Diphenyl H-phosphonate

Cyclic Monophosphates and Their Analogues. - A new preparative route to cyclic phosphorothioates of type 199 involves the reaction of 5 -0-Dmtr-nucleo-sides with diphenyl H-phosphonate in the presence of pyridine, followed by treatment of the resultant cyclic H-phosphonates with sulfur and final deprotection with acetic acid. The method was used with all four ribonucleobases, and gave the products as 1 1 mixtures of diastereoisomers. ... 

Diphenyl H-phosphonate is obtained by the treatment of H-phosphonic acid with a twofold excess of triphenyl phosphite [35-37]. 

Diphenyl H-phosphonate is reactive enough to undergo fast and quantitative reaction with various nucleophiles at room temperatures [32-34]. Different authors assume that this compound reacts by its tricoordinated tautomeric form. 

Nucleophilic substitutions at the phosphorus atom of the H-phosphonate diesters depend on the degree of occupation of its d-orbitals. The conjunction existing between the oxygen atom and the aromatic nucleus decreases the degree of interaction between the oxygen and phosphorus thus the degree of occupation of d-orbitals of the phosphorus atom in diphenyl H-phosphonate is lower than that in H-phosphonate dialkyl esters. 

It should be pointed out that the side reactions during the transesterification of diphenyl H-phosphonate are strongly depressed. In diphenyl H-phosphonate, there is only one electrophilic center—the phosphorus atom. It is shown that reaction mixtures resulting from transesterification of diphenyl H-phosphonate with alcohols in pyridine were contaminated with triphenyl phosphite and phenyl H-phosphonate, products of the disproportionation of diphenyl H-phosphonate [34]. 

Diphenyl H-phosphonate reacts with aliphatic saturated mercaptans and unsaturated mercaptans with the formation of thio and dithio H-phosphonates [59]. 

The disproportionation of diphenyl H-phosphonate to the corresponding triester and the H-phosphonate monoester was found to be practically an irreversible process. Both compounds were completely stable and did not undergo any reactions. Kers et al. [289] proposed a plausible mechanism for the disproportionation of diphenyl H-phosphonate to take into account the characteristic chemical features of diaryl H-phosphonates. The presence of electron-withdrawing substituents (two phenyl groups) makes the phosphorus more electrophilic in diphenyl H-phosphonate and enables abstraction of the proton from the P-H group even by a weak base (e.g. pyridine). 

Diphenyl H-phosphonate represents an inexpensive, commercially available reagent suitable for the convenient and efficient conversion of partially protected deoxyribo- and ribonucleotides into the corresponding 3 -phosphonate monoesters. The reagent is stable, easy to handle, and affords H-phosphonate monoesters of purity usually better than 95% even without column chromatography. Considering that phosphonylation with diphenyl phosphonate occurred effectively in rather mild conditions, it could be expected that this procedure will find applications outside the nucleotide field, for example, peptides, carbohydrates, etc. 

The diphenyl H-phosphonate/pyridine mixture has been found to be the most effective catalyst for this reaction. Carbamides and thiocarbamides are formed in high yields when diamines are substituted for aniline in the above scheme [131]. 

Premia J, Kaluzynski K, Szymanski R, Penczek S (1997) Preparation of poly(alkylene H-phosphonate)s and their derivatives by polycondensation of diphenyl H-phosphonate with diols and subsequent transformations. Macromolecules 30 8172-8176... 

A new one-pot method has been developed by Kraszewski for the synthesis of aryl nucleoside phosphate (3a-p) and phosphorothioate (4a-p) diesters. This method, based on H-phosphonate chemistry, employed diphenyl phosphoroch-loridate and a series of phenols. Depending on the substituents present on the phenols, oxidation conditions were optimized to avoid competing hydrolysis. A versatile procedure that permits easy access to H-phosphonoselenoate monoesters (5) has been developed by Stawinski. These monoesters, obtained by selenisation of a phosphinate using triphenylphosphine selenide in combination with trimethylsilyl chloride, reacted with a suitable nucleoside in pyridine/acetonitrile in the presence of diphenyl phosphorochloridate to yield... 

