Substituted Phenoxyacetyl Chlorides

We chose the following synthetic routes (1) or (2) to obtain 0,0-dialkyl 1-(substituted phenoxyacetoxy)alkylphosphonates lA-IF (Scheme 2.5). In the synthetic route (1), the title compounds can be synthesized by the reaction of substituted phenol sodium with corresponding l-(chloroacetoxy)alkylphosphonates M3 in the presence of sodium iodide. In the synthetic route (2), the title compounds can be synthesized by the condensation of 0,0-dialkyl 1-hydroxyaIkylphosphonates M2 and substituted phenoxyacetyl chlorides M5 (Scheme 2.5). 

The synthetic yields of lA-IF using the method of route (2) were better than that of route (1). Therefore, we mainly chose the synthetic route (2) to obtain lA-IF. O, 0-DiaIkyl 1-hydroxyaIkylphosphonates M2, substituted phenoxyacetic acids M4 and substituted phenoxyacetyl chlorides M5 are the important intermediates for the synthesis of lA-IF. The preparation of M2, M4 and M5 is described in Sects. 2.1.2 and 2.1.3, respectively. 

Synthesis of Substituted Phenoxyacetic Acids M4 and Substituted Phenoxyacetyl Chlorides MS... 

In order to condense with 1-hydroxyalkylphosphonates in a highly effective way, substituted phenoxyacetic acids were converted to the corresponding substituted phenoxyacetyl chlorides MS by using thionyl chloride in high yields (>90 %). 

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). 

Heterocyclylmethylphosphonates IG-IJ were synthesized by the condensation of (9, (9-dimethyl 1-hydroxyl-1-heterocyclylmethylphosphonates M2 (M2-37, M2-38 and M2-39) and substituted phenoxyacetyl chloride MS. The synthetic route in Scheme 2.19 was carried out for preparations of IG-IJ. 

The method for preparations of substituted phenoxyacetic acids M4 and substituted phenoxyacetyl chlorides MS has been discussed in Sect. 2.1.3. MS were prepared from corresponding substituted phenoxyacetic acids M4. M4-1-M4-3, M4-6-M4-8, and M4-9-M4-14 which were used to prepare IGr-U are shown in Table 2.7. M4 could be prepared according to the general synthesis procedure of M4 in Sect. 9.1.5. 

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). 

O-methyl [1-(substituted phenoxyacetoxy)alkyl]methylphosphinates IIIA-IIIG were easily synthesized by the reaction of O-methyl (l-hydroxyalkyl)meth-ylphosphinates with substituted phenoxyacetyl chlorides. The synthetic route of IIIA-IIIG is shown in Scheme 4.6. O-Methyl methylphosphinate Mil was prepared in a two-step sequence starting from phosphorus trichloride, methyl iodide, and aluminium trichloride. O-Methyl (l-hydroxyalkyl)methylphosphinates M12 were prepared by the addition of Mil and several kinds of aldehydes using tri-ethylamine as the catalyst. Substituted phenoxyacetic acids M4 and substituted phenoxyacetyl chlorides MS were prepared using the method which has been introduced in Chap. 2. IIIA-IIIG were obtained by the condensation of M12 with different substituted phenoxyacetyl chlorides MS. 

The preparation of 0-methyl [1-(substituted phenoxyacetoxy)alkyl]methylphosph-inates IIIA-IIIG involved the condensation of substituted phenoxyacetyl chlorides MS and 0-methyl (1-hydroxyalkyl)methylphosphinates M12 (Scheme 4.6) [24]. 

Substituted phenoxyacetyl chlorides MS could be easily obtained by the reaction of substituted phenoxyacetic acids M4 and thionyl chloride in high yields (>90 %). Substituted phenoxyacetic acid M4 could be prepared starting from the substimted phenol and chloroacetic acid [24, 25]. It should be noticed that chloroacetic acid reacted with fluoro-substituted phenol or trifluoromethyl-subslituted phenol producing M4 in very low yield because of the electron withdrawing effect of the fluorine atom. Fluorine-substituted phenoxyacetic acids could be prepared in satisfactory yields by the reaction of fluorine-containing phenol and ethyl 2-bromo-acetate followed by alkaline hydrolysis. This has been discussed in Chap. 2 in detail. 

O-Methyl [1-(substituted phenoxyacetoxy)aIkyl]methylphosphinates IIIA-IIIG including 54 compounds were easily synthesized by condensation of O-methyl (1-hydroxyatkyl)methylphosphinates M12 with substituted phenoxyacetyl chlorides MS in the presence of base under mild reaction conditions. 

