Extension of the Nenitzescu Reaction to Simple Ketones Provides an Efficient Route to 1‘-Alkyl-5‘-hydroxynaltrindole Analogues, Potent and Selective δ-Opioid Receptor Antagonists

Abstract

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.

Nenitzescu 5‐Hydroxyindole Synthesis

“…A summary of these reports is listed in Table 2 [26][27][28][29][30][31][32][33][34][35][36][37][38][39]. A summary of these reports is listed in Table 2 [26][27][28][29][30][31][32][33][34][35][36][37][38][39].…”

Intramolecular Hydroamination of Selenoalkynes to 2‐Selenylindoles in the Absence of Catalyst

“…Reactions that have emerged in the last decades involve cyclisation of o ‐alkynylanilines and derivatives, reductive cyclisations of nitrocompounds, Larock heteroannulation and more specific reactions, such as the Nenitzescu and Madelung reactions . Usually, these methods require metal catalysis or the use of strong bases, such as t BuOK, to promote the cyclisation .…”