Phosphorylation methylphosphonates

An estimate of the rate enhancement associated with the intramolecular phosphorylation can be made by using isopropyl p-nitrophenyl methyl-phosphonate as a model for the covalent intermediate formed in the initial step of the reaction of cycloheptaamylose with bis (p-nitrophenyl) me thy 1-phosphonate. The first-order rate constant for the alkaline hydrolysis of isopropyl p-nitrophenyl methylphosphonate at pH 9.86 can be obtained from the data of van Hooidonk and Groos (1970) kun = 1.4 X 10-5 sec-1. This value may be compared with the maximal rate constant for the reaction of cycloheptaamylose with bis(p-nitrophenyl) methylphosphonate— k2 = 1.59 X 10-1 sec-1 at pH 9.86—which must be a minimal value for the rate of the intramolecular phosphorylation. This comparison implies a kinetic acceleration of at least 104 which is similar to rate enhancements associated with the formation of cyclic phosphates from nucleoside phosphate diesters. 

Nucleophilic Reactions.—Attack on Saturated Carbon. Selected examples of the Arbusov reaction include phosphorylation of the chloroacetophenones (1) to give phosphonates, which cyclized to (2) in the presence of acid chlorides,1 formation of the azodiphosphonate (3) from 2,2 -dichloro-2,2 -azopropane,2 3 and the reaction of 2-chloro-3,4-dihydro-3-oxo-2//-l,4-benzothiazine (4) with triethyl phosphite to give the 2-phosphonate (5), which is used as an olefin synthon.8 Bis(trimethylsilyl) trimethylsiloxymethylphosphonite (6) has been synthesized by silylation of hydroxy-methylphosphonous acid, and, as expected, undergoes a normal Arbusov reaction with alkyl halides to give the phosphonates (7).4 This series of reactions, followed by... 

Nolan and co-workers have extended the scope of transesterification reactions to include phosphonate esters as phosphorylating agents [137]. In this publication the authors use dimethyl methylphosphonate 273 and benzyl alcohol with a variety of imidazolylidene carbenes (Table 23). The nse of molecnlar sieves to absorb methanol leads to increased conversion however, longer reaction times lead to decreased... 

Metal Ion Effect Complexation of PMPS with Zn2+ ion could be observed by the decrease of absorption intensity of the pyridine ring (Figure 20b). A similar decrease was observed for the parent pyridyl-methylphosphonate (Figure 20b). Therefore, the 1 1 complex in which a metal ion is bridged between pyridyl nitrogen and phosphoryl oxyan-ion likely is involved (Figure 16a). Meanwhile, no detectable change of spectrum was observed in the case of Mg2+ ion, in accordance with very weak chelation of Mg2+ ion with a pyridine base. 

Chiral vinyl sulfoxides can also be prepared Horner-Emmons reaction of carbonyl compounds with a-phosphoryl sulfoxides which are obtained from lithiated dimethyl methylphosphonate and (-)-menthyl (S)-p-toluenesulfinate (eq 8). However, this reaction applied to carbonyl compounds often gives a mixture of the (E) and (Z) isomers of the vinylic sulfoxide. 

The electron-withdrawing properhes of the phosphoryl group were explored and exploited in the very earliest studies. In 1927, A.E. Arbuzov and Dunin reported a study of the reacrion of diethyl l-(ethoxycarbonyl)methylphosphonate with sodium or potassium metal and showed that a-metallated phosphonate produets react with alkyl halides to form a-substituted phosphonoacetates. This approach not only complemented the Michaelis-Arbuzov reaction but also provided access to a more diversified range of phosphonates. The development of phosphonate carbaiuons became more sophisticated with the introduction of powerful bases such as NaH and NaNHj and hthium reagents. Subsequently, two major synthetic advances revolutionized phosphonate chemistry. 

Recent investigations in this standard synthetic procedure have featured the use of LDA (3 eq) or t-BuLi in the presence of HMPA at low temperature for promotion of the 1,2-phosphoryl migration conducive to fonnation of diethyl l-(alkoxycarbonyl)methylphosphonates in satisfactory yields (58-74%, Scheme 8.13). ... 

It has not proved possible to obtain C-alkylated products from diethyl 1-(ethoxycarbonyl )meth-ylphosphonate by the action of acetyl chloride on the alkali metal salts. However, when the ethoxymagnesium salt of diethyl l-(ethoxycarbonyl)methylphosphonate is employed, diethyl 1-ethoxycarbonyl-l-acetyhnethylphosphonate is isolated in a good yield (73%, Scheme 8.20). Similarly, diethyl 1-ethoxycarbonyl-l-benzoyhnethylphosphonate has been prepared in 56% yield from diethyl l-(ethoxycarbonyl)methylphosphonate and benzoyl chloride. The diethyl 1-lithio-1-fluoro-l-(ethoxycarbonyl)methylphosphonate generated with n-BuLi in THF reacts with acid chlorides, fluorine-substituted acid chlorides, and oxalylchloride to form the corresponding acylated phosphonates. By contrast, phosphorylation of the sodium diethyl l-(ethoxycarbonyl)meth-ylphosphonate leads to the O-phosphory lation product. The synthetically useful potassium enolate of diethyl 1,2-/ .v(ethoxycarbonyl)-2-oxocthylphosphonatc is prepared by reaction of the potassium salt of diethyl l-(ethoxycarbonyl)methylphosphonate with diethyl oxalate. ... 