Arylselenophosphates are useful intermediates in organic chanistry [273] and biochemistry [274]. Due to its importance, a variety of procedures have been developed to prepare arylselenophosphates [272,275]. It was shown that arylselenophosphates can be obtained in mild condition and high yield by reacting dialkyl H-phosphonates with diphenyl diselenide in the presence of AIBN [276]. 

Probably, the reaction involves as an initial step a nucleophilic attack of the oxygen atom of the diphenyl phosphonate anion at the phosphorus atom of the diphenyl H-phos-phonate. A resulting intermediate 4 may then react with phenol, affording the final products 2 and 3 (pathway B) or alternatively, be converted into another intermediates (pathway B and C). 

Peptides containing a P-terminal aminophosphonic acid have been prepared by coupling protected amino acids with dialkyl or diaryl esters of aminoalkanephosphonic acids or free acids. Protection of the amino phosphonic acid groups is an important step in the phospho-nopeptide synthesis. Aminophosphonates based on the H-phosphonate diesters are used directly for the preparation of phosphonopeptides. Diphenyl aminoalkanephosphonates are attractive starting materials for phosphonopeptide synthesis because they are readily available, and efficient coupling is easily achieved by most methods used in peptide chemistry. 

Diphenyhnethylamine was reacted with formalin to give 2,4,6-tris(benzydryl)hexahy-dro-l,3,5-triazine 1. Addition of diethyl H-phosphonate to 1 gave diethyl N-(diphenyl-methyl)methylphosphonate 2. The oxidation of 2 furnished the imine 3, which was... 

Formation of the undesired symmetrical product (R2 = ribonucleoside) can be completely eliminated by using three molar excess of diphenyl phosphonate and the reaction went to completion in 15 min under these conditions. Lower reactivity of the ribonucleoside phenyl H-phosphonates (R2 = phenyl) has been manifested in their slower hydrolysis to the nucleoside H-phosphonates upon addition of water. The hydrolysis was found to be substantially faster in the presence of a base. 

Todd et al. used nucleoside 3 -H phosphonates to prepare 3 -5 -intemucleotidic bonds for the first time [189], Diphenyl chlorophosphale was used to activate nucleoside H-phosphonate. 

Kraszewski et al. [208] have developed a new, efficient method for the synthesis of phosphorothioate diester, based on the H-phosphonate chemistry. The reaction of aryl nucleoside H-phosphonate with elemental sulfur furnished the corresponding aryl nucleoside phosphorothioate. The synthesis of phosphorothioates can be carried out as a four-components-one-pot reaction, by allowing nucleoside H-phosphonate to react with phenols in the presence of diphenyl phosphorochloridate to furnish aryl nucleoside H-phosphonates, which react with elemental sulfur. 

Diphenyl and dimethyl H-phosphonates react with complexes of the type cw-[PtCl2L2] (L = R3P or EtjAs) with liberation of one equivalent hydrogen chloride [426]. 

Ribonucleoside H-phosphonates were introduced by Todd in 1957 to prepare diribonucleotide phosphate diesters (1). The H-phosphonates were activated for condensation with diphenyl chlorophosphate, and this activator was later extended to the synthesis of deoxyribonucle-otide dimers (2). Activation of deoxynucleoside H-phosphonates with acyl chlorides allows for the synthesis of oligodeoxynucleotides greater than 100 bases in length (3,4). Since these initial results, a number of laboratories have used acyl chlorides and nucleoside H-phosphonates in the synthesis of oligodeoxynucleotides (5-9). This chemistry has also been extended to the synthesis of phosphate analogs of oligodeoxynucleotides (10-16). 

