Mesityl acetic acid, synthesis

Several possibilities for a large-scale synthesis of mesitylacetic acid 12, a central building block in the synthesis of spiromesifen 8a, were examined (Scheme 28.4.2). Using the classical standard route, mesitylene 13 is transferred into mesityl acetonitrile 14 via chloromethylation and cyanide exchange, which is then saponified to the aryl acetic acid. Another route examined is the Friedel-Crafts alkylation of mesitylene with 1,3-dichloro-propene to the adduct 15, which is ozo-nolyzed to the corresponding aldehyde in the form of its dimethyl acetal and than further oxidized with hydrogen peroxide under acidic conditions to mesityl acetic... 

In a model synthesis <81CC524>, a nitro-Michael addition of the readily available nitroalkyl pyrrole 36 to mesityl oxide was used to introduce a geminally dimethylated structural element into an AD component rac-39 for the desired chlorin. Reduction of the nitro function in rac-37 leads to the desired AD dimer rac-38 which is combined in the presence hydrobromic acid with the well known a-bromo-a -bromomethyl dipyrromethene 40 after acid induced ester clevage and decarboxylation to yield the tetrapyrrolic biline rac-41. In the final step the linear tetrapyrrole rac-41 undergoes oxidation and cyclization in the presence of copper(II) acetate to give the copper chlorin. The cyclization occurs via the enamine tautomer of rac-41 by nucleophilic attack of the enamine structure on the bromo imine part of the linear tetrapyrrole. 

By 1916 Dilthey had synthesized 2,4,6-triphenylpyrylium ferrichlo-ride (tetrachloroferrate) from acetophenone and benzaldehyde in acetic anhydride in the presence of ferric chloride. He discovered other syntheses of pyrylium salts having aryl and alkyl substituents, as aryl groups enhanced the stability of pyrylium salts. Most often, the anions were perchlorate and tetrachloroferrate, but tetrafluoroborate began to be appreciated. A simple synthesis of alkyl-substituted pyrylium salts had to wait till the treatment of mesityl oxide with acetic anhydride was described by Schneider and Sack using sulfoacetic acid, and by Diels and Alder using perchloric acid. Then a lack of interest followed till the late 1950s, when Karl Dimroth and Klaus Hafner in Germany described new reactions of pyrylium salts, and new synthetic approaches were developed in Bucharest and in London. 

---