Substituted phenoxyacetic acids

In addition to the examples of coumarin syntheses given in the reviews mentioned above and in the treatise on heterocyclic compounds (B-51MI22400), more recent studies have made use of the Perkin synthesis. These include the use of substituted phenoxyacetic acids to prepare 3-phenoxycoumarins (78CI(L)628> and the synthesis of chlorocoumarins from chlorosalicylaldehydes (81T2613). The use of DBU in place of sodium acetate was necessary to effect the ring closure of a number of o-hydroxyketones (78BCJ1907). 

The substituted phenoxyacetic acids are used as herbicides. If Fe oxide anodes are used in the electrochemical oxidation of diethylene glycol, l,4-dioxan-2-ol is initially formed... 

Solvent-free synthesis of substituted phenoxyacetic acids (77) with substituted phenols and chloroacetic acid was carried out under microwave irradiation by Nagy et al. (1997). 2-Chlorophenol reacted with ethanol in the presence of sodium hydroxide and a phase transfer catalyst under microwave irradiation to give 2-ethoxyphenol (78) conveniently within a few minutes (Pang et al., 1996). 

Nagy, G., FUip, S.V., Surducan, E., and Surducan, V. 1997. Solvent-free synthesis of substituted phenoxyacetic acids under microwave irradiation. Synthetic Communications, 27 3729-36. 

Phenoxycoumarins. 3-Phenoxycoumarins have been obtained by a Perkin reaction of salicylaldehyde with the sodium salt of a substituted phenoxyacetic acid in... 

Using Hammett Equations recorded in Appendix 4 calculate the a value where the of a substituted anilinium ion equals that of a substituted phenoxyacetic acid. Suggest a substituent to provide this a value and calculate pK at the equality. 

Partition coefficients are of extreme value in medicinal chemistry as they may be related to drug transfer across membranes and binding at active centres. The parameter logP models various kinds of transport between aqueous and lipid phases and P is defined as the partition coefficient of a substance between water and n-octanol. The free energy of the transport process is often linearly related to standard hydro-phobic parameters (re) for substituents (X) determined from Px values for substituted phenoxyacetic acids and that for the parent acid Ph (Equation 16). 

The work of many investigators soon showed it to be extremely widespread in plants, and it became clear that it was a fundamental plant hormone (e.g., reviews 530, 655a). Excessive production of indoleacetic acid by parasites is responsible for certain types of plant tumor (e.g., 948). The synthetic plant growth regulators, which are in general substituted phenoxyacetic acids, probably function as indoleacetic acid analogues. 

The derivatives of substituted phenoxyacetic acids are in practice the most important and most widely used of the hormone-type herbicides. 

The other group of auxin-type phenoxyalkanoic acids comprises the a-methyl homologues of substituted phenoxyacetic acids. 

The substituent X has a tr value defined from the partitioning of substituted phenoxyacetic acids between n-octanol and water. Thus tt for the parent (x = H) is defined as zero. Both w and log P (Table 17) may be used as parameters, the former in a restricted series of substituted phenyl groups and the latter in more general correlations. 

Figure 5.9 Root concentration factor in barley roots for substituted phenoxyacetic acids as a function of pH. The lines represent predictions based on the ion-trap mechanism. O, 2,4-D ( ), 3,5-D. [Reproduced from G. G. Briggs, R. L. O. Rigitano, and R. H. Bromilow, Physico-chemical factors affecting uptake by roots and translocation of weak acids in barley Pesticid. Sci. 19, 101. Copyright 1987, Society of Chemical Industry. Reproduced with permission granted by John Wiley and Sons, Ltd on hehalf of the S.C.I.]...

While partition coefficients from many different organic solvent/water systems have been used in early structure-activity relationships, n-octanol became the organic solvent of choice after the pioneering work of Hansch on n-octanol/water partition coefficients of substituted phenoxyacetic acids and the lipophilicity parameter 7t derived from these partition coefficients [14, 15, 17, 18, 173, 180]. 

