Modular Access to Azepines by Directed Carbonylative C-C Bond Activation of Aminocyclopropanes.

Gang-Wei Wang,John F Bower

doi:10.1021/jacs.7b13087

Abstract

A modular Rh-catalyzed entry to azepines is outlined. Under a CO atmosphere, protecting group directed C–C bond activation of aminocyclopropanes provides rhodacyclopentanones. These intermediates are effective for intramolecular C–H metalation of either an N-aryl or N-vinyl unit en route to azepine ring systems. Thus, byproduct-free heterocyclizations are enabled by sequential C–C activation and C–H functionalization steps.

Highlights

The azepine ring system is present in a wide range of bioactive compounds, with this motif or closely related variants representing the core structure of over 25 pharmaceutical products.[1]
Heterocyclization strategy where “capture” of transient rhodacyclopentanones 2 by tethered nucleophiles occurs in advance of a C−Nu bond forming “collapse” to the targets (Scheme 1B).6e Conceptually, this approach is appealing because it harnesses the strain embodied within readily available and stereodefined aminocyclopropanes 1 for reaction initiation, and achieves otherwise challenging ring closures via the intermediacy of kinetically accessible bicycles 3
It is well-established that Rh(III)-complexes can promote aryl C−H metalation in other contexts,[10] and we considered whether this type of process might be exploited from 2 to provide benzazepines 6

Summary

Introduction

The azepine ring system is present in a wide range of bioactive compounds, with this motif or closely related variants representing the core structure of over 25 pharmaceutical products.[1]. Oxidative addition, metallacyclobutane carbonylation (to 2), aryl C−H metalation (to 5), C−C reductive elimination, and protodemetalation.

Results

Conclusion