Steroids, 21-bromo rearrangements

The substitution reactions of a-bromo-ketones to give a -acetoxy-ketones are generally considered to proceed vih an enol, with allylic (SN2r) substitution in the cis stereochemical sense.62 A new investigation of the reaction between 4/3-bromo-3-oxo-5/3-steroids (29) and acetate ion shows that the initial product is the 2a-acetoxy-ketone (30), which rearranges rapidly under the reaction conditions to give the stable... 

The number and variety of reported studies on the bro-mination of steroid ketones is so great [133] that it would be impossible to survey the field adequately in a small space. The situation is complicated by uncertainty in some early work as to whether the bromo-ketones are products of kinetic or thermodynamic control. It often happens that the initial product of electrophilic attack on an enol is the unstable epimer (kinetic control), which rearranges under acidic conditions into the more stable epimer or may even undergo positional isomerisation under thermodynamic control (see p. 385). Only under experimental conditions which inhibit subsequent rearrangements is it possible to be sure of isolating the primary product. In recent years the products of kinetically-controlled bromination have been obtained by permitting the enol acetate of the ketone to react with bromine in a buffered solution. Few free ketones are brominated at a useful rate under such mild conditions,... 

The bromination of steroid ketones is often complicated by rearrangement of the primary products under the normal conditions of catalysis by hydrogen bromide. The steric and dipole effects which decide the relative stabilities of a -bromo-ketones have already been discussed (p. 14), and we are concerned here with the mechanisms by which equilibration reactions can occur. 

Bromo- and 2,4-dibromo-3-oxo-steroids are dehydrobrominated smoothly, and without rearrangement, by suitable phosphate and phosphonate salts [e.g. (Me0)2P02"NMe or Me0(Me)P02 NMe+] in DMF or acetonitrile. ... 

Full details have appeared on the formation of the novel 4(5 6)u6eo-steroid system (374) which is produced in about 90% yield by prolonged treatment of 6) -bromo-4, 5 -epoxycholestan-3)S-ol with lithium aluminium hydride. The structure has been confirmed by independent synthesis " of the derivative (375) and the rearrangement has been shown ° to be, in essence, a 1,3-elimination of the initial lithium aluminium hydride reduction product (373), which can be isolated after brief treatment of the bromo-epoxide with hydride. On the basis of the spectral data, the preferred conformations of the seven-membered ring have been deduced. ... 

Androsta-l,4,6-trien-3-ones react with N-bromoamides to give solely the 6)3,7a-dibromo-derivatives with no detectable products of allylic bromination. The 6/5,7a-dibromides eliminated HBr with rearrangement to 4-bromo-l,4-dien-3-ones on treatment with organic bases. 5a,6)5-Dichloro-steroids may be prepared in fair yield from 3)8-acetoxy-5-enes by treatment with a mixture of lead tetra-acetate and acetyl chloride (1 4). ... 

Such rearrangements are particularly common among brominated steroidal ketones.64 Bromination of a steroidal ketone usually affords first the axial bromo ketone which can pass into the stable equatorial isomer in a reaction catalysed by hydrogen bromide 65... 

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