Lewis acid, amide acetal cyclization

Another category Ic indole synthesis involves cyclization of a-anilino aldehydes or ketones under the influence of protonic or Lewis acids. This corresponds to retro.synthetic path d in Scheme 4.1. Considerable work on such reactions was done in the early 1960s by Julia and co-workers. The most successful examples involved alkylation of anilines with y-haloacetoacetic esters or amides. For example, heating IV-substituted anilines with ethyl 4-bromoacetoacetate followed by cyclization w ith ZnClj gave indole-3-acetate esterfi]. Additional examples are given in Table 4.3. 

Swaminathan and co-workers discovered an unprecedented Lewis acid-mediated cyclization of the amide acetal 536 to afford 37 in excellent yield (Scheme 1.147). The crude oxazoline 537 is not isolated but immediately treated with Na0CH3/CH30H to produce 37 in excellent yield and purity. The initial reaction conditions used an expensive Lewis acid TMSOTf together with the teratogenic solvent 1,2-dimethoxyethane. These were subsequently replaced with the inexpensive acid chlorosulfonic acid and with methyl acetate as the solvent. Ultimately, this process was refined to a one-pot procedure that afforded 37 in 81% overall yield. The amide acetal 540 was readily prepared in 45% overall yield from methyl 3-methoxyacrylate. 

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