Sodium [1-(substituted phenoxyacetoxy)alkyl]methylphosphinates lllH could be easily prepared from the corresponding 0-methyl [1-(substituted phenoxyacetoxy) alkyl]methylphosphinates which were prepared by the condensation of substituted phenoxyacetyl chlorides M5 and 0-methyl (l-hydroxyalkyl)methylphosphinates M12. The synthetic route is shown in Scheme 4.12. A detailed synthetic procedme for IIIH is introduced in the Sect. 9.1.18. The structures of HIH-l-IIIH-lO are listed in Table 4.21. 

Cyclic phosphonates IVC-IVE could be conveniently prepared by the condensation of 2-(l-hydroxyalkyl)-5,5-dimethyl-l,3,2-dioxaphosphinane-2-one IVB with substituted phenoxyacetyl chlorides MS in the presence of a base (Scheme 5.6). 

IVB could be prepared according to the description in Sect. 5.1.2. The substituted phenoxyacetyl chlorides MS could be easily synthesized starting from substituted phenols and chloroacetic acid or bromoacetic acid ester [45, 46], as... 

Since cyclic 1-hydroxyalkylphosphonates IVB were easily decomposed at a high temperature and phosphonates IVC-IVF containing carboxylic acid ester groups were also very sensitive to acid, base or water. Therefore the reaction required a moderate control of temperature. The reagents and solvents should be preprocessed in anhydrous state. The reaction was carried out in three stages firstly, a solution of substituted phenoxyacetyl chloride was added dropwise to the solution of cyclic 1-hydroxyaIkylphosphonate under 5 °C secondly, the reaction solution was stirred at room temperature for several hours, and then at a higher temperamre for further reaction in 1-2 h. By above synthetic method, 57 of cyclic phosphonates including IVC (23 compounds), IVD (13 compounds), IVE (13 compounds), and... 

Caged bicyclic phosphates IVG were synthesized by the condensation of substituted phenoxyacetyl chlorides M5 and 4-(hydroxymethyl)-2,6,7-trioxa-l-phosp-habicyclo[2.2.2]octane-l-one M21 in the presence of base (Scheme 5.9). Substituted phenoxyacetic acids M4 and substimted phenoxyacetyl chlorides MS were prepared using the method which has been described in Chap. 2. The intermediate M21 could be prepared by the treatment of the pentaerythritol with 1 equiv. of phosphorus oxychloride in dioxane according to the method reported in the literature [65]. Caged bicyclic phosphates IVG were found to be easily regenerated... 

Two asymmetric synthesis strategies including synthetic routes 1 and 2 were considered to prepare the optically active 1-(substituted phenoxyacetoxy)al-kylphosphonates including molecular skeletons of open-chain phosphonates lo and cyclic phosphonates IV. In synthetic route 1, optically active 1-(substituted phen-oxyacetoxy)alkylphosphonates lo or IV could be prepared by the condensation of substituted phenoxyacetyl chlorides MS and optically pure 1-hydroxyalkylphosph-onates M2 or cyclic 1-hydroxyaIkylphosphonates IVB, respectively (Scheme 6.1). 

Thionyl chloride was used as both the reagent and solvent. Thionyl chloride and substituted phenoxyacetyl chloride are corrosive. 

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]. 

General procedure A solution of substituted phenoxyacetyl chlorides M5 or phenoxypropionyl chlorides M20 (0.01 mol) in dichloromethane (15 mL) was added dropwise to the stirred mixture of appropriate 2-(hydroxy(substituted) methyl)-5,5-dimethyl-l,3,2-dioxaphosphinan-2-one IVB (0.01 mol) and triethylamine (0.011 mol) in dichloromethane (20 mL) under 5 °C, the reaction solution was stirred at room temperature for 2—4 h, and then at 40 °C for another 1-2 h. The resultant mixture was washed with 0.1 M hydrochloric acid solution, saturated sodium bicarbonate solution and brine separately, dried and evaporated. The residue was chromatographed on silica with ethyl acetate/petroleum ether (1/3) as eluent to give the corresponding cyclic alkylphosphonate as a white or yellowish solid. AU IVC-IVF series could be obtained by this procedure. 

Caged bicyclic phosphate IVG and IVH could be conveniently synthesized by the condensation of 4-(hydroxymethyl)-2,6,7 -trioxa-1 -phosphabicyclo[2.2.2]octane 1-oxide M21 or 4-(hydroxymethyl)-2,6,7-trioxa-l-phosphabicyclo[2.2.2]octane 1-sulfide M22 and substituted phenoxyacetyl chlorides M5 or substituted phen-oxypropionyl chlorides M20 in the presence of triethylamine as a base (Scheme 9.28). 

The Arbuzov reaction of trialkyl phosphite and acetyl chlorides gave a-keto phosphonates M24, which were then treated with various substituted phenoxyacetyl chlorides MS to afford 0,0-dialkyl 1-(substituted phenoxy acetoxy)vinylphosph-... 

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