Dialkyl 1-Hydroxyalkylphosphonates

Method M2-A To a stirred appropriate dialkyl phosphonate (40 mmol) in tri-chloromethane (15 mL), an appropriate aldehyde (44 mmol) in trichloromethane (15 mL) was added at room temperature. The mixture was cooled to 8-10 °C, triethylamine (20 mmol) was added drop wise and then the mixmre was stirred at 20-70 °C for 2-3 h. The component with lower boiling point was evaporated in vacuo to give the corresponding cmde 1-hydroxyalkyIphosphonate. Purification by column chromatography on silica gel and elution with petroleum ether/ acetone (4/1, v/v) or crystallization in ethyl ether gave the corresponding pure 1 -hydroxyalkylphosphonate. 

Method M2-B (9,(9-DiaIkyl phosphonate (10 mmol) and an appropriate aldehyde (11 mmol) were stirred at room temperature for 10 min. Potassium fluoride (2.5 g) was mixed with aluminum oxide (2.5 g) which was dried by oven and ground into powder before use. The heterogeneous catalyst was added slowly by 

The structures, physicochemical data, and yields of M2 are listed in Table 9.2. 

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The catalytic enantioselective reduction of 1-ketophosphonates has recently been developed. This approach takes advantage of a development in the enantioselective reduction of prochiral ketones to chiral alcohols by means of catalytic amounts of oxazaborolidines with borane as reducing agent. Thus, the enantioselective reduction of 1-ketophosphonates is accomplished by treatment with different boranes, BH. THF (0.9 eq), BII3Me2S (0.66 eq),5 545 qj- catccholborane (1.1 eq)5° 5 6 in different solvent systems in the presence of a catalytic amount of freshly prepared B-n-butyloxazaborolidine, (5) or (R) (Scheme 7.93). The reaction is complete in about 5 h and produces the expected dialkyl 1-hydroxyalkylphosphonates in satisfactory yields (53-98%). 

A clear illustration of the advantages of this synthetic procedure is provided by the conversion of optically active dialkyl 1-hydroxyalkylphosphonates into dialkyl 1-aminoalkylphosphonates by the Mitsunobu azidation. For example, a sequence of reactions for the conversion of optically active diethyl 1-hydroxyalkylphosphonates into diethyl 1-aminoalkylphosphonates proceeding in 50-88% overall yields and 48-82% ee s has been developed (Scheme 7.94).- ... 

Dialkyl 1-hydroxyalkylphosphonates, which are conveniently available by addition of aldehydes to dialkyl H-phosphonates, are used as starting compounds for the preparation of a-aminoalkanephosphonic acids [78],... 

Dialkyl 1-hydroxyalkylphosphonates M2 could be prepared by the addition reaction of dialkylphosphonates and several kinds of aldehydes (Scheme 9.2) using triethylamine as the catalyst (method M2-A) in yields of 58-93 % according to the literature or using potassium fluoride and aluminum oxide (mass ratio is 1 1) as the catalysts (method M2-B) in yields of 70-95 % according to the literature [3, 4]. 

Table 9.2 Structure and physicochemical data of 0,0-dialkyl 1-hydroxyalkylphosphonates M2... 

General procedure A solution of the appropriate substituted phenoxyacetyl chloride MS (0.022 mol) in trichloromethane (10 mL) was added to a stirred mixture of 0,0-dialkyl 1-hydroxyalkylphosphonate M2 (0.02 mol) and pyridine (0.022 mol) in trichloromethane (25 mL) at 10-25 °C. The resultant mixture was stirred for 3-5 h at room temperature, and then for 1-2 h at 40-42 °C. The trichloromethane layer was washed with 0.1 M hydrochloric acid, saturated sodium hydrogen carbonate solution and brine, dried and concentrated. The residue was purified by column chromatography on silica gel and eluted with petroleum ether/ acetone (2/1, v/v) to give the corresponding pure title compound. The title compounds lA-IJ as a yellow liquid or colorless crystal could be obtained by this procedure [8-17]. 

Hydroxyalkyt and Epoxyalky Acids. The reaction of aldehydes or ketones with dialkyl hydrogenphosphonate continues to be widely used for the synthesis of a-hydroxyalkylphosphonates ° and magnesium oxide has been reported to be an effective catalyst for the reaction. The reaction has been used in enantioselective synthesis. For example, in the preparation of chiral a, -dihydroxyphosphonic acids 171 and 172 (Scheme 14), with preferential formation of the jyn-isomer 171, and the statin analogue 2-amino-1-hydroxy-3-phenylpropylphosphonic acid (173) (Scheme 15). Catalytic asymmetric... 

