Extension of the Nenitzescu reaction to simple ketones provides an efficient route to 1'-alkyl-5'-hydroxynaltrindole analogues, potent and selective delta-opioid receptor antagonists.

The well-established Nenitzescu reaction of imines of beta-dicarbonyl systems, as their enamine tautomers, with benzoquinone has been applied to a wide range of such imines to give 5-hydroxyindoles, some of which are of significant biological importance. This reaction has now been extended to the benzylimines of simple ketones, including those of the potent mu-opioid receptor antagonists naltrexone and naloxone. The products of the latter reactions, 1'-benzyl-5'-hydroxyindolomorphinans (7), are potent delta-opioid receptor (DOR) antagonists, confirming the enhancement of DOR antagonist potency and selectivity resulting from the introduction of the 1'-benzyl group.