Sulfuric Acid → 1-Naphthalenecarboxylic acid, 4-formyl-, methyl ester

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Reaction Steps

In Scheme 1, intermediate (2), (E)-methyl 4-styryl-1-naphthoate can be prepared by reacting commercially available 4-bromo naphthoic acid (1, Combi Blocks, San Diego, Calif.) with methanol in the presence of catalytic sulfuric acid followed by coupling with trans-2-phenylvinyl-boronic acid in EtOH/toluene with a palladium source (e.g., Pd(dppf2)Cl2) and an inorganic base such as NaHCO3. Ozonolysis can be performed on intermediate 2 in a solvent system such as dichloromethane/MeOH to provide the aldehyde 3, methyl 4-formyl-1-naphthoate. The oxime, (E/Z)-methyl 4-((hydroxyimino)methyl)-1-naphthoate (4) can be synthesized by reacting hydroxylamine hydrochloric acid with the precursor aldehyde (3) in a protic solvent such as ethanol (EtOH). The oxime is converted to the isoxazoline in a two step, one reaction pot procedure. Conversion of the oxime to the chloro-oxime with N-chlorosuccinamide in DMF and subsequent cyclization with the aryl olefin 5 (as shown below in Scheme 3A/3B) affords the desired isoxazoline intermediate 6 compounds. Saponification of the intermediate 6 compounds using a base such as LiOH or NaOH in a solvent system such as dioxane/water can be used to afford the naphthoic acid compounds (7) after acidic work-up.

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