Fused bicyclic piperidines and dihydropyridines by dearomatising cyclisation of the enolates of nicotinyl-substituted esters and ketones

Heloise Brice,Jonathan Clayden,Stuart D Hamilton

doi:10.3762/bjoc.6.22

Abstract

The silyl enol ether derivatives of ketones or esters tethered by a hydrocarbon or ether linkage to the 3-position of a pyridine ring undergo dearomatising nucleophilic attack on the ring once it is activated (as an acylpyridinium species) by the addition of methyl chloroformate. The bicyclic dihydropyridine products are in some cases unstable, but may be isolated after hydrogenation as fused bicyclic piperidines.

Highlights

While reactive carbanions derived from allyl or benzyllithiums will undergo dearomatising addition even into relatively electron rich rings [35,36,37,38], the scope of the dearomatisation can be extended to much less reactive nucleophiles with a more electron deficient aromatic acceptor [39,40,41]
The study was initiated with the synthesis of the δ-nicotinyl ketone 7 as illustrated in Scheme 2
We surmised that effective cyclisation onto the acylpyridinium species, avoiding the N- vs. C-acylation problem, might be made possible by decreasing the reactivity of the enolate still further, transforming it into a silyl enol ether 9

Summary

Introduction

Oxidative [1,2,3] or reductive (nucleophilic) [4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21] dearomatising cyclisation reactions are effective strategies for rapidly building complexity and new reactivity from simple, readily made starting materials.

Results

Conclusion