Dealkylation phosphonates

In related chemistry, the borane/silane catalytic system can cleanly dealkylate phosphonic and phosphinic esters RPO(OR,)2 or R2PO(OR/) to give silyl esters with trialkyl silanes.259 If more active silane reagents like Ph2SiH2 or PhSiH3 are employed, catalytic reduction to primary or secondary phosphines is observed. Mechanistic experiments strongly support a silane activation pathway for this chemistry. 

Mixture of phosphonate and mono-dealkylated phosphonate, 19F NMR yield isolated yield... 

Fluoromethyl)phosphonate ester anions react with CO2 or COS to yield esters of the type (161 Y=0 or S) which may be dealkylated to the free acid through the use of bromotrimethyl-silane, but the course of the reaction with CS2 depends on the individual ester thus, (162) yields (163), but (165) is formed from (164). 22... 

We found that dichloro diorgano silanes are suitable reagents for the synthesis of diorgano bis(0-alkyl)phosphonates. A different reactivity of both chlorine atoms of the silanes is observed in the dealkylation reaction of dialkylphosphonates in contrast to Me3SiBr [2]. 

Formation of the nucleoside phosphorodichloridite at -30 °C by PCI3 in CH2CI2 solution (step a) is followed by reaction with ethanol (step b). Subsequently dealkylation occurs with the assistance of hydrogen chloride formed in reaction (a) to give the desired 5 -nucleoside H-phosphonate (step c). It was found that a mixture of ethanol and tcrt-butanol (1 1) as alcoholysis agent prevented side reactions and gave a higher yield than when ethanol alone was used. 

Demethylation of, POCH3. Phosphate and phosphonate esters are partially dealkylated by tertiary amines. r-Butylamine is superior Tor this cleavage, and it is very selective. Only O—Cl I3 bonds are affected ethyl esters are stable to the amine for several weeks. A benzyl group can be cleaved under forcing conditions.1 [Examples ... 

The condensation of an aldehyde, benzyl carbamate, and triphenyl phosphite, first described by Oleksyszyn et al., 25,26 affords a direct route to a-aminoalkylphosphonates 4 that are conveniently protected for subsequent reactions (Scheme 4). Since dealkylation of the quaternary phosphonium intermediate 3 is not possible in this case, formation of the pen-tavalent product 4 presumably involves activation of the solvent and formation of phenyl acetate. This method is useful for the synthesis of aliphatic and aromatic amino acid analogues. However, monomers with more elaborate side chains are often incompatible with the reaction conditions. The free amine can be liberated by treatment with HBr/AcOH or by hydrogenolysis after removal of the phenyl esters. The phosphonate moiety can be manipulated by ready exchange of the phenyl esters in alkaline MeOH and activation as described in Section 10.10.2.1.1. Related condensations with other trivalent phosphite derivatives have been reported. 27-30 ... 

The reaction of a trialkyl phosphate with an alkyl halide to produce an alkyl phosphonate. The first step involves nucleophilic attack by the phosphorus on the alkyl halide, followed by the halide ion dealkylation of the resulting trialkoxyphosphonium salt. 

When the substituent becomes very anion-stabilising, as in 42, the ylid may not react with ketones and anions of phosphonate esters are usually preferred in the Homer-Wadsworth-Emmons (HWE) variant.11 The reagent triethyl phosphonoacetate 46 is made by combining a phosphite (EtO)3P instead of a phosphine, with ethyl bromoacetate. Displacement of bromide 44 gives a phosphonium ion that is dealkylated by bromide 45. 

The O-dealkylation of organophosphorus triesters differs from the above reactions in that it involves the dealkylation of an ester rather than an ether. The reaction was first described for the insecticide chlorfenvinphos (Figure 10.2B), but is now known to occur with a wide variety of vinyl, phenyl, phenylvinyl, and naphthyl phosphates and the thionophosphate triesters. At least one phosphonate, O-ethyl O-p-nitrophenyl phenylphosphonate (EPNO), is also metabolized by this mechanism. 

Selective phosphonate ester dealkylation. Alkyl phosphonate esters are selectively and nearly quantitatively cleaved by bromotrimethylsilane in the presence of alkyl carboxylate esters, carbamates, acetylenes, ketones, and halides. Alkyl iodides do not exchange under the reaction conditions. The resulting bis(trimethylsilyl) phosphonates are hydrolyzed in acetone by a small excess of water. 

