The use of amide solvents

The bromination of 4,5-j -dihydrocortisone acetate in buffered acetic acid does not proceed very cleanly ( 70%) and, in an attempt to improve this step in the cortisone synthesis, Holysz ° investigated the use of dimethylformamide (DMF) as a solvent for bromination. Improved yields were obtained (although in retrospect the homogeneity and structural assignments of some products seem questionable.) It was also observed that the combination of certain metal halides, particularly lithium chloride and bromide in hot DMF was specially effective in dehydrobromination of 4-bromodihydrocortisone acetate. Other amide solvents such as dimethylacetamide (DMA) and A-formylpiperidine can be used in place of DMF. It became apparent later that this method of dehydrobromination is also prone to produce isomeric unsaturated ketones. When applied to 2,4-dibromo-3-ketones, a substantial amount of the A -isomer is formed. 

A modification introduced by Joly allows clean dehydrohalogenation of (5a or 5)8) 2,4-dibromo-3-ketones to -3-ketones. This involves the use of an excess of lithium carbonate in DMF, which presumably prevents the 

A variation of this procedure, employing calcium carbonate in refluxing DMA, was introduced by the Glaxo group. 

The Joly procedure may be used under milder conditions ( 30 min at 100°) for selective dehydrobromination  

This provides A -5j -3-ketones e.g. 35) which are normally difficult to obtain. 

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