Redox‐Neutral Aromatization of Cyclic Amines: Mechanistic Insights and Harnessing of Reactive Intermediates for Amine α‐ and β‐C−H Functionalization

Abstract

Cyclic amines such as pyrrolidine and piperidine are known to undergo condensations with aldehydes to furnish pyrrole and pyridine derivatives, respectively. A combined experimental and computational study provides detailed insights into the mechanism of pyrrole formation. A number of reactive intermediates (e.g., azomethine ylides, conjugated azomethine ylides, enamines) were intercepted; outlining strategies for circumventing aromatization as a valuable pathway for amine C–H functionalization.

Metal-free C(sp3)–H functionalization of sulfonamidesviastrain-release rearrangement

“…3 Given the medicinal value of βsubstituted amine derivatives, 4 some methods for β-C-H functionalization have been developed based on oxidative cross-coupling pathway (Scheme 1A). 5,6 These reactions often require transition metal (Ru, Ir, Pd and Fe), 7-10 oxidizing reagent 11 and high temperature 12 . In contrast, transition metalfree protocols are greatly rare in this field.…”

Synthesis of Polycyclic Imidazolidinones via Amine Redox-Annulation

“…Again based on precedent, 4 could lose benzoic acid to form azomethine ylide 5 . Following the general mechanism of other redox-annulations, 11 5 could reengage benzoic acid to form N , O -acetal 6 . The latter ultimately undergoes ring closure to final product 3e with loss of benzoic acid, possibly via the zwitterionic intermediate 7 (pathway A).…”

Acetic Acid Promoted Redox Annulations with Dual C–H Functionalization

“…6 Accordingly, acetic acid promoted condensation of 1a and THIQ is expected to give rise to the initial formation of N , O -acetal 6 . This species can undergo loss of AcOH to form azomethine ylide intermediate 7 .…”

“… 3 − 5 Specifically, aldehydes with a pendent nucleophilic site undergo condensations with amines in reactions that combine reductive N -alkylation with concurrent oxidative α-C–H bond functionalization. 6 While a broad range of polycyclic amines have been accessed with this general method, in all cases, the nucleophilic site has been limited to rather activated systems including anilines, 3a , 3c , 3d phenols, 3e thiophenols, 3f electron-rich aromatics, 3b malonates, 3h nitroalkanes, 3g and ketones. 3i Here, we report the first examples of redox annulations that involve alkyl azaarenes as relatively nonactivated nucleophiles.…”

“…The overall mechanism of the redox annulation likely shares many features with previously reported redox transformations ( Scheme 4 ). 6 Accordingly, acetic acid promoted condensation of 1a and THIQ is expected to give rise to the initial formation of N , O -acetal 6 . This species can undergo loss of AcOH to form azomethine ylide intermediate 7 .…”