Preparation,stability, reactivity and synthetic utility of a cadmium stabilized complex of difluoromethylene phosphonic acid ester

Diethyl bromodifluoromethyl phosphonate reacts readily with cadmium metal to form a stable cadmium complex. Depending on solvent, this functionalized organocadmium reagent exhibits stability for days to months. It reacts with a variety of electrophiles and serves as a synthetically useful source for the introduction of the difluoromethylene phosphonate group into organic compounds.The synthetic utility of a wide variety of fluoromethylene phosphonium ylides has been a major effort in our laboratory over the past several years [1]. The generation and capture of difluoromethylene ylides ($\text{1}$) as a general route to difluoromethylene olefins has been of especial interest to us [2]. In an effort to increase the nucleophilicity of the ylide, we have attempted to prepare the analogous phosphonate ylide ($\text{2}$). Although we have achieved modest success [3] by $\text{insitu}$ capture of ($\text{2}$) in the reaction of

sodium dialkyl phosphites with diethyl bromodifluoromethylphosphonate ($\text{3}$), attempts to pregenerate ($\text{2}$), either from diethyl difluoromethylphosphonate ($\text{4}$) or ($\text{3}$), have met with little success. ($\text{2}$) appears to have minimal stability even at low temperatures, and scale up processes of synthetic value would seem to be difficult.     

Difluoromethylene analogues of aspartyl phosphate: the first synthetic inhibitors of aspartate semi-aldehyde dehydrogenase

The difluoromethylene analogue of aspartyl phosphate 6 has been prepared by the fluoride catalysed coupling of diethyl trimethylsilyldifluoromethyl phosphonate with an appropriate aldehyde followed by Dess-Martin oxidation and deprotection; the deprotected compound inhibited (KI 95 microM) aspartate semi-aldehyde dehydrogenase, a key enzyme involved in bacterial amino acid and peptidoglycan biosynthesis.     

Synthesis of Functionalized Diethyl(pyrrolidin-2-yl)phosphonate and Diethyl(5-oxopyrrolidin-2-yl)phosphonate

Short and efficient syntheses of functionalized (pyrrolidin-2-yl)phosphonate and (5-oxopyrrolidin-2-yl)phosphonate have been developed. The synthetic strategy involved the diastereospecific 1,3-dipolar cycloaddition of N-benzyl-C-(diethoxyphosphoryl)nitrone to cis-1,4-dihydroxybut-2-ene and dimethyl maleate, respectively. O,O-Diethyl 3-carbamoyl-4-hydroxy(5-oxopyrrolidin-2-yl)phosphonate was obtained from O,O-diethyl 2-benzyl-4,5-dimethoxycarbonyl(isoxazolidin-3-yl)phosphonate by hydrogenation and subsequent treatment with ammonia, whereas transformation of O,O-diethyl 2-benzyl-4,5-dihydroxymethyl(isoxazolidin-3-yl)phosphonate into O,O-diethyl 3-aminomethyl-4-hydroxy(pyrrolidin-2-yl)phosphonate was accomplished by mesylation followed by hydrogenolysis to undergo intramolecular cyclization and the introduction of amino group via ammonolysis. Stereochemistry of the isoxazolidine cycloadducts, as well as the final functionalized (pyrrolidin-2-yl)- and (5-oxopyrrolidin-2-yl)phosphonates were established based on conformational analyses using vicinal H–H, H–P, and C–P couplings and supported by the observed diagnostic NOESY correlation signals.     

Preparation,stability and acidity of difluoromethylene bis phosphonic acid

Hydrolysis of difluoromethylene phosphonate esters quantitatively yields difluoromethylene $\text{bis}$ phosphonic acid as a dihydrate. $\text{In vacuo}$ drying leads to either the monohydrate or the anhydrous acid. Titration of either the free acid or its disodium salt and computer fit of the data gives all four pKas. The disodium salt and the free acid are thermally stable, and the disodium salt is extremely stable even to strong base.     

