Direct remote δ-C(sp2)–H olefination of β-aryl-substituted aliphatic aldehydes via palladium/enamine co-catalysis?

Organic Chemistry Frontiers Pub Date: 2020-08-31 DOI: 10.1039/D0QO00911C

Abstract

Direct remote C–H bond functionalization of aldehyde derivatives is of great importance in organic and medicinal chemistry research, but a challenging task due to their weak coordinating ability, high reactivity and propensity toward oxidation. Here, we report for the first time a palladium/secondary amine co-catalysis strategy that enables olefination of the remote C(sp2)–H bonds at positions δ or ε to the aldehyde group of β/γ-aryl-substituted aliphatic aldehydes. The success of this strategy is attributed to the in situ generated transient enamine as a directing group that, after undergoing α-palladation, makes remote δ or ε aromatic C–H bonds accessible for activation. Diverse β/γ-aryl-substituted aliphatic aldehydes, including the derivatives of natural products and drug molecules, can be efficiently olefinated. The merit of this strategy is demonstrated by the scale-up synthesis and post-synthetic modification of the product to various useful functional groups. Mechanistic investigations supported our hypothesis of involvement of enamine α-palladation in the C–H bond activation step.

Graphical abstract: Direct remote δ-C(sp2)–H olefination of β-aryl-substituted aliphatic aldehydes via palladium/enamine co-catalysis
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