Iron Lewis acid-catalyzed reactions of aromatic aldehydes with diazo compounds: Synthesis of precursors for commercially important drugs from 3-hydroxy-2-arylacrylic acid ethyl esters.

摘要

Part I. The iron Lewis acid, [η5-(C ₅ H₅)Fe+(CO)₂(THF)]BF₄ −, was found to catalyze the reactions of aromatic aldehydes with both phenyldiazomethane and ethyl diazoacetate. The reactions between aromatic aldehydes and pheny1diazomethane resulted in the formation of cis-epoxides along with the corresponding ketones. The effect of substituents on the aldehyde was studied, and it was found that the yields of epoxides improved with electron-withdrawing substituents. The opposite effect was observed with electron-rich aldehydes. We also studied the effect of temperature on the reaction and it was found that the highest yields of epoxides were obtained at room temperature. The reaction was found to go through an intermediate aldehyde complex, which was isolated and characterized.; In contrast, the products isolated from the reactions with ethyl diazoacetate were a mixture of 3-hydroxy-2-arylacrylic acid ethyl esters and the corresponding β-keto esters. Electron-rich aldehydes were found to favor the formation of the enol esters. No ketone was formed. Whereas, with electron deficient aldehydes, such as 2,4-dinitrobenzaldehyde the corresponding β-keto ester was formed exclusively in 78% yield. The yield of enol ester was found to be better at lower temperatures. This reaction was also found to go through an intermediate benzaldehyde complex.; The iron Lewis acid, when supported on silica was found to catalyze the reaction of 2,4-dimethoxybenzaldehyde and ethyl diazoacetate to form the corresponding enol ester in 72% yield. Unlike the non silica-supported iron Lewis acid, the catalyst is recoverable and reusable, and the products are simply extracted from the catalyst. After 6 uses over a period of 52 days, the silica-bound catalyst is still active, converting EDA and the aldehyde to the enol ester in 53% yield.; Part II. The 3-hydroxy-2-arylacrylic acid ethyl ester was successfully converted into different commercially important drugs. For example, 2-(6-methoxy-2-napthyl)propenoic acid, a precursor of (S)-Naproxen, was synthesized from 3-hydroxy-2-(6-methoxy-2-napthyl) acrylic acid ethyl esters in three simple steps in moderate to excellent yields.; The 3-hydroxy-2-phenylacrylic acid ethyl ester was reduced with sodium borohydride to get the racemic tropic acid ethyl ester, which was resolved kinetically with enzymes. Two different enzymes have been used, namely Lipase VII and Lipase Amano PS. It was found that the latter had better selectivity for our substrate.; The 3-hydroxy-2-phenylacrylic acid ethyl ester was also subjected to asymmetric reduction with sodium borohydride in the presence of a chiral oxazoborolidine ligand. The resulting tropic acid ethyl ester was found to be optically active. (Abstract shortened by UMI.)