Ready Access to Fluorinated Phosphonate Mimics of Secondary Phosphates. Synthesis of the (alpha,alpha-Difluoroalkyl)phosphonate Analogues of L-Phosphoserine, L-Phosphoallothreonine, and L-Phosphothreonine

In addition to the previously recorded reactions of diethyl lithio(difluoromethyl)phosphonate (8) with primary triflates and aldehydes, we report here that 8 reacts with functionalized, but unactivated, methyl esters to give efficient acyl substitution. Thus, 8 reacts cleanly (-78 degrees C, THF) with the following methyl esters (product, yield): methyl (S)-isopropylideneglycerate (14, 99%), methyl (S)-3-O-(tert-butyldimethylsilyl)-2 -O-tetrahydropyranylglycerate (16, 85%), and the Garner ester derived from D-serine (15, 77%). Expeditious treatment of the resultant alpha,alpha-difluoro-beta-keto phosphonates with hydride or Grignard reagents followed by alcohol deoxygenation provides a general method for the synthesis of (alpha,alpha-difluoroalkyl)phosphonate analogues of secondary phosphates. For tertiary alcohols, Dolan-MacMillan deoxygenation conditions are employed. The requisite methyl oxalate esters are obtained by an improved procedure wherein the lithium alkoxide of the hindered tertiary alcohol is irreversibly generated at low temperature and then condensed with methyl oxalyl chloride. Relative stereochemistry is assigned via conversion of the Garner ester derived Boc-amino alcohols to the corresponding cyclic, six-membered phosphonate esters and examination of their (1)H NMR spectra. The relevant vicinal coupling constants are extracted from these spectra by performing double quantum-filtered phase-sensitive COSY experiments. This new (difluoromethylene)phosphonate anion-methyl ester condensation, Grignard (hydride) addition, deoxygenation sequence has been applied to the synthesis of (alpha,alpha-difluoroalkyl)phosphonate analogues of L-phosphoserine (>/=96% ee) and L-phosphoallothreonine (93% ee) from D-serine and of L-phosphothreonine (91% ee) from L-glycerate, respectively.     

Ferromagnetic exchange coupling in phosphonato-bridged dinuclear copper(II) compound with monoethyl (pyridyn-2-ylmethyl)phosphonate ligand (2-mpmpe): Cu2(2-mpmpe)2(H2O)2(NO3)2

The interaction of diethyl (pyridyn-2-ylmethyl)phosphonate (2-pmpe) with Cu(NO₃)₂ · 6H₂O leads to a partial hydrolysis of the starting ligand and formation of the compound of the formula Cu₂(2-mpmpe)₂(H₂O)₂(NO₃)₂, where 2-mpmpe = monoethyl (pyridyn-2-ylmethyl)phosphonate. The crystal and molecular structure of a copper(II) compound was determined by single X-ray diffraction method. Its structure consists of five-coordinated in distorted square planar geometry (CuNO₄ chromophore) copper(II) ions doubly bridged by OPO from phosphonate. The Cu?Cu distance is 4.69 Å. The crystal packing is determined by the interdinuclear hydrogen bond system, which leads to a three-dimensional (3D) H-bonds network. The compound was characterized by infrared, ligand field, EPR spectroscopy, and magnetic studies. The magnetic properties of the title compound investigated over the 1.8–300 K, revealed the occurrence of a weak ferromagnetic coupling through phosphonate bridge (J = 1.86 cm⁻¹) and interdimer superexchange coupling through H-bond network (zJ′ = −0.17 cm⁻¹). Spectroscopic and magnetic properties are presented in the light of crystal structure.     

Introducing difluoromethylene sulfonamide group via nucleophilic addition of difluoromethylene anion with aromatic aldehydes

A new fluorine-containing synthon, R¹COCF₂SO₂R² (2, R¹, R²=morpholino, piperidino, etc.), was developed for the introduction of difluoromethylene sulfonamide or difluoromethylene group. Under different conditions, 2 reacted readily with aromatic aldehydes to give the corresponding difluoromethylene-containing alcohols or diols in moderate to good yields in the presence of potassium tert-butoxide. Difluoromethylene sulfonamide group was introduced into organic compounds directly for the first time by this method.     

