Doubly dearomatising intramolecular coupling of a nucleophilic and an electrophilic heterocycle

Abstract

Isonicotinamides carrying N-furanylmethyl, N-pyrrolylalkyl or N-thiophenylmethyl substituents at nitrogen undergo cyclisation induced by an electrophile, giving spirocyclic compounds or doubly spirocyclic compounds in which both the nucleophilic and electrophilic heterocycles are dearomatised.

Nucleophilic Dearomatization of Activated Pyridines

“…Such dearomatizing spirocyclizations were first explored by the Clayden group in 2008, when N-aryl isonicotinamides, activated by triflic anhydride, underwent dearomatization, with the aryl group reacting in a Friedel-Crafts fashion to the C-4 position of the activated pyridinium [50,51]. More recently, Parameswarappa and Pigge developed a variation of this methodology, based on 4-aminomethyl-or 4-aminoethylpyridines, in which the nucleophile, tethered to the C-4 position of the pyridine ring, is generated by a Lewis-acid promoted enolization of a 1,3-dicarbonyl moiety [52][53][54].…”

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

“…While reactive carbanions derived from allyl or benzyllithiums will undergo dearomatising addition even into relatively electron rich rings [ 35 – 38 ], the scope of the dearomatisation can be extended to much less reactive nucleophiles with a more electron deficient aromatic acceptor [ 39 – 41 ]. Thus enolates of glycine esters 1 carrying isonicotinoyl or nicotinoyl N-substituents cyclise readily to yield bicyclic amino acid derivatives 2 ( Scheme 1 for example) [ 39 ].…”

“…Thus enolates of glycine esters 1 carrying isonicotinoyl or nicotinoyl N-substituents cyclise readily to yield bicyclic amino acid derivatives 2 ( Scheme 1 for example) [ 39 ]. Even greater reactivity towards intramolecular nucleophilic attack is exhibited by isonicotinamides when activated by N-sulfonation [ 40 – 41 ]. For example, the N -furylmethyl isonicotinamide 3 cyclises to the doubly dearomatised bis-spirocycle 4 on treatment with triflic anhydride in the presence of an alcohol [ 41 ] ( Scheme 1 ).…”

“…Even greater reactivity towards intramolecular nucleophilic attack is exhibited by isonicotinamides when activated by N-sulfonation [ 40 – 41 ]. For example, the N -furylmethyl isonicotinamide 3 cyclises to the doubly dearomatised bis-spirocycle 4 on treatment with triflic anhydride in the presence of an alcohol [ 41 ] ( Scheme 1 ).…”

Intramolecular cyclizations of alkyl pyridines & alkylidene dihydropyridines as synthetic intermediates toward synthesis of bis(piperidine) alkaloids

“…In another attempt, double dearomatization of electrophilic and nuclephilic arene pairs tethered together was exploited via tandem intramolecular cyclizations (Scheme 1.19). 74,75 The pyridine substrate 1.90 was activated by acylation and consequent nucleophilic attack by the electron rich furan ring afforded [77][78][79] Anhydrobases are also of importance due to their presence in the skeletal frameworks of some alkaloids such as semepervarine (1.98), flavopereirine (1.99), flavocarpine (1.100), and alstonine (1.101) ( Figure 1.3). [80][81][82][83] that could be ultimately used for the synthesis of bioactive natural products.…”