Phenols, esterification separation

Sequential Methylation Technique. A sequential methylation-extraction technique has been devised primarily to separate phenolics from aromatic and aliphatic acids. The procedure, outlined below, allows quantitative conversion of phenolic hydroxyls to methyl ethers in one step and esterification of carboxyl groups in another. 

Active ester formation by the mixed anhydride method is accompanied by the side reaction of esterification at the carbonate moiety of mixed anhydride 51 which generates mixed carbonate 52 (Scheme 12).This decreases the yields, but is more of a nuisance than an obstacle as the side products do not interfere with crystallization of the esters as the former are soluble in the crystallizing solvent. More mixed carbonate is formed from derivatives of the hindered amino acids and proline none is formed from a-unsubstituted acids. A-Hy-droxysuccinimide gives rise to much less byproduct than 4-nitrophenol other phenols generate intermediate amounts. Less byproduct is generated when the reagent is isopropyl chloroformate. The impurity can be readily removed from a solution of the ester by adsorption of the compounds on reverse-phase chromatography beads followed by separation by selective displacement. ... 

To apply the MaNP acid method, the phenol group of KAT-2003 has to be protected, e.g., as methyl ether. So, racemic KAT-2003 ( )-9 was methylated with Cl 1,1 and CS2CO3 in acetonitrile yielding trimethylated alcohol ( )-80 in a good yield (Fig. 9.25). Esterification of ( )-80 with (S)-(-i-)-MaNP acid 3 gave a diastereomeric mixture of esters, which was easily separated by HPLC on sihca gel... 

Indoleamines and indole alcohols, typically acid-sensitive compound, may be smoothly acylated with HFB-imidazole. The indolic compounds (1—2 mg) are dissolved in HFB-imidazole (100—200 fil) and heated in a reaction vial with a PTFE-lined screw-cap at 80 °C for 2-3 hours. After cooling, the products are extracted into hexane (3x5 ml). The hexane extracts are combined and chilled to —14 "C to precipitate residual reagent. The hexane layer is decanted, the precipitate is washed with hexane and the combined hexane solutions are concentrated to 500 1 for analysis by GC (113, 114]. Alternatively, excess reagent may be decomposed with water (1 ml) in the presence of toluene (2 ml), the aqueous layer being extracted with three further 2 ml portions of toluene. These extracts are washed once more with water, separated and filtered through filter paper before concentration for analysis [115,116). A novel way of separating the layers is to freeze the two layers in a solid COj/acetone bath and to withdraw the upper layer from the ice with a Pasteur pipette [117[. Phenolic acids, after esterification, may be acylated in a similar procedure, but here with 10% PFP-imidazole in ethyl acetate for 10 minutes at 70 °C [118]. 

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