AIBN-initiated radical addition of gem-difluorinated alkyl iodides to alkynes and the Pd-catalyzed Sonogashira coupling reaction of E-phenyl difluoromethylene vinylic iodides with terminal alkynes

The addition of gem-difluorinated alkyl iodides to alkynes initiated by AIBN neatly gave the corresponding difluoromethylene vinyl iodides among which the stereoselectivity of aromatic acetylenes was high. The further coupling reaction of E-phenyl difluoromethylene vinyl iodides with terminal alkynes in the presence of catalytic palladium afforded the substituted difluorinated enynes.     

Synthesis of poly(silylenephosphonate)s incorporating 2-chloroethylphosphonic acid (ethephon), a stimulant for the latex production by the Hevea brasiliensis

2-Chloroethylphosphonic acid (ethephon) is a well-known stimulant commonly used to improve the latex production by the rubber tree (Hevea brasiliensis). In order to prolong its stimulating activity, the purpose was to insert ethephon inside polymer chains which, afterwards, will be able to degrade slowly through time, and thus to release ethephon molecules. For that, linear poly(silylenephosphonate)s incorporating ethephon groups were synthesized by using a polycondensation procedure between ethephon (or one of its dialkyl phosphonate derivatives) and an α,ω-dihalogeno-silylated monomer. To make sure that polycondensation can occur, the reactivity of halogenotrimethylsilanes (X=Cl or Br) toward ethephon and its various dialkyl phosphonate derivatives, was examined first. Then, poly(silylenephosphonate) synthesis was achieved by polycondensation between diisopropyl (2-chloroethyl)phosphonate and α,ω-dichloro-silylated monomers. According to this procedure, cyclic polymers of low average molecular weights (M_n<2000) were obtained, whatever the α,ω-dihalogeno-silylated monomer used.     

Structural and spectroscopic investigations of europium(III) entrapped by the ethylenediaminetetra(methylenephosphonate) ligand in K12H8[Eu4(EDTMP)4] · 45H2O crystal

The X-ray crystal structure of an anionic octacoordinate Eu³⁺ complex of the formula K₁₂H₈[Eu₄(EDTMP)₄] · 45H₂O, where EDTMP is the ethylenediaminetetra(methylenephosphonate) anion, hereinafter referred to as I, has been determined. The crystal consists of cyclic tetrameric complex anions, in which the surrounding of each Eu³⁺ ion is composed of two nitrogen atoms and six oxygen atoms from phosphonate groups. One of the phosphonate groups in the ligand molecule is tridentate (O:O′,O″), thus giving rise to the formation of the tetramers. The compound was characterized by UV–Vis electronic spectroscopy. At room and liquid nitrogen temperatures the complex shows luminescence from both ⁵D₀ and ⁵D₁ states, the latter one, which is very rare in Eu³⁺ compounds with organic ligands, is probably brought about by the saturation of the coordination sphere with the phosphonate groups.     

5-phenyl-2H-tetrazol-2-ylmethyl ketones in the synthesis of tetrazolylalkanols and tetrazolyl(hydroxy)alkylphosphonates

The reduction of 1-(5-phenyl-2H-tetrazol-2-yl)propan-2-one and 1-phenyl-2-(5-phenyl-2H-tetrazol-2-yl)ethanone with sodium tetrahydridoborate gave 1-(5-phenyl-2H-tetrazol-2-yl)propan-1-ol and 1-phenyl-2-(5-phenyl-2H-tetrazol-2-yl)ethanol, respectively. Only 1-(5-phenyl-2H-tetrazol-2-yl)propan-2-one was reduced with baker’s yeast with an appreciable yield. 1-(5-Phenyl-2H-tetrazol-2-yl)propan-2-one and 1-phenyl-2-(5-phenyl-2H-tetrazol-2-yl)ethanone reacted with diethyl phosphonate in the presence of potassium fluoride to produce the corresponding diethyl [hydroxy(5-phenyl-2H-tetrazol-2-yl)alkyl]phosphonates.     

