The N-methoxy substituent of the hydroxamic esters ( ) is important in facilitating directed C-H activation and doubles as an amide protecting group. N-Deprotection followed by 6π-aza-electrocyclization provides direct and facile entry into the target oxyberberine scaffold. We evaluated three possible mechanistic scenarios by density functional theory (DFT) via Gaussian 16 17 at the B3LYP/6-311+G(2d,p) level of theory, 18-21 including a solvent correction using the CPCM method 22 with dimethylformamide as the solvent (Figure ). The pathway where NaH acts as a base, participating in an E1cb elimination reaction via rate-limiting TS22-23 to release conjugate base 23 and formaldehyde as the byproduct (Scheme 2a, pathway 1) occurs with a ratelimiting barrier of 28.4 kcal/mol. Subsequent fragmentation with loss of formaldehyde generates quinolone anion 24 (see SI for full energy diagram and mechanism). If this pathway was operative, we expected to observe side-products originating from Friedel-Crafts reactivity with formaldehyde, 23 especially under high temperature conditions. However, Friedel-Crafts-type products were never detected over the course of our studies. Although there are no practical examples of NaH behaving in a nucleophilic displacement (SN2-type) reaction, 14 a transition state (TS22-24, ∆∆G ≠ = 26.0 kcal/mol) was located where the hydride engages in an SN2-type fashion to cleave the N-O bond, directly forming quinolone anion 24 (pathway 2). We posited that NaH can potentially engage the carbonyl in a reduction manner, and computed TS22-25 with a significantly lower barrier 16.5 kcal/mol, to arrive at tetrahedral intermediate 25, which then collapses (∆∆G25-24 ≠ = +6.0 kcal/mol, see SI) to the same aromatic anion 24 (pathway 3). Such a nucleophilic hydride transfer NaH would represent previously undisclosed reduction reactivity occurring under additive-free conditions. Previous DFT calculations to understand NaH-mediated nucleophilicity explicitly included two molecules of solvent ligating sodium; 24b therefore, pathway 3 was also computed via both implicit (CPCM with DMF) and explicit solvation. The inclusion of two molecules of DMF supporting sodium provided additionally stabilization to both the rate-determining hydride-delivery transition state (TS22-25•DMF) (∆∆G ≠ = 15.0 kcal/mol, Scheme 2b) and the resulting tetrahedral intermediate 25•DMF. This unusual nucleophilic hydride delivery is likely proceeding under chelation assistance by the N-methoxylactam motif and the analogous transition state structure for NaH-mediated hydride transfer to formaldehyde lacking a chelating group could not be located (see SI). When fluorinated N-methoxyisoquinolone 11i was subjected to deprotection/aza-6πelectrocyclization, remote N-to-C migration of the methoxy group ensued, leading to the isolation of methoxysubstituted oxyberberine 20 as the sole product, presumably through the intermediacy of 26 and 27 (Scheme 2c). Supportive of pathway 3 (Scheme 2a), this outcome is rationalized to occur through a nucleophilic aromatic substitution by the methoxide anion ejected from N-deprotection.