Multi-Ion Bridged Pathway of N-Oxides to 1,3-Dipole Dilithium Oxide Complexes

Abstract

Roussi's landmark work on the generation of 1,3dipoles from tertiary amine N-oxides has not reached its full potential since its underlying mechanism is neither well explored nor understood. Two competing mechanisms were previously proposed to explain the transformation involving either an iminium ion or a diradical intermediate. Our investigation has revealed an alternative mechanistic pathway that explains experimental results and provides significant insights to guide the creation of new Noxide reagents beyond tertiary alkylamines for direct synthetic transformations. Truhlar's M06-2x functional and Møller−Plesset second-order perturbation theory with Dunning's [jul,aug]-cc-pv[D,T]z basis sets and discrete-continuum solvation models were employed to determine activation enthalpies and structures. During these mechanistic explorations, we discovered a unique multiion bridged pathway resulting from the rate-determining step, which was energetically more favorable than other alternate mechanisms. This newly proposed mechanism contains no electrophilic intermediates, strengthening the reaction potential by broadening the reagent scope and limiting the possible side reactions. This thoroughly defined general mechanism supports a more direct route for improving the use of N-oxides in generating azomethine ylide−dilithium oxide complexes with expanded functional group tolerance and breadth of chemistry.

[3 + 2] Cycloadditions of Tertiary Amine N-Oxides and Silyl Imines as an Innovative Route to 1,2-Diamines

“…Following our previously published work, two explicit equivalents of LDA/diisopropylamine and THF plus implicit solvation through a polarizable continuum model 27 were utilized within our method. 16 These results were consistent with the previously reported mechanism, 16 where a second deprotonation 12a is energetically preferred over dissociation of the nitrogen–oxygen bond 12b ( Figure 1 ). This forms the multi-ion-bridge intermediate 13a , eliminating the strongly electrophilic iminium intermediate from the mechanism, thus allowing for broader substrate flexibility than previously postulated.…”

“…Employing the M06-2x functional with Dunning’s correlation consistent JUL-cc-pVDZ basis set, all ground and transition structures were calculated (Figure S1 of the Supporting Information). Following our previously published work, two explicit equivalents of LDA/diisopropylamine and THF plus implicit solvation through a polarizable continuum model were utilized within our method . These results were consistent with the previously reported mechanism, where a second deprotonation 12a is energetically preferred over dissociation of the nitrogen–oxygen bond 12b (Figure ).…”

“…We recently reported that a tertiary amine N -oxide forms an azomethine ylide through a multi-ion-bridged intermediate, as opposed to a discrete iminium intermediate . Our proposed reaction pathway strongly suggested that this transformation should have a greater synthetic utility than had been previously reported.…”

Diastereoselective [3 + 2] Cycloaddition between Tertiary Amine N-Oxides and Substituted Alkenes to Access 7-Azanorbornanes

“…work by Davoren expanded this area through use of various stilbenes. 42 Previously, we probed this chemistry computationally 43 and established a synthetic method producing 1,2diamines and imidazolidines by coupling tertiary amine Noxides with silyl imines. 44 We present here our most recent studies into the reaction of pyrrolidine N-oxides with substituted alkenes to give endo-7-azanorbornanes in good yields and high diastereoselectivities.…”

“…The mechanism of this reaction is expected to be analogous to our previous studies with generation of an azomethine ylide. 43,44 Of greater interest to this work was an explanation for the diastereotopic selectivity for the endo product. We postulate that this is due to steric considerations since we saw a universal increase in d.r.…”