Selective Halogenation of Steroids Using Attached Aryl Iodide Templates

Abstract

The free radical chlorination of steroids by phenyliodine dichloride in aromatic solvents can be rather selective, leading to functionalization at unactivated tertiary positions. This process involves a solvent complex of the chlorine atom and can be directed by substituents in the substrate. More selectivity is achieved by a different mechanism when the aryliodine dichloride reagent is directly attached to the substrate. Thus 3a-cholestanyl m-iodobenzoate dichloride undergoes internal hydrogen abstraction in a free radical chain process to afford a 9a-chlorosteroid. The process is directed by the geometric relationship between substrate and reagent, and other geometries can be used to direct functionalization at C-14 or at C-17. A variant is the radical relay process, in which the intermediate chloroiodoaryl radical is generated by chlorine atom transfer to a template molecule attached to the substrate. Here too, geometric relationships can be adjusted to direct the reactions. The processes are illustrated by a cortisone synthesis, by the conversions of sitosterol and cholesterol to androsterone, and by synthesis of a cardenolide intermediate. In one case the template directed halogenation of an unactivated carbon took place even in the presence of an unprotected enone system. © 1977, American Chemical Society. All rights reserved.