Formal [1 + 2 + 3] Annulation of Anilines and CF3‑Containing Ynones via 6π-Electrocyclization

Abstract

Six-membered N-heterocycles, such as 2-pyridones, are crucial in bioactive compounds and prevalent in natural products and pharmaceuticals, necessitating innovative synthesis approaches. Traditional methods, typically reliant on the transition-metal-catalyzed direct cyclization of alkynes, face limitations in product complexity. This study introduces a [1 + 2 + 3] annulation strategy for synthesizing 2-pyridones, employing anilines and CF₃-ynones through a base-promoted metal-free catalytic system. This method offers a more streamlined approach to generating polysubstituted 2-pyridones, demonstrating enhanced functional group compatibility across substrates compared with existing transformations. The anilines' adjacent dialkyl amino groups significantly contribute to the reaction, serving as both proton reservoirs and directing groups, facilitating the formation of 2-pyridones. This reaction involves a ring closure/opening sequence, followed by aza-6π-electrocyclization and a C-C bond cleavage-driven aromatization process. The method's synthetic utility is further validated by its applicability in subsequent transformations, marking an advancement in the synthesis of complex N-heterocyclic compounds.

Keywords: 2-Pyridones; Anilines; CF3-containing ynones; Metal free; [1 + 2 + 3] annulation.

1. Strategies for the Synthesis of 2-Pyridones

2. Control Experiments

3. Proposed Reaction Mechanism

4. Representative Derivatizations