Benzylphosphonates

Benzyl chloride readily forms a Grignard compound by reaction with magnesium in ether with the concomitant formation of substantial coupling product, 1,2-diphenylethane [103-29-7]. Benzyl chloride is oxidized first to benzaldehyde [100-52-7] and then to benzoic acid. Nitric acid oxidizes directly to benzoic acid [65-85-0]. Reaction with ethylene oxide produces the benzyl chlorohydrin ether, CgH CH20CH2CH2Cl (18). Benzylphosphonic acid [10542-07-1] is formed from the reaction of benzyl chloride and triethyl phosphite followed by hydrolysis (19). 

Benzylphosphonates have been used in the synthesis of polymethoxy-stilbenes and of (174) and (175). The hydrocarbon (175) obtained in this way was much easier to purify than that prepared using the bis-phosphonium salt. 

Scheme 2.18 gives some representative olefination reactions of phosphonate anions. Entry 1 represents a typical preparative procedure. Entry 2 involves formation of a 2,4-dienoate ester using an a, 3-unsaturated aldehyde. Diethyl benzylphosphonate can be used in the Wadsworth-Emmons reaction, as illustrated by Entry 3. Entries 4 to 6 show other anion-stabilizing groups. Intramolecular reactions can be used to prepare cycloalkenes.264... 

Methanesulfonates 844, obtained by addition of diphenyl phosphite to aldehydes At1 Cl IO and mesylation of the hydroxyl group of the adducts, react with benzotriazole to give diphenyl a-(benzotriazol-l-yl)benzylphosphonates 845. Lithiation and treatment with aldehydes Ar2CHO converts phosphonates 845 into stilbenes 846, which can eliminate benzotriazole to give diarylacetylenes 847 (Scheme 135) <2002ARK(xiii)17>. 

Preparation of benzylphosphonic acid — Preparation of a phosphonic acid from red phosphorus in aqueous acid23... 

C in a stream of inert gas. On cooling, white crystals precipitated from the mixture. The precipitate was recovered by filtration and washed with hexane (10 ml) to yield pure 3,5-di-f-butyl-4-hydroxy-benzylphosphonate (28.4 g, 80%) of mp 122°C, which exhibited NMR and analyses in accord with the proposed structure. 

We similarly prepared diethyl benzylphosphonate, C6H5CH2PO(OEt)2 (IV), using benzyl chloride in place of bromofluoroethane. 

In passing, it may be noted that we prepared diethyl 2-fluoroethylphosphonate (III) and diethyl benzylphosphonate (IV) by an alternative route from sodium diethyl phosphite and the corresponding halides.6... 

Miscellaneous Reactions.—The reaction of phosphorus trichloride with toluene in the presence of oxygen is known to yield the hydrocarbon (58) and benzylphosphonic dichloride (59).48 The product ratio is now found to be greatly dependent upon the partial pressure of oxygen,49 and earlier views on the relation between the products have been altered. 

Orthophosphoric and benzylphosphonic acids have been selectively alkylated with triethyl phosphite in a new synthesis of mono-, di-, and triethyl phosphates and of mono- and di-methyl phosphonates.62 A-Methylol carboxamides and sulphonamides react with trialkyl phosphites to give the phosphonate derivatives (78) and (80), respectively.63 However, the mechanism appears to be quite different in each case while the carboamides react by a transesterification-rearrange-ment pathway, the sulphonamides undergo elimination-addition via the imine (79). 

General.—Triethyl phosphite has been used to achieve stepwise O-ethylation of phosphoric and benzylphosphonic acids.5 The disulphide linkage in bis(phosphinyl) disulphides is cleaved by ammonia in a suitable solvent to yield the phosphinyl-sulphenamides (l).6... 

Y. Morioka, M. Ohmizo, M. Harada, K. Goto, S. Naito, K. Tsutsumi, Metabolism of Diethyl 4-[(4-Bromo-2-cyanophenyl)-carbamoyl]-benzylphosphonate in the Rat , Xenobiotica 1996, 26, 853-861. 

The usual synthesis from a hydrazone and PCI3 has been applied to prepare p-(l,2,3-diazaphos-phol-5-yl)benzylphosphonates, analogues to Fostedil in which the benzothiazol unit is replaced by a diazaphosphole ring. However, their activity to inhibit calcium transfer through biological membranes is weak <93PS(85)225>. 