Formation of cage phosphonate via hydrolysis of 2-(5-methyl-2-phenyl-2<Emphasis Type="Italic">H</Emphasis>-1,2,3-diazaphosphol-4-yl)-1,5-dioxo-4-trifluoromethyl-4-ethoxycarbonylbenzo[<Emphasis Type="Italic">f</Emphasis>]-1,3,2-dioxaphosphepine

A new approach to obtaining of caged bicyclic phosphonate, 4-hydroxy-3-trifluoromethyl-3-ethoxycarbonyl-8-(1-phenylhydrazonoethyl)-5,6-benzo-2,7,1-dioxaphosphabicyclo[3.2.1^1.5]octane, based on hydrolysis of 2,5-dioxobenzo[f]1,3,2-dioxaphosphepine derivative bearing 5-methyl-2-phenyl-2H-1,2,3-diazaphosphol-4-yl substituent at the phosphorus was developed. The hydrolysis process includes elimination of P(II) atom and intramolecular cyclization involving endocyclic carbonyl group of the phosphepine. Structure of the caged phosphonate was established by NMR and XRD methods.     

Photochemical substitution of olefins and aromatic compounds with difluoromethyl radicals bearing ester and phosphonate groups

Efficient and selective substitution of cyclic and acyclic vinyl ethers with photo-generated difluoromethyl radicals bearing ester and phosphonate groups, in the presence of 2,4,6-trimethylpyridine and diphenyl diselenide was successfully carried out to provide the corresponding regioselective unsaturated difluoromethylene adducts selectively. The reaction involves phenylselenyl transfer at an early stage followed by elimination of phenylselenol from the adducts once formed to provide the unsaturated difluoromethylene adducts selectively. This novel photochemical method was successfully extended to aromatic and heteroaromatic substitutions to provide the corresponding α-aryl-α,α-difluoroacetates and α-aryl-α,α-difluoromethylphosphonates in good to moderate yields.     

Co[HO2C(CH2)3NH(CH2PO3H)2]2: a new canted antiferromagnet

A new cobalt(II) carboxylate-phosphonate, namely, Co[HO2C(CH2)3NH(CH2PO3H)2]2, with a layered architecture has been synthesized by hydrothermal reactions. The Co(II) ion in the title compound is octahedrally coordinated by six phosphonate oxygen atoms from four carboxylate phosphonate ligands. Neighboring CoO6 octahedra are interconnected by phosphonate groups into a 2D layer with a 4,4-net topology. Adjacent layers are further cross-linked via hydrogen bonds between the noncoordinate carboxylate groups and noncoordinate phosphonate oxygens. The ac and dc magnetic susceptibility and magnetization measurements indicate that Co[HO2C(CH2) 3NH(CH2PO3H)2]2 is a canted antiferromagnet with T(c) = 8.75 K.     

Synthetic and mechanistic aspects of the reactions between bromodifluoromethyltriphenylphosphonium bromide and dibromofluoromethyltriphenylphosphonium bromide and trialkylphosphites

Bromofluoromethyltriphenylphosphonium bromides react with trialkylphosphites in two distinct ways. Bromodifluoromethyltriphenylphosphonium bromide undergoes a rapid exchange reaction with trialkylphosphites to give the corresponding bromodifluoromethylphosphonates in good to excellent yields. A similar exchange reaction also occurred with an analogous diethoxyphenylphosphonite to give the corresponding ethoxyphenylphosphinate. Mechanistically, the exchange process involves the formation of difluorocarbene via dissociation of the intermediate difluoromethylene ylide, capture of the difluorocarbene by the trialkylphosphite to give , which captures bromine followed by dealkylation to the product, bromodifluoromethylphosphonate. The equilibria involved in the multi-step mechanism are all shifted to the phosphonate product by the final dealkylation step. In contrast, the dibromofluoromethyltriphenylphosphonium bromide does not under exchange reactions with trialkylphosphite. The phosphite serves as a halophilic reagent to abstract Br from the dibromofluoromethylphosphonium salt to generate the bromofluoromethylene ylide, which can easily be trapped in situ with aldehydes or ketones to give good yields of the E/Z-bromofluoroalkenes. No dissociation of the bromofluoromethylene ylide was observed.     

