The necessity for base suggests that the anionic attributes of intermediates 12 (Scheme 1a), 24 (Scheme 2a), and 27 (Scheme 2b) may be facilitating the subsequent 6π-aza-electrocyclization. While anionic aza-Cope 25 and anionic 4π-electrocyclic reactions have been documented in the literature, our study highlights the first example of an anionic 6π-electrocyclic ring closure. We computed the Gibbs free energy profiles for both the anionic and neutral pathways by DFT and found the anion acceleration effect to be significant (Figure ). The barrier to anionic 6π-aza-electrocyclization is 18.3 kcal/mol lower in energy compared to the neutral pathway when examining the transition state energies of TS29-30 and TS32-33 (∆∆G ǂ = 44.4 -26.1 = 18.3 kcal/mol), the origin of which is rationalized to be ground state destabilization akin to the anionic oxy-Cope 27 , anionic oxy-Claisen 28 and carbanionic Claisen 29 rearrangements. In the present azaelectrocyclization, isomerization of the enamide component of isoquinolone 28 to acylimine 29 is 20.2 kcal/mol uphill by DFT, a consequence that is negated upon deprotonation to anion 32. In other words, the anionic path effectively bypasses the tautomerization step required in the neutral path. The annulation process to tetracycle 33 is thermodynamically uphill, and the driving force is attributed to protonation by solvent DMF. This and the reversible nature of the electrocyclization is corroborated by experimental mechanistic studies conducted in deuterated DMF (Scheme 3). In most cases, KOt-Bu is necessary Scheme 3. The roles of bases in sequential deprotection/aza-6π-electrocyclization.