Phenoxyacetic Acid

[122-59-8]  · C8H8O3  · Phenoxyacetic Acid  · (MW 152.16) (dilithio dianion)

[67774-23-6]  · C8H6Li2O3  · Dilithiophenoxyacetate  · (MW 164.02)

(dianion used for a-alkylation,1 carboxymethylation of organoboranes,2,3 aldol addition reactions to give a-phenoxy-b-hydroxy acids,2-5 and phenyl enol ether synthesis;2,3 phenoxymethylation of quinones;6 OH and NH protection of nucleosides7,8)

Physical Data: mp 98-99 °C; pKa 5.12.

Form Supplied in: commercially available.

Preparative Methods: the title reagent and other substituted aryloxyacetic acids are easily synthesized by a Williamson ether synthesis using a phenol, base, and an a-haloacetic acid derivative.9

Purification: recrystallization from H2O.

General Discussion.

Deprotonation of phenoxyacetic acid by Lithium Diisopropylamide (LDA) generates dilithiophenoxyacetate that can be alkylated by alkyl halides and carbonyl compounds (eq 1).1,4

The dilithio anion formed in the above chemistry is useful as a reagent to carboxymethylate organoboranes (eq 2).2,3 The yields are poor with very hindered alkyl groups; only a single alkyl group is transferred. 9-Borabicyclo[3.3.1]nonane can be used to maximize the efficiency and yield in terms of transfer of the alkyl group.

Reaction of the dianion with carbonyl compounds gives the expected a-phenoxy-b-hydroxy acids.4,10 The reaction with aldehydes can be stereoselective for the threo isomer.4,5 Subsequent cyclization of the intermediate b-hydroxy acid to the b-lactone then allows for a thermal decarboxylation to provide phenyl enol ethers (eq 3).10 Magnesium Bromide-catalyzed rearrangement of the b-lactone derived from the dianion and cyclopentanecarbaldehyde provides an entry to trans-fused cyclohexane butyrolactones.4

1,2-Addition occurs in reaction of the dianion with a,b-unsaturated aldehydes and again high stereoselection can be observed.5

Decarboxylation of phenoxyacetic acid with Ammonium Peroxydisulfate-Silver(I) Nitrate in the presence of 1,4-Benzoquinone gives 2-phenoxymethyl-1,4-benzoquinone by a radical alkylation (eq 4).6

Phenoxyacetyl derivatives are useful for the protection of hydroxy and amino groups. Phenoxyacetate esters can be selectively cleaved by aqueous or methanolic ammonia in the presence of simple acetate or benzoate esters.7 Similarly, phenoxyacetamide derivatives are reportedly useful in nucleotide synthesis.8 Specifically, the acid chloride of phenoxy acetic acid has been used to protect the exocyclic amino group of purine or pyrimidine nucleic acid bases. The phenoxyacetamide group increases the lipophilicity of the intermediate nucleic acid bases and improves their stability to acid treatment in oligodeoxyribonucleotide synthesis.

Related Reagents.

Dilithioacetate; Ethyl Lithioacetate; Ethyl Mandelate; Ethyl Trimethylsilylacetate; Methyl O-Methyllactate; b-Propiolactone; Trimethylsilylacetic Acid.

1. Adam, W.; Fick, H.-H. JOC 1978, 43, 772.
2. Hara, S.; Kishimura, K.; Suzuki, A.; Dhillon, R. S. JOC 1990, 55, 6356.
3. Hara, S.; Kishimura, K.; Suzuki, A. TL 1978, 2891.
4. Black, T. H.; DuBay, W. J. TL 1988, 29, 1747.
5. Mulzer, J.; Brüntrup, G.; Hartz, G.; Kühl, U.; Blaschek, U.; Böhrer, G. CB 1981, 114, 3701.
6. Jacobsen, N. OS 1977, 56, 68; OSC 1988, 6, 890.
7. Reese, C. B.; Stewart, J. C. M. TL 1968, 4273.
8. Singh, R.; Misra, K. IJC(B) 1988, 27B, 409.
9. Meerwein, H. MOC 1965, 6, 1.
10. Adam, W.; Fick, H.-H. JOC 1978, 43, 4574.

David J. Ager

The NutraSweet Company, Mount Prospect, IL, USA

David E. Bergbreiter

Texas A & M University, College Station, TX, USA

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