Ketal rearrangement

When Finkbeiner first proposed the ketal rearrangement mechanism, this type of reaction was unknown, but similar rearrangements of cyclo-hexadienones have been demonstrated since. Miller (25) has shown that the rearrangement of 4-anilinocyclohexadienones to diaryl ethers is an intramolecular reaction, with a geometry almost identical to that of Reaction 12. 

An even closer parallel is found in the work of Kreilick (33, 34), who prepared the ketal derived from 2,6-di-tert-butyl-4-acetoxyphenol. From a study of the effect of temperature on line broadening in the NMR spectrum of this compound he concluded that rearrangement occurs both by dissociation to radicals and recombination and by a direct intramolecular process. The former corresponds to the key reaction of the redistribution mechanism, while the latter is entirely analogous to the ketal rearrangement mechanism (Reaction 15). 

Similar results were obtained by Cooper and by Mijs et ah (24) from a number of other substituted dimers. With lightly substituted dimers, however, Mijs observed that at low temperatures the initial products consist almost entirely of tetramers the tetramer, moreover, is that corresponding to the quinone ketal rearrangement, rather than to head-to-tail coupling (Reaction 20). 

Figure 7.4 Schematic representation of the quinone-ketal rearrangement and redistribution [26],...

Cross-conjugated dienones are quite inert to nucleophilic reactions at C-3, and the susceptibility of these systems to dienone-phenol rearrangement precludes the use of strong acid conditions. In spite of previous statements, A " -3-ketones do not form ketals, thioketals or enamines, and therefore no convenient protecting groups are available for this chromophore. Enol ethers are not formed by the orthoformate procedure, but preparation of A -trienol ethers from A -3-ketones has been claimed. Another route to A -trien-3-ol ethers involves conjugate addition of alcohol, enol etherification and then alcohol removal from la-alkoxy compounds. 

In this reaction only 5% of the expected 12a-methyl steroid (19) can be isolated from the mother liquors after ketal cleavage. Rearrangement is undoubtedly due to magnesium halides in solution, since dimethylmagnesium smoothly effects the transformation of (17) to (19). A 41 % overall yield of (19) is obtained in this experiment. ... 

During the preparation of the dihalo-(usually dibromo) 20-ketopregnanes, other reactive sites must be protected (e.g., addition of bromine to the A -double bond, ketal formation with a 3-ketone). An elegant method which avoids such problems has been devised by the Upjohn group in their studies on the conversion of 11-ketoprogesterone to hydrocortisone. The former is reacted with ethyl oxalate at C-2 and C-21, then addition of three moles of bromine gives a 2,21,21-tribromide. Alkaline rearrangement produces the side chain unsaturated acid, and the bromine at C-2 is subsequently removed with zinc. 

Selective hydroxylation with osmium tetroxide (one equivalent in ether-pyridine at 0 ) converts (27) to a solid mixture of stereoisomeric diols (28a) which can be converted to the corresponding secondary monotoluene-sulfonate (28b) by treatment with /7-toluenesulfonyl chloride in methylene dichloride-pyridine and then by pinacol rearrangement in tetrahydrofuran-lithium perchlorate -calcium carbonate into the unconjugated cyclohepte-none (29) in 41-48 % over-all yield from (27). Mild acid-catalyzed hydrolysis of the ketal-ketone (29) removes the ketal more drastic conditions by heating at 100° in 2 hydrochloric acid for 24 hr gives the conjugated diketone (30). 

The method of choice for preparing tropone (45) is to treat the initial mixture of monoadducts (43a) and (43b) with methanolic 1 TV hydrochloric acid to complete ketal hydrolysis and then carry out the pyridine rearrangement to give 3-bromo-4-methoxy-A-homo-estra-2,4,5(10)-trien-17-one (44) as described above for monoadduct 17-ketone (43b). 

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