Synthesis and resolution of diethyl (1S,2S)-1-amino-2-vinylcyclopropane-1-phosphonate for HCV NS3 protease inhibitors

We herein describe an efficient synthesis of optically active diethyl 1-amino-2-vinylcyclopropane-1-phosphonate (analogous to 1-amino-2-vinylcyclopropane-1-carboxylate). The racemic phosphonate diethyl ester was obtained from an imine derived from aminomethylphosphonate diester and trans-1,4-dibromo-2-butene. Crystallizations of the dibenzoyl-l-tartaric acid salt allowed for separation of enantiomers. The enantiomerically pure material was used to synthesize an extremely potent tripeptide phosphonate inhibitor of HCV NS3 protease. X-ray crystal structure of the inhibitor bound to the HCV NS3 protease confirmed the absolute stereochemistry of the title compound.     

Synthesis of four enantiomers of 2-acetamido-1-hydroxypropylphosphonates

Enantiomerically pure diethyl 2-acetamido-1-hydroxypropylphosphonates were synthesised from N-[(R)-(1-phenylethyl)]aziridine-(2S)- and N-[(S)-(1-phenylethyl)]aziridine-(2R)-carboxaldehydes via phosphonylation followed by acetylation of the hydroxy groups and the simultaneous hydrogenolytic cleavage of the aziridine rings and the removal of the chiral auxiliaries. In addition, enantiomerically pure diethyl (1S,2R)- and (1R,2S)-2-amino-1-hydroxypropylphosphonates (the phosphonate analogues of isothreonine) were separated.     

Reaction of unsaturated phosphonate monoesters with bromo- and iodo(bis-collidine) hexafluorophosphates

Reaction of unsaturated phosphonate monoesters with bromo- and iodo(bis-collidine) hexafluorophosphates are reported to lead to the formation of five- to seven-membered phostones by exo mode cyclizations. When the chains of the unsaturated phosphonate monoesters are substituted in α of the double bond by a dioxolane group endo mode cyclizations are observed. These cyclizations give rise to the formation of 1,2-oxaphosphepane-2-oxide and 1,2-oxaphosphocane-2-oxide.     

Hydrothermal syntheses, characterizations and crystal structures of a new lead(II) carboxylate-phosphonate with a double layer structure and a new nickel(II) carboxylate-phosphonate containing a hydrogen-bonded 2D layer with intercalation of ethylenediamines

Hydrothermal reactions of N,N-bis(phosphonomethyl)aminoacetic acid (HO₂CCH₂N(CH₂PO₃H₂)₂) with metal(II) salts afforded two new metal carboxylate-phosphonates, namely, Pb₂[O₂CCH₂N(CH₂PO₃)(CH₂PO₃H)]·H₂O (1) and {NH₃CH₂CH₂NH₃}{Ni[O₂CCH₂N(CH₂PO₃H)₂](H₂O)₂}₂ (2). Among two unique lead(II) ions in the asymmetric unit of complex 1, one is five coordinated by five phosphonate oxygen atoms from 5 ligands, whereas the other one is five-coordinated by a tridentate chelating ligand (1 N and 2 phosphonate O atoms) and two phosphonate oxygen atoms from two other ligands. The carboxylate group of the ligand remains non-coordinated. The bridging of above two types of lead(II) ions through phosphonate groups resulted in a 〈002〉 double layer with the carboxylate group of the ligand as a pendant group. These double layers are further interlinked via hydrogen bonds between the carboxylate groups into a 3D network. The nickel(II) ion in complex 2 is octahedrally coordinated by a tetradentate chelating ligand (two phosphonate oxygen atoms, one nitrogen and one carboxylate oxygen atoms) and two aqua ligands. These {Ni[O₂CCH₂N(CH₂PO₃H)₂][H₂O]₂}⁻ anions are further interlinked via hydrogen bonds between non-coordinated phosphonate oxygen atoms to form a 〈800〉 hydrogen bonded 2D layer. The 2H-protonated ethylenediamine cations are intercalated between two layers, forming hydrogen bonds with the non-coordinated carboxylate oxygen atoms. Results of magnetic measurements for complex 2 indicate that there is weak Curie-Weiss behavior with θ=−4.4 K indicating predominant antiferromagnetic interaction between the Ni(II) ions. Indication for magnetic low-dimension magnetism could not be detected.