The
formation of an unexpected heterocyclic scaffold, a benzoxazole,
in a three-component reaction between a ketone, isocyanide, and 2-aminophenol
was encountered. This reaction involved a benzo[b][1,4]oxazine intermediate resulting from intramolecular attack of
the aminophenol hydroxyl group on the nitrilium ion. Unlike previous
literature examples, the trapped nitrilium benzo[b][1,4]oxazine could readily be subjected to ring opening with bis-nucleophiles.
The reaction scope includes simple linear as well as complex cyclic
ketones and substituted 2-aminophenols. A representative benzoxazole
product could be further diversified to yield drug-like compounds.
Nearly any aryl or alkyl isocyanide is also effective in transforming (I) to (IV) in low to very good yields. Decreasing the reaction time yields mixtures of the corresponding nitrilium intermediate such as (V) and (IVa) in varying ratios with the exception of 2,6-dimethylphenylisocyanide which yields the nitrilium intermediate (XV) as the single product. The phenol functionality in compound (IV) is further converted in various transformations such as alkylation, carbamoylation, acylation and triflation with subsequent Suzuki-coupling or Buchwald-Hartwig amination. The method is applied to the synthesis of the opioid antagonist naloxone. -(VARADI, A.; PALMER, T. C.; NOTIS, P. R.; REDEL-TRAUB, G. N.; AFONIN, D.; SUBRATH, J. J.; PASTERNAK, G. W.; HU, C.; SHARMA, I.; MAJUMDAR*, S.; Org. Lett. 16 (2014) 6, 1668-1671,
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