Meier, C., Laux, W.H.G., and Bats. J.W.. Asymmetric synthesis of chiral, nonracemic dialkyl a-hydroxyarylmethyl- and a-, P-. and y-hydroxyalkylphosphonates from keto phosphonates, Liebigs Arm., 1963, 1995. 

The reactions of dialkyl phosphonates and secondary phosphine oxides with aldehydes have been used to prepare ct-hydroxyalkylphosphonates and various a-functionalized tertiary phosphine oxides. In contrast to previous reports, dialkyl phosphonates have been shown to react exothermically with benzophenone in the presence of base to give... 

Dialkyl alkylene diphosphonates obtained by transesterification of dialkyl H-phosphonates with diols in the excess of H-phosphonate diesters are bifunctional monomers possessing two reactive P-H groups. The addition of ketones or aldehydes to dialkyl alkylene diphosphonates resulted in the formation of the corresponding bis(a-hydroxyalkylphosphonate)s [185]. 

Chemical transformations of a-hydroxyphosphonates Phosphonate-phosphate rearrangement. Dialkyl alkylphosphonates are, in general, more reactive than the corresponding phosphate esters because the carbon has no unpaired electrons to contribute to allow a pn-dm contribution to the P-C bond. This makes the phosphorus atom of phosphonates more electrophilic than the phosphorus atom of the corresponding phosphate ester. The P-C bond is usually stable to hydrolitic procedures. However, a-hydroxyalkylphosphonates, in the presence of alkali, rearrange to give phosphate with cleavage of the P-C bond [220]. 

Since Kabachnik and Medved found that a-hydroxyalkylphosphonates are present in the reaction mixture of ammonia, carbonyl compound, and dialkyl H-phosphonate, they accepted that the reaction proceeds via formation of a-hydioxyalkylphosphonate followed... 

DiaLkyl 1-(substituted phenoxyacetoxy)alkylphosphonates lA-IF could be conveniently synthesized by the condensation of 1-hydroxyalkylphosphonates M2 with substituted phenoxyacetyl chlorides M5 in the presence of pyridine as a base (Scheme 2.9). 

Alkali metal salts of 0-alkyl 1-(substituted phenoxyacetoxy)alkylphosphonic acids IIA-IIE could be easily synthesized by the reaction of (9,(9-dialkyl 1-(substituted phenoxyacetoxy)alkylphosphonates lA or IC with corresponding lithium bromide, sodium iodide, or potassium iodide in refluxing acetone. The synthetic route of IIA-IIE is shown in Scheme 3.5. For the synthesis of IIA-IIE, 1-hydrox-yalkylphosphonates M2, substituted phenoxyacetyl chloride MS, and 0,(9-dialkyl 1-(substituted phenoxyacetoxy)alkylphosphonates lA or IC could be prepared according to the known methods as stated in Chap. 2. 0,0-Dialkyl phosphonate Ml was used directly as obtained commercially or prepared by the reaction of phosphorus trichloride and methanol. Ml reacted with different aldehydes to give 0,0-diaUtyl 1-hydroxyalkylphosphonates M2. The substituted phenoxyacetic acids M4 were prepared in satisfactory yields by the reaction of corresponding substituted phenols with 2-chloroacetic acid or ethyl 2-bromoacetate followed by hydrolysis. The substituted phenoxyacetyl chlorides M5 could be easily obtained by the treatment of M4 with excess thionyl chloride. M2 reacted with MS to provide lA or IC (Scheme 3.5). 

As stated in Chap. 2, several series of open-chain 0,0-dialkyl 1-hydrox-yalkylphosphonates M2 have been prepared and studied. In order to examine the herbicidal activity of phosphorus-containing heterocyclic 1-hydroxyalkylphosph-onate and their derivatives, firstly two series of cyclic 1-hydroxyalkylphosphonates including 2-(l-hydroxyalkyl)-5,5-dimethyl-4-pheny-l,3,2-dioxaphosphinane-2-ones IVA and 2-(l-hydroxyalkyl)-5,5-dimethyl-l,3,2-dioxaphosphinane-2-ones IVB were synthesized. 

One approach is enantioselective hydrophosphonylation. Chiral 1-hydroxyalkylphosphonates M2 could be prepared by the enantioselective hydrophosphonylation of dialkyl phosphonates Ml and aldehydes (Scheme 6.4) [50-54]. 

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