The kinetics of deuterium isotope exchange between diphenyl phosphine and t-butylthiol have been studied by H n.m.r. spectroscopy.274 A negative temperature coefficient was observed for the reaction of a perf1uoroalky1 phosphite with a fluorinated aldehyde.275 The kinetics for the reaction of alcohols with phosphoryl trichloride bore strong similarities to those of carboxylic acid derivatives.276 An interesting report desribed the solvolysis of ary 1 hydroxymethyl-phosphonates. It was shown that a phosphoryl group does not prevent carbocation formation on an immediately adjacent carbon atom.277... 

A soln of the diphenyl [l-(benzyloxycarbonylamino)alkyl]phosphonate 4 in 45% HBr/AcOH (150 mL per 0.1 mol) was kept at rt for 1 h. Removal of the solvent and volatile products in vacuo yielded the oily hydrobromide, which crystallized upon addition of anhyd Et20. The free amine was obtained by suspending the hydrobromide in CHC13 and shaking in a separatory funnel with an equal volume of 2M NaOH until all the solid dissolved. The CHC13 layer was separated, washed with brine, dried (MgS04), and concentrated to yield 19 in >90% yield mp (R1 = Me) 36-39°C mp (R = iPr) 60-63°C mp (R1 = iBu) 57-58 °C mp (R = Ph) 63-65 °C mp (R = Bzl) 65-67 °C. 

General method for preparation of diphenyl esters of Gong-chain alkyl)phosphonic acids Equivalent amounts of the alcohol and triphenyl phosphite, together with 10 moles-% of sodium iodide, are placed in a flaskfitted with a thermometer, gas-inlet tube, stirrer, and distillation head water at about 50° is circulated through the attached condenser to prevent crystallization of the phenol. Nitrogen is led into the flask while the mixture is heated at the required temperature by a radiant heater until no more phenol distils (about 20 h). The remaining material is distilled at < 0.05 mm and the distillate is taken up in ether. The ethereal solution is washed with 2N-sodium hydroxide solution, dried and evaporated, and the residue is redistilled. 

The addition of hydrogenphosphonates to chloroketones, and also to other mono halo-genated carbonyl compounds, is aided by the presence of AI2O3, yields of 78-96% being achievable. However, reactions between dialkyl or diphenyl hydrogenphosphonates and chloroacetone " ", 5 m-dichloroacetone or a ym-dichloroacetone " do occur in the absence of a catalyst when mixtures of reactants are heated to 100-120 °C the products are the phosphonates 173 (R = H or Cl). Aryl trichloromethyl ketones are mon-odechlorinated by the action of trialkyl phosphites or dialkyl hydrogenphosphonates and both further dechlorination and the formation of phosphate esters have been... 

To a solution of phosphonate (1.0 eq. 0.02 M in THF) and 18-crown-6 (5 eq.), precooled to -78°C, was added KHMDS (1.0 eq.) under argon. The mixture was stirred for 30 min and then transferred via cannula to a precooled solution of 1.1-2.2 eq. of 2-diphenylphosphinoyloxy-n-deca-aldehyde. The mixture was stirred at -78°C under argon for 3 h, whereafter a 1 M solution of acetic acid in methanol was added. After the mixture was stirred for 5 min more, phosphate buffer at pH 7 was added, and the mixture was allowed to warm to room temperature. Extraction with EtOAc afforded a crude mixture that was purified by flash chromatography (twice 20-25% EtOAc in hexanes) to give (T/ ,2 5,5 / )-8-phenylmenthyl (2Z,45)-4-diphenyl-phosphinoyloxy-2-dodecenoate and R,2 S,5 i )-8 -phenylmenthyl (2 ,4/ )-4-diphenylphosphinoyloxy-2-dodecenoate, both as a colorless oil, in a combined yield of 96%. 

Phosphonate (23, R = H) is a potential anti hypertensive agent as it is a potent inhibitor of neutral endopeptidase. However, it has low oral bioavailability, whereas the diphenyl analogue (23, R = Ph) has been shown to be an orally active prodrug [37]. The chemical hydrolysis of prodrug (23, R =... 

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