Dealkylation of phosphonates. Vigorous acid treatment is usually required for this reaction. To circumvent this difficulty, both bromo- and chloro-trimethylsilane have been used with limited success. lodotrimethylsilane is more selective the parent phosphonic acids can be obtained under very mild conditions without modification of a variety of other functional groups. However, monodealkylation is not practical with this reagent. Aryl esters are not cleaved hence selective dealkylation of alkyl aryl esters of phosphonic acids may be possible. 

Phosphonic derivatives bearing chlorofluorinated chains e.. diethyl-1,1,2-trifluoro-2-chloroethylphosphonate have been prepared by radical telomeriz-ation of chlorotrifluoroethylene with dialkyl hydrogenphosphonates in the presence of peroxide inhibitors. The 0,0-diethylaryldifluoromethylphos-phonothioates (230) undergo the sodium iodide-assisted thiono-thiolo rearrangement and subsequent Pd-catalysed dealkylation of (231) provides several 1,1-difluoromethylenephosphonothioic acids (232) (Scheme 61). These compounds can act as small molecule inhibitors for the protein tyrosine phosphatase enzymes. 

Agrofoglio has reported the syntheses of carbocyclic analogues of phos-phononucleosides (28a-e). Compound (28a) was synthesised by introducing the heterocycle under Mitsunobu conditions, while compounds (28b-e) were obtained by building up the base around a cyclopentylamine moiety0-Alkyl-ff-phosphonates of AZT (29a-e) and D4T (30a-e) have been prepared via a simple one-pot route under mild conditions and in reasonable isolated yields using phosphorus trichloride, followed by alcoholysis and dealkylation by triethylamine. ... 

Whereas alkylphosphonic diesters react readily with lithium or organomagnesium reagents with the formation of the metallated phosphonate carbanions, the reactions between such esters and the metals themselves result, by contrast, in dealkylation of the ester groups involving both C-0 and P-0 cleavage traces of unsaturated hydrocarbons, even including alkynes and aromatics, are thought to be formed by radical-induced reactions. 

The phosphonic acid analog of NSAID (Non-Steroidal Anti-Inflammatory Drug) diclofenac was successfully synthesized in the laboratory of B. Mugrage using a novel acid catalyzed Arbuzov reaction as the key step followed by a TMSBr promoted dealkylation. It needs to be pointed out that the nucleophilic attack takes place on the ortho-quinonoid intermediate in a non-SN2 process. 

Bromo- and iodotrimethylsilane, reagents compatible with alkyne and other functionalities, are suitable for the mild P-0 dealkylation of dialkyl 1-alkynylphosphonates to give the corresponding phosphonic acids.The greater reactivity of iodotrimethylsilane will probably prove advantageous for the low-temperature dealkylation of phosphonates having triple bonds. However, transesterification of diethyl 2-propynylphosphonate with iodotrimethylsilane at -30°C followed by solvolysis with MeOH led quantitatively to the 1-propynylphosphonic icid. ... 

Rudinskas, A.J., Hullar. T.L., and Salvador, R.L., Phosphonic acid chemistry. Part 2. Studies on the Arbuzov reaction of l-bromo-4.4-diethoxy-2-butyne and Rabinowitch method of dealkylation of phosphonate diesters using chloro- and bromotrimethylsilane, J. Org. Chem., 42, 2771, 1977. 

Blackburn. G.M., and Ingleson, I ),. Specific dealkylation of phosphonate esters using iodotrimethyl-silane, J. Chem.. Soc., Chem. Commun.. 870, 1978. 

McKenna, C.E., Higa, M.T., Cheung. N.H., and McKenna, M.C., The facile dealkylation of phosphonic acid dialkyl esters by bromotrimethylsilane. Tetrahedron Lett., 18, 155, 1977. 

Gross, H., Bock, C., Costisella. B.. and Glode, J., a-Substituted phosphonates. Part 30. Dealkylation of phosphonates with labile functional groups using trimethylsilyl bromide, J. Prakt. Chem., 320, 344, 1978. 

Morita, T., Okamoto, Y., and Sakurai. H., A convenient dealkylation of dialkyl phosphonates by chlorotrimethylsilane in the presence of sodium iodide. Tetrahedron Lett., 19, 2523, 1978. 

Morita, T., Okamoto, Y. and Sakurai. 1L, Dealkylation reaction of acetals, phosphonate, and phosphate esters with chlorotrimethylsilane/mclal halide reagent in acetonihile, and its application to the synthesis of phosphonic acids and vinyl phosphates. Bull. Chem. Soc. Jpn.. 54, 267, 1981. 

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