Figure 5.1. Relationship between pKg values of substituted benzoic acids and their equivalent acetic acid and phenoxyacetic acid derivatives, o = o-substituted benzoic acids against o-substituted phenoxyacetic acids, x = m- and p-substituted benzoic acids against the corresponding phenoxyacetic acids. = p-substituted benzoic acids against a-substituted acetic acids.

Uses 2,4-D is a chlorine-substituted phenoxyacetic acid herbicide used for postemergence control of annual and perennial broad-leaved weeds in fruits, vegetables, turfs and ornamentals. 

Introduction of an alkyl group into the side-chain of phenoxy- or substituted phenoxyacetic acids ( -substituted propionic, butyric, isobutyric or valeric acids) is interesting mainly because of the resulting optical activity and the different activities of the antipodes cf. Section 9) or because of... 

The rates of oxidation of p- and m-substituted phenoxyacetic acids in ACOH-H2O-HCIO4 by TPCC increase with increasing AcOH%. The rate is accelerated by electronreleasing substituents and subject to catalysis by Al + ions." ... 

Compounds Derived from Substituted Phenoxyacetic Acids... 

Compounds Derived from Substituted Phenoxyacetic Acids [5958] p. 1355... 

We proposed a metabohc pathway of phosphonates with structure lo in plants when these compounds lo were initially designed. lo might be metabolized to substituted phenoxyacetic acids (lo-a) as auxin-type herbicide and acylphospho-nates (lo-c) as PDHc El inhibitors after the hydrolysis and oxidation by esterases and oxidases took place in plants (Scheme 1.21). 

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... 

According to the Ref. [9], substituted phenoxyacetic acids were prepared by the condensation of corresponding substituted phenols with chloroacetic acid in the presence of alkali, such as sodium hydroxide (method M4-A). The synthetic route is shown in Scheme 2.7. Substituted phenoxyacetic acids M4-1-M4-16 prepared by this method M4-A are summarized in Table 2.3. 

In the reaction of chloroacetic acid with fluoro-substituted phenols or trifluo-romethyl-substituted phenols in the presence of sodium hydroxide, products had low yields because of a strong electron-withdrawing nature of the substituent. However, by using the method of Brayer et al. [10], fluoro-substituted phenoxy-acetic acids and trifluoromethyl-substituted phenoxyacetic acids M4-17-M4-27 (Table 2.4) could be prepared in satisfactory yields by the reaction of fluoro-substituted phenols or trifluoromethyl-substituted phenols with ethyl bromoacetate in the presence of K2CO3 in DMSO followed by alkaline hydrolysis (Scheme 2.8, method M4-B). Thus, a series of substituted phenoxyacetic acids M4-1-M4-27 was prepared by method M4-A or M4-B. 

Scheme 2.8 Synthesis of fluoro and trifluoromethyl-substituted phenoxyacetic acids M4...

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 %). 

The herbicidal activity of IC-IF including lA and IB were evaluated at different rates in the greenhouse. Substituted phenoxyacetic acid as an structure unit of auxin-type herbicide was contained in the stracture of lA-IF, therefore an auxin-type herbicide 2,4-D was used as a positive control for the test in the greenhouse. Considering 2,4-D against broadleaved weeds for post-emergence at a recommended rate of 0.2-2.0 kg ai/ha, a preliminary bioassay was first carried out at... 

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. 

They often decomposed to afford substituted phenoxyacetic acids in three days. The reason was possibly that the carboxylic ester bond in the molecule cleaved easily in the acid environment supplied by phosphonic acid. Subsequently, alkali metal salts of 1-(substituted phenoxyacetoxy)alkylphosphonic acids IIF, IIG and IIH (Scheme 3.2) were further synthesized as alternatives of 1-(substituted phen-oxyacetoxy)phosphonic acids. These IIF, IIG and IIH, unlike 1-(substituted phenoxyacetoxy)alkylphosphonic acids, are neutral salts with good stability. 

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. 

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. 

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... 

Substituted phenoxyacetic acids M4 were prepared by the condensation of corresponding substituted phenols with chloroacetic acid in the presence of alkali, such as sodium hydroxide (Scheme 9.4, method M4-A). 

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