Allylic Acetals as Acrolein Oxonium Precursors in Tandem C−H Allylation and [3+2] Dipolar Cycloaddition

Abstract

The ruthenium(II)‐catalyzed C−H functionalization of (hetero)aryl azomethine imines with allylic acetals is described. The initial formation of allylidene(methyl)oxoniums from allylic acetals could trigger C(sp2)−H allylation, and subsequent endo‐type [3+2] dipolar cycloaddition of polar azomethine fragments to deliver valuable indenopyrazolopyrazolones. The utility of this method is showcased by the late‐stage functionalization of bioactive molecules such as estrone and celecoxib. Combined experimental and computational investigations elucidate a plausible mechanism of this new tandem reaction. Notably, the reductive transformation of synthesized compounds into biologically relevant diazocine frameworks highlights the importance of the developed methodology.

Transition-metal-catalyzed C–H allylation reactions

“…Recently in 2019, Kim and co-workers described the Ru(II)-catalyzed C-H allylation of (hetero)aryl azomethine imines with allylic acetals to afford allylidene-(methyl)oxoniums, which eventually formed indenopyrazolopyrazolones via (3 + 2) cycloaddition of polar azomethine fragment (Scheme 24B). 87 Electronic modulations with high inductive effect at allylic position of electrophile were necessary for this scheme.…”

Synthesis of gem-difluorinated pentacyclic indenopyrazolopyrazolones via Rh(iii)-catalyzed cascade C–H functionalization/[3 + 2] dipolar cycloaddition

“…2 To date, a series of versatile directing groups (DGs) and coupling partners (CPs) have been discovered for addressing the synthesis of complex polycyclic ring-fused structures via a TM-catalysed C-H coupling/ cyclization cascade involving the formation of multiple new bonds in a simple one-pot operation, illustrating that the combination of TM-catalysed C-H functionalization and the cascade strategy should be a viable tool for the efficient construction of fused heterocycles. 3 However, among the developed CPs, the fluorinated unsaturated π-compounds have recently attracted special attention due to their distinctive reactivity and innovative reaction modes compared with the nonfluorinated analogues. Moreover, the incorporation of a fluorine atom or a fluorinated group into organic molecules can not only significantly enhance their biological activity but also provide unique chemical and physical properties, which have been widely applied in pharmaceutical chemistry.…”