Copper-Catalyzed [4+2] Cycloaddition of 9H-Cyclohepta[b]pyridine-9-one and Electron-Rich Alkenes

Abstract

9H-Cyclohepta­[b]­pyridin-9-one was used as a diene cycloaddition partner to construct [3.2.2] bicycles in a copper-catalyzed [4+2] cycloaddition. Oxygen- and nitrogen-substituted terminal, disubstituted, trisubstituted, and cyclic alkenes reacted to afford the cycloadducts as single constitutional isomers in 48–80% yields and diastereomeric ratios up to 5.6:1.

Synthetic Entry to the 2-Azatricyclo[4.3.2.04,9]undecane Ring System via Tropone

“…We then sought to further investigate the effect of electronics on the spontaneity of this intramolecular Diels–Alder reaction. In particular, we were curious whether the cycloaddition was proceeding via an inverse electron-demand regime, as it does for similar reactions involving tropone or troponoid cycloaddition partners . To this end, we prepared substrate 21 containing an electron-deficient dienophile via cross-metathesis of 12a with ethyl acrylate (Scheme A) .…”

“…However, this substrate similarly failed to undergo cycloaddition and underwent the same rearrangement upon heating to give triene 37 (Scheme B). We also attempted to promote cycloaddition of 33 or 37 via addition of various Lewis acids, which might facilitate the Diels–Alder reaction by lowering the lowest unoccupied molecular orbital (LUMO) energy of the diene or dienophile, as observed for intermolecular Diels–Alder reactions for related cycloheptadienones . However, these conditions failed to promote the cycloaddition at room temperature, and heating these reactions led only to the [1,5]-hydrogen shift observed previously.…”

Recent Advances in Transformations Involving Electron‐Rich Alkenes: Functionalization, Cyclization, and Cross‐Metathesis Reactions

“…In 2019, Sarpong and coworkers reported a copper‐catalyzed [4+2] cycloaddition of electron‐rich alkenes 29‐1 with 9 H ‐cyclohepta[ b ]pyridine‐9‐one for the synthesis of [3.2.2]‐bicycles (Scheme 29). [55] This bridged framework is found in phleghenrine alkaloids, which have been regarded as palliatives for combating the early effects of Alzheimer's disease. To achieve full conversion of the reaction, several Lewis acids including zinc salts, copper salts, tin salts etc .…”

The α,α‐Dihalocarbonyl Building Blocks: An Avenue for New Reaction Development in Organic Synthesis

“…Recently, the research group of Richmond Sarpong, synthesized the phleghenrine alkaloids 249 and 250 from readily accessible cyclic α,α‐dibromoketone 251 (Scheme D). To obtain the bicyclo[3.2.2] framework of phleghenrines 249 and 250 , they applied a formal [4+2] cycloaddition strategy, where α,α‐dibromoketone 251 was converted to seven membered cyclic diene.…”