The nucleosidyl-3 -methylfluoridophosphonates (67) and (68) have been used for the synthesis of the corresponding methylphosphonate (69) and methyl-phosphonothioate (70) dimers respectively. The diastereomers (67) and (68) were prepared by phosphorylation of the corresponding 5 -protected nucleosides with (71) and for the latter mixture (68), separation of the individual diastereomers was possible using silica chromatography. Coupling of (67) and (68) with a 3 -0-protected nucleoside in the presence of DBU or sodium hydride gave over 95% yield of the respective dimers. 

The simplest application of the Darzens reaction is outlined in Scheme 29. The production of the phosphoryl carbanion has been normally carried out with a metal alkoxide in this respect, r r -butoxide is better than ethoxide, some reactions proceeding only with the former base butyllithium or Ida has also been employed. The carbanion 357 is also available through the chlorination of dialkyl methylphosphonate carbanion with PhSO.CP ... 

In the presence of BuLi in thf, the active methylene compounds (Et0)2P(0)CH2Z (Z = P03Et2, COOMe, S02Me or CN) add to PhCH—CMe(N02) to give the products 78 as intermediates in a synthesis of C-phosphorylated 2-isoxazoline derivatives Other reactions have been performed between 2-aryl-1-nitroethenes and the anions from dimethyl methylphosphonate " or dimethyl (difluoromethyl)phosphonate in the initial steps towards syntheses of phaclofen 80 X = H) and its difluoro analogue (80 X = F) by the reduction (H2-Raney nickel) of the initial adduct 79 (Scheme 6). 

Stereochemistry — The conformational analysis of various deuteriated ethyl-phosphine-borane adducts and dimethyl methylphosphonates were based on vibrational spectral data. The stereochemistry of diethylphosphonyl acetamide,the unusual vinyl compounds (60 X = L.E.P., O, and a number of l,3,2-dioxaphosphorinanes have been studied. It was found that the Raman-active ring vibration is related to the orientation of the phosphoryl group. Conformational data for dioxaphosphepane was compared with calculated parameters. A low-temperature study of several cyclopropyl-phosphonates (61) revealed rotational isomerization about the P-O bonds but not about the P-C bond. The variable temperature i.r. and Raman spectra of the silyl phosphates (62) also revealed rotational isomerism. ... 

The presence of cyclohexaamylose diflFerently influences the kinetics of alkaline hydrolysis of the two enantiomers of isopropyl methylphos-phonofluoridate and of isopropyl 4-nitrophenyl methylphosphonate. Although all enantiomers become bound to the cycloamylose, the (R)-( — ) enantiomers react selectively in the nucleophilic reactions that give the phosphorylated cyclohexaamyloses. 

Diarylphosphinic and diarylphosphoric azides are rapidly hydrolysed by water to diarylphosphinic and diarylphosphoric acids, respectively. Monophosphazenes are obtained by reaction with phosphines (7.225). Methyl phosphonic diazide (7.223c) can be obtained by reacting methylphosphonic dichloride with sodium azide in pyridine (7.226), while phosphoryl triazide is obtainable with... 

The phosphorylated 2-deoxy-D-eo r TO-pentofuranose derivative (58) has been prepared in three steps from the fi-ee sugar for use as a building block in the construction, by automated methods, of oligodeoxynucleotides with apurinic and/or apyrimidinic sites. Facile syntheses of adenosine 3, 5 -cyclic methylphosphonate (59) and... 

Diethyl pyrocarbonate has been used to convert uridine 2 - or 3 -phosphate into the 2, 3 -cyclic phosphate in high yield, and an adamantyl 2, 3 -cyclic phosphonate (421) was obtained when uridine reacted with I-adamantylphos-phonyl chloride. Phosphorylation of ribonucleosides with pyrophosphoryl chloride followed by hydrolysis in neutral solution afforded a simple synthesis of ribonucleoside 2, 3 -cyclic phosphate 5 -phosphates. Two phosphorylating agents mentioned earlier in this section can also yield 3, 5 -cyclic phosphates either by treatment of nucleoside 5 -(2-iV7V-dimethylamino-4-nitrophenyl phosphates) with acetic acid in pyridine (Scheme I4i) i, 83 qj. treatment of nucleoside 5 -(5 -methyl phosphorothioates) with iodine in pyridine. Another route to 3, 5 -cyclic phosphates involved cyclization of the nucleoside 5 -trichIoro-methylphosphonates (422) (obtained by the action of trichloromethylphosphonyl... 

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