A personal account of the process research and development effort at Merck and Company, leading to the first commercial process for the manufacture of cortisone acetate, is described.

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Aluminum chloride catalyzed Friedel-Crafts cyclialkylations of 2-and 3-bromo-and -chloro-4'-fluoro-2-methylpropiophenones lb, IC, 6b, and 6c have been studied in detail by in situ I3C NMR spectroscopy as well as by the more conventional techniques requiring reaction quench. Clear evidence removes the historical mechanistic ambiguity relative to 2-methyl-Iindanone formation from 1 and establishes cyclization as proceeding through the methacrylophenone 3. With the P-halo isomers, skeletal rearrangement leads to 3-as well as 2-methylindanones. A stable oxonium ion by-product 10 has been observed which requires the equivalent of a transformation of a secondary carbonium ion to a primary carbonium ion. This is rationalized in terms of a neighboring group effect by the carbonyl group. Cyclialkylations with @-halo compounds 6b and 6c have been studied in HzS04 for purposes of comparison. Facile oxidation of Br-to Br2 in H2S04 intrudes upon the simplicity of the reaction of 6b, relative to 6c, leading to brominated products.In his review on cyclialkylation of aromatics, Barclay,l citing the work of Layer and MacGregor,* pointed out that a-bromo aralkyl ketones are considered to undergo aluminum chloride catalyzed cyclization to indanones through the corresponding unsaturated ketone 3 (Scheme I). Formation of the tertiary carbonium ion 2 by aluminum chloride initiates the sequence. Barclay mentioned as an alternative possibility a pathway which requires a hydride shift and conversion of a tertiary to a primary carbonium ion (2 -5).lIn another chapter of the same treatise, Gore3 reported the reaction of 2-bromo-2-methylpropionyl bromide with benzene to give l a as a first intermediate which lost HBr to form both the unsaturated ketone 3a and the indanone 4a. H e continued, "If 4a arises, as seems probable, by cyclization of 3a, a likely intermediate may bethe@-bromoketone,C6H~COCH(CH3)-CH2Br" (6a). It is one purpose of this paper to settle these mechanistic ambiguities.We have chosen to d o so by examining the reaction of 2-bromo-4'-fluoro-2-methylpropiophenone (lb), by in situ 13C N M R spectroscopy as well as by more conventional chromatographic analysis of reaction mixtures following workup. The power of the 13C N M R spectroscopic method has been made abundantly clear in identifying, e.g., stable c a r b o~a t i o n s .~~ Its use in studying evolving reactions is seldom if ever cited,4b and reports of the study of ongoing Friedel-Crafts reactions are to our knowledge nonexistent.We have also studied and report upon related cyclialkylations of halo analogues and isomers of lb. For some of these, H2SO4 catalysis was also examined. In all cases, intermediates and products have been identified and characterized. We have developed new mechanistic insight to these reactions principally through the in situ study, and have even discovered a neighboring group effect not previously observed in FriedelCrafts reactions. These experiments and others convince us that Professor Olah's suggestionS to restudy this segment of Friedel-Cr...