Chapter 28. Reactions of Interest in Medicinal Chemistry

Abstract

This chapter discusses the various reactions of interest in medicinal chemistry, such as aromatic substitution, halogenation, oxidation, by the use of oxidants absorbed on alumina or silica, reactions regarding carboxylic acids and derivatives, and various miscellaneous reactions. Several improvements in the aldol reaction have been noted. Coupling of an α-bromocarbonyl compound with another carbonyl compound via dialkylaluminum chloride–zinc, produces aldol regiospecifically in high yield. Fluoride ion catalyzed reaction of enol sily ethers and carbonyl compounds prepares aldol products regiospecifically. Aldol type products are stereoselectively synthesized by Claisen rearrangement of silylketene acetals. For aromatic substitution, arylamines are directly converted to aromatic hydrocarbons by alkyl nitrites in DMF­. Alternatively, an aryl halide is produced when cupric halides are added in acetonitrile. The alkyl-nitrite deamination method also provides a convenient variant of the meerwein arylation reaction. In a related method, diazonium ions are converted to phenols with cuprous oxide-cupric nitrate. This radical process avoids the problems of the strongly acidic classical transformation. Phenols may also be converted to anilines via smiles rearrangement that is greatly accelerated by HMPA solvent. An interesting anionic equivalent of the Friedel–Crafts cycloacylation is demonstrated in this chapter. The oxidative reagents absorbed on alumina or silica are generally milder and more selective, and provide for convenient reaction workup. Oxidations of cyclobutanol to cyclobutanone, and β-hydroxysulfides and selenides to the β-keto compounds are accomplished by trichloroacetaldehyde on alumina.