Redox-Neutral α-Oxygenation of Amines: Reaction Development and Elucidation of the Mechanism

Abstract

Cyclic secondary amines and 2-hydroxybenzaldehydes or related ketones react to furnish benzo[e][1,3]oxazine structures in generally good yields. This overall redox-neutral amine α-C–H functionalization features a combined reductive N-alkylation/oxidative α-functionalization and is catalyzed by acetic acid. In contrast to previous reports, no external oxidants or metal catalysts are required. Reactions performed under modified conditions lead to an apparent reductive amination and the formation of o-hydroxybenzylamines in a process that involves the oxidation of a second equivalent of amine. A detailed computational study employing density functional theory compares different mechanistic pathways and is used to explain the observed experimental findings. Furthermore, these results also reveal the origin of the catalytic efficiency of acetic acid in these transformations.

Stronger Brønsted Acids: Recent Progress

“…147 The reaction of cyclic secondary amine 130 with salicylaldehyde 125 or related ketones in the presence of 1 equiv of acetic acid proceeded to furnish benzo[e] [1,3]oxazine derivatives 131 (Scheme 48). 148 According to the DFT calculation of the uncatalyzed reaction, the reaction is proposed to proceed by way of hemiaminal 132 and then zwitterionic intermediate 133 followed by proton transfer to generate azomethine ylide intermediate 134. 149 It is proposed that acetic acid acts as a proton shuttle within the transition states TS1−3, thereby lowering the activation energy for each step.…”

Redox-Neutral α-Sulfenylation of Secondary Amines: Ring-Fused N,S-Acetals

“…8 Through extensive experimental and computational studies, we have established the mechanisms of the α-amination and α-oxygenation reactions and revealed an important role for azomethine ylides as reactive intermediates. 9,10 We recognized that an analogous α-sulfenylation of secondary amines with thiosalicylaldehydes would provide a practical entry to ring-fused N , S -acetals not easily accessible by other means.…”

“…8 Figure 3 summarizes the calculated transition states for the uncatalyzed and acetic-acid-catalyzed N , S -acetal formation. Similar to the formation of N , O -acetals, acetic acid stabilizes the transition states TS1-S (ΔΔ G ⧧ = −1.5 kcal mol –1 ) and TS3–S (ΔΔ G ⧧ = −2.6 kcal mol –1 ).…”

Classical-Reaction-Driven Stereo- and Regioselective C(sp3)-H Functionalization of Aliphatic Amines

“…A similar method was reported by Seidel et al for the synthesis of ring-fused oxazines using a stoichiometric amount of acid as additive. [39] This strategy was extended by the same group for the a-CAH sulfenylation of aliphatic amines. [40] Qu et al developed similar redox-neutral CAH oxygenation of pyrrolidine using 3,5-di-tert-butyl-o-benzoquinone.…”