Cyclic phosphonamides (tetrahydro-2//-l, 3,2-oxazaphosphorine 2-oxides) were obtained by reaction of / -amino alcohols with benzylphosphonic dichloride in moderate yield. In the case of the 6-monomethyl derivative the diastereomers were separated by chromatography. Deprotonation with /erz-butyllithium followed by alkylation occurred in a highly stereoselective manner (d.r. 96 4-99 1), independent of the nature of the alkylating reagent, counterion and solvent, as demonstrated for the 6,6-dimethyl derivative6. 

However, acidic p-substituted benzylphosphonates as expected fail to offer such correlation (5). 

Aguila, A. O Shea, E. Kamat, P. V. Radiolytic reduction and oxidation of diethyl benzylphosphonate. A pulse radiolysis study, Advance Oxidation Technology 1998, in press. 

Allow the reaction mixture to cool, set up the distillation unit and then distil under reduced pressure6 to afford the desired diethyl benzylphosphonate (b.p. 106-109°C/1 mmHg) as a colourless liquid (quantitative). 

Diethyl benzylphosphonate can be used without distillation. However, a lower yield in subsequent... 

Purify the residue by flash chromatography on silica, eluting with hexanes ethyl acetate (9 1) to yield dimethyl benzylphosphonate, 30 (0.88 g, 97%), as a clear yellow oil. 

The original Kabachnik-Fields procedure employing ammonia as the amine component used ammonia in ethanol and the reactions were performed in sealed vessels at circa 100°C.90,123 This method avoids such conditions by using ammonium acetate as the source of ammonia, and it is also thought to act as an acid catalyst for imine formation other ammonium salts were unsatisfactory. Addition of water to produce a homogeneous reaction mixture resulted in diethyl 1-hydroxy-1-benzylphosphonate formation (i.e. from direct attack of diethyl phosphite 25 on benzaldehye, a common side reaction in the Kabachnik-Fields reaction). The yields of this reaction are serviceable, and better for aromatic than aliphatic aldehydes. The product 58 may be further purified by crystallization as the hydrochloride salt by treatment of 58 with hydrogen chloride in ethanol/diethyl ether.122... 

The reactions of 7-aldiminoalcohol 296 with diethyl and diisopropyl phosphorochloridites in CHCI3 at 0°C afforded diastereomeric mixtures of substituted benzylphosphonates 299 and 300, respectively, which are believed to be formed from a common intermediate, 298 <2005RCB1496>. 

Methyl sulfonic acid reacts with antimony(V) chloride and water to yield Cl3Sb0(0H)(02S(0)CH3)SbCl3, a binuclear complex with bridging sulfonato groups. Binuclear Sb(V) complexes are also formed from SbCls and diphenylphospho-ric acid or benzylphosphonic acid alkyl ester in water. ... 

SYNS DI-N-BUTYL BENZYLPHOSPHONATE PHOSPHONIC ACID, BENZYL-, DIBUTYL ESTER PHOSPHONIC ACID, (PHENYLMETHYL)-, DIBUTYL ESTER... 

DI-N-BUTYL BENZYLPHOSPHONATE see BFD760 DIBUTYLBIS((3-CARBOXYACRYLOYL)OXY)-STANNANE DIiMETHYL ESTER (Z,Z) (SCI) see BKO250... 

To aid hepato-cellular uptake of antisense ODNs, the phosphoramidites of cholic and taurocholic acids were prepared and added to the 5 -end of antisense oligomers." The oligonucleotides were further modified by the inclusion of phosphorothioate and benzylphosphonate internucleotide linkages. The bile acid conjugated oligomers exhibited enhanced lipophilicity as determined by HPLC, and when incorporated into duplexes no destabilisation was observed. An antisense phosphorothioate ODN targeted to the HIV-1 gag-mKNA was... 

When the halogen compound employed in the first step has an activated halogen atom (RCH CHCHjX, QHjCHjX, XCH2CO2H) a simpler procedure known as the Horner phosphonate modification of the Wittig reaction is applicable. When benzyl chloride is heated with triethyl phosphite, ethyl chloride is eliminated from the initially formed phosphonium chloride with the production of diethyl benzylphosphonate. This phospho-... 

However, the acidities of the benzyltriphenylphosphonium cation (pATa = 17.4) and of diethyl benzylphosphonate (pATa = 27.6) are sufficiently different to throw into question the likelihood of deprotonation of diethyl benzylphosphonate by the radical anion of 1. On the basis of a detailed study of the processes associated with the reduction of 1 (discussed later), it is likely that the effective base may well be the much more basic triphenylmethyl-derived carbanion, 4 in Scheme 20 (pATa of PI13CH = 30.6). This may possibly be produced by adventitious protonation of the fuchsone radical anion. Alternatively, the active EGB may be the dianion formed by disproportionation. 

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