Ethyl H-phosphonate

In a 2-L round-bottom flask is placed concentrated NH4OH (675 mL) and diethyl phosphite (129 mL, 1 mol, see Note 5) is slowly added with stirring. The flask is capped and stirred at room temperature for 24 h, and evaporated to dryness. The solid is suspended into 500 mL of CH3CN, evaporated to dryness, and dried by dessication overnight to yield solid ammonium ethyl H-phosphonate (mol wt = 127 g/mol). 

A solution of triethylammonium ethyl H-phosphonate is prepared for the synthesizer as follows 3.2 g of ammonium ethyl H-phosphonate is weighted into a 250-mL round-bottom flask, and to this is added CH3CN (75 mL) and Et3N (25 mL). The contents are stirred until all material is in solution (caution NH3 gas is evolved). The solution is evaporated to an oil, then evaporated from CH3CN (2 x 100 mL Note 6), and the resulting oil is dissolved into anhydrous pyri-dine/acetonitrile (1/1, 250 mL) to a final concentration of 100 mAf and transferred to the appropriate bottle for machine synthesis. 

Cap (optional)—50 niM ethyl H-phosphonate and 65 mM pivaloyl chloride in anhydrous pyndine/CH3CN (60 s). 

The capping step in H-phosphonate synthesis is essentially another coupling reaction with an aliphatic H-phosphonate, such as cyanoethyl (25) or iso-propyl (9) H-phosphonate. This step is optional and not always necessary. The preparation of ethyl H-phosphonate and its use in capping is described above. 

Diethyl H-phosphonate reacts with ethyl hypochloride to give triethyl phosphate [73],... 

Dimethyl H-phosphonate adds to the C=C bond of the ethyl ester of 4,4,4-trichloro-2-cyano-2-butenoic acid [153],... 

Alkylammonium salts of monoalkyl H-phosphonic acid, having at least one ethyl group in the cation, undergo Hoffman s elimination [283],... 

The rather low yields of the aminophosphonic acids can be fairly substantially improved over those reported by Kabachnik and Medved if anhydrons ammonia and the aldehyde are premixed in alcohol solution. Using this procedure, a few amino-substituted phosphonic acids are prepared a-aminobenzylphosphonic acid (benzaldehyde, dibutyl H-phosphonate, solution of dry ammonia in absolute ethyl alcohol) a-amino-propylphosphonic acid propionaldehyde, diethyl H-phosphonate, and a solntion of dry ammonia in absolute ethyl alcohol) p-methoxybenzyl-a-aminophosphonic acid (p-hydroxybenzaldehyde, diethyl H-phosphonate, and solution of dry ammonia in absolute ethyl alcohol). 

Heating various H-phosphonic acid diesters with a hydroxyalkylcarbamate mixture [87,88] yielded 3-ethyl-2-hydroxy-2-oxo-l,4,2-oxazaphosphorinane 1, which is water--soluble and hydrolytically stable. 

The Atherton-Todd reaction was used for the preparation of a new class of hydrophihc drug-carriers with an organic polyphosphate main chain. Pharmacologically active ethyl-4-aminobenzoate and phenethylamine were attached to poly(propylene H-phosphonate) and poly(3,6,9-trioxaundecamethylene H-phosphonate) [325]. 

Me3SiBr, CH3CN, 1-2 h, 25°, >97% yield. This reagent is also useful for the cleavage of ethyl phosphates and phosphonates. ... 

Loss of C2H3 by double H rearrangement in ethyl-containing phosphites and phosphonates ... 

Phosphite (C2H50)2P0H, phosphonate (C2H50)2P(0)H, ethyl phosphonate (R0)2P(0)C2H5. 

Preparation of vinyl tellurides. To a mixture of NaH (1 mmol) (80% suspension in oil) and (phenyltelluromethyl)-phosphonate (1 mmol) in THF (5 mL) at reflux under Nj, aldehydes (1 mmol) were added dropwise. Following 3 h at reflux, the solution was cooled to room temperature. Then, saturated aqueous NH4CI was added and the mixture was extracted with diethyl ether. The organic extract was dried (MgS04) and evaporated to give vinyl tellurides, which were purified by column chromatography on silica gel with ethyl acetate/hexane (1 20) or by preparative TLC,... 

In the same way, the anion of ethyl 3-cyano-2-methylprop-2-enyl-phosphonate was reacted with the p-methylenealdehyde to give the 9-methylene-retinonitrile in 50% yield, as a mixture of 13E/13Z isomers (65/35). DIBAL-H reduction of the latter compound provided the related retinal (70%, 13E/13Z 65/35). Alternatively, MnCh oxidation of the... 

The 1,3,2-oxazaphospholanes 90a-c and 91a-c were obtained in excellent yields by cyclization of the amino alcohols 89a -c with ethyl phosphonic dichloride in toluene in the presence of triethylamine. The mixture of diastereomers at the phosphorus center were separated by silica gel chromatography. Assignation of the absolute configurations was possible through a complete analysis of the H NMR spectra of the diastereomers and was confirmed by X-ray analysis for one derivate (Scheme 41). 

Diethyl phosphonate (4 mmol) was added dropwise to a stirred mixture consisting of ethyl 4,4.4-tri-fluorobutynoate(3a 4 mmol) and EtjN (0.4 mmol). The mixture was allowed to warm to 80 C and stirred for 2 h. After chromatography (silica gel, petroleum ethcr/EtOAc 9 1), pure 4a was obtained yield 0.71 g (46%) bp 64 C/2 Torr. 

In the case of the synthesis of 10,19,19,19- H4-vitamin A, the most useful for biological studies, three deuterium atoms were incorporated into )6-ionone 30, in >98% by deuterium exchange with excess D2O in the presence of NaO H (and pyridine). The tri-deuteriated 30, utilized in Wittig-Horner reaction with dideuterio triethyl phosphonate, provided tetradeuteriated ethyl )6-ionilidene acetate 31 with more than 98% H4 (by NMR). No deuterium loss in the subsequent synthetic steps was observed as evidenced by MS and NMR analysis. 

Ethyl phosphonoacetate reacts with 3-keto-substituted thiophenes to give 81 which are precursors to bridged dithienylethylenes such as 82. The synthesis of a-ylidene-y-amidobutyronitriles, RCONH(CH2)2C(CN) = CR R" (R = NPh2, r2 = R" rz Me R = R = Ph, R" = H, Me, Ph), has been achieved by the reaction of the phosphonates RC0NH(CH2)2CHCNP(0)(0Et)2 (R = NPh2, Ph) with ketones. The enantioselective synthesis of allenecarboxylates is accomplished by asymmetric Homer-Wadsworth-Emmons reaction of chiral phosphonoacetate-... 

Moorhoff, C.M., and Schneider, D.F., Comments on the reaction of ethyl 4-(diethoxyphosphinyl)-3-oxobutanoate and related phosphonate esters with enals. Tetrahedron Lett., 28, 559, 1987. Heathcock, C.H., Hadley, C.R., Rosen, T., Theisen, P.D., and Hecker, S.J., Total synthesis and biological evaluation of structural analogues of compactin and dihydromevinolin, 7. Med. Chem., 30, 1858, 1987. 

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