates and β-ketophosphonates via Perkow/Arbuzov reaction.

A regioselective O/C phosphorylation of α-chloroketones with trialkyl phosphites was performed for the first time, which employed solvent-free Perkow reaction and NaI-assisted Arbuzov reaction under mild conditions respectively. Versatile enol phosphates were prepared in good to excellent yields as well as β-ketophosphinates.

Iodine catalyzed one-pot four component synthesis of coumarinyl phosphoramidates via sequential addition of reactants

An unprecedented synthetic route for the preparation of a library of novel coumarinyl phosphoramidate derivatives via iodine catalysed one-pot four component reactions of ethyl 4-bromo-3-oxo-alkanoate, sodium azide, trialkyl phosphites, and phenols in ethanol is reported.

Acid and 1, 2‐Dichloroethane Co‐Promoted Substitution of the Amino Groups in Gramine and its Analogues with Trialkyl Phosphites

AbstractThe transformation of gramine and its analogues represents an important strategy in organic chemistry. Here, we report an acid and DCE co‐promoted phosphonation of gramine and its analogues using trialkyl phosphites as nucleophilic reagents. This reaction avoided the use of stoichiometric alkylation reagents, PBu3 (Tributyl phosphine) and noble metal catalyst. Except for the tertiary amino group in indoles, the primary amino and secondary amino groups, which the previous work did not mentioned were explored.

Fast‐Synthesis of α‐Phosphonyloxy Ketones as Drug Scaffolds in a Capillary Microreactor

A simple, room temperature approach for the fast single‐step synthesis of α‐phosphonyloxy ketone, a drug scaffold, has been developed which involves highly reactive species i.e., 1,2‐dicarbonyls that readily react with trialkyl phosphites and formic acids in batch as well as in continuous‐flow with the flow rate of 3 ml/min (tR = ∼4 s). The present approach reduced the synthesis time from hours to minutes in batch, which was further lowered to a few seconds precisely controlled by single capillary microfluidics. A wide range of 1,2‐dicarbonyl derivatives were smoothly transformed to their corresponding α‐phosphonyloxy ketones in moderate to good yields (50–82 %) under optimized flow‐reaction conditions. Further, the α‐phosphonyloxy ketones produced can be utilized in batch process to form benzoin, oxazole core, and α,α′‐diarylated carbonyl compounds in 82 %, 50 %, and 54 % yields, respectively, which are alternative key precursors/scaffolds of natural products and active pharmaceutical ingredients (APIs).

Features of the Identification of Trialkyl Phosphites in Reaction Mixtures and Their Characterization by Gas Chromatography–Mass Spectrometry

The interaction of aliphatic alcohols ROH with phosphorus trichloride in the absence of bases leads to the formation of exclusively dialkyl phosphonates (RO)2PHO. To obtain trialkyl phosphites (RO)3P, insufficiently described to date, the pH of the reaction mixtures was adjusted by adding N,N-dimethylaniline (pKa 5.1 ± 0.1). The identification of trialkyl phosphites directly in reaction mixtures without preparative isolation implies a joint consideration of their mass spectra and gas chromatographic retention indices, provided that all other components of such mixtures are identified. The need to comply with this condition has led to the identification of several homologues of a previously uncharacterized series of 2-alkoxy-1,3,2-dioxaphospholanes, formed from a random admixture of ethylene glycol. The use of such combined mass spectrometric parameters as homologous increments of retention indices helps to distinguish trialkyl phosphites from isobaric dialkyl phosphonates; the compounds of both series belong to the homologous group of y = 12, y ≡ M(mod14). Despite the absence of molecular ion signals in the electron ionization (EI) mass spectra, the molecular weights of trialkyl phosphites can be estimated. In addition, a comparison of the homologous increments of retention indices shows that, compared with dialkyl phosphonates, trialkyl phosphites are significantly less polar.

New Bioactive Esters and Phosphonates Semisynthesized From (±)-Vasicinone: An Alkaloid Isolated From Peganum harmala

A series of N-tosyl α-amino acids 2a-e, prepared using a tosyl chloride protecting group, was condensed with (±)-vasicinone 1, isolated from the seeds of the plant Peganum harmala, to generate the corresponding esters 3a-e and 3b′-e′. (±)-Vasicinone 1 was also reacted with chloroacetic acid chloride to afford a new chlorinated ester 4 which was refluxed with trialkyl phosphites to give 2 new phosphonates 5a,b. All synthesized compounds were characterized with the help of spectroscopic means, including NMR (1H, 13C, and 31P) and ES-HRMS, and then screened for their in vitro anti-acetylcholinesterase (AChE), anti-5-lipoxygenase (5-LOX), and cytotoxic activities (MCF-7, OVCAR-3, and HCT-116 cell lines). Most synthesized derivatives exhibited a cytotoxic activity against 3 cell lines used. The phosphonate derivative 5b was found to be the most active one (IC50 = 63.7 ± 1.4 µM) against AChE enzyme. Only 2 diastereoisomers 3e and 3e′ exhibited activity against 5-LOX enzyme with IC50 values of 63.1 ± 4.2 and 79.2 ± 8.3 µM, respectively.

Transition‐Metal‐Free Three‐Component Synthesis of Tertiary Aryl Amines from Nitro Compounds, Boronic Acids, and Trialkyl Phosphites

AbstractThe synthesis of aromatic amines is of continuous interest in chemistry. An exceptionally versatile three‐component reaction that directly transforms inexpensive nitro compounds, boronic acids, and trialkyl phosphites into tertiary aromatic amines has been realized. The reaction tolerates alkyl and aryl substituents on the nitro and boronic acid moieties, as well as functionalized phosphites. No transition‐metal catalysis is required. The method is orthogonal to other classical metal‐catalyzed syntheses since it tolerates the presence of halogens, and also permits the synthesis of functionalized compounds such as α‐amino ester derivatives.magnified image