Synthesis of Heterocyclic Analogues of Epibatidine via 7-Azabicyclo[2.2.1]hept-2-yl Radical Intermediates. 1. Intermolecular Reactions

Abstract

The synthesis and reactivity of the 7-azabicyclo[2.2.1]hept-2-yl radical has been extensively investigated in inter- and intramolecular reaction processes for the first time. In this work we will present the preparation of the radical and its successful intermolecular reaction with radical acceptors such as tert-butylisocyanide and acrylonitrile. Computational analyses have been carried out to show and explain the mechanisms and stereochemical outcome of these transformations. Overall and from the chemical point of view, a new and convenient synthetic approach has been developed for the synthesis of exo-2-(cyano)alkyl substituted 7-azabicyclo[2.2.1]heptane derivatives, a series of compounds of wide interest for the synthesis of heterocyclic analogues of epibatidine. As a result, we describe here the synthesis of the tetrazoloepibatidines (8 and 15) and the oxadiazoloepibatidine (10).

Mechanistic Analysis of Intramolecular Free Radical Reactions toward Synthesis of 7-Azabicyclo[2.2.1]heptane Derivatives

“…From the selected precursors (Figure ), the intramolecular cyclization of carbamate 1 and amides 2 and 3 should be expected a difficult given the low flexibility of the carbamate and amide functionalities due to the effective conjugation. On the other hand, previous results on such molecular skeletons have revealed a moderately low rotational barrier for the -N-CO bond as compared with acyclic amides due to a loss of the resonance stabilization, i.e., the delocalization stabilization of the lone pair electrons of N from the nonbonding n N orbital to the antibonding π* CO orbital . This would induce a somewhat higher flexibility in the linker than expected thus allowing the intramolecular cyclization.…”

“…This potent and simple methodology has proven very useful for the synthesis of heterocyclic analogues via intermolecular free radical reactions exploiting the rich and unexplored reactivity of 7-azabicyclo[2.2.1]hept-2-yl radicals. Although the synthesis and reactivity of 7-norbornenyl, norborn-5-en-2-yl, and norborn-2-yl , radicals is well-known, the chemistry of 7-azabicyclo[2.2.1]hept-2-yl radicals has been scarcely investigated.…”

Reaction mechanisms : Part (i) Radical and radical ion reactions

“…Consistent with the thoughts above, Marco-Contelles reported the successful addition of the 7-azabicyclo[2.2.1]hept-2-yl radical to electron deficient olefins such as acrylonitrile (Scheme 16). 45 Linker and coworkers demonstrated that glycals were stable under the oxidative conditions used to generate electrophilic radicals such as (CH 3 O 2 C) 2 CH d ; the addition of this electron deficient radical to an electron rich glycal is shown in Scheme 17. 46 As predicted by Baldwin's rules, Alabugin et al reported the first example of a 5endo-dig cyclization of a carbon-centered radical (Scheme 18).…”

Chemoenzymatic enantioselective synthesis of 7-azabicyclo[2.2.1]heptane derivatives

“…24,25 Due to the importance of these compounds, there has been considerable interest in the design of efficient methods for their synthesis. [26][27][28][29][30][31][32][33] Enzymatic desymmetrization of prochiral or meso compounds to yield enantiomerically enriched products has proved to be a valuable tool in asymmetric synthesis. [34][35][36] In contrast to the classic kinetic resolution of racemic mixtures, the theoretical maximum yield of these transformations is 100%.…”