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.

中文翻译：

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β-芳基取代的脂族醛通过钯/烯胺共催化直接进行远程δ-C（sp2）-H烯化反应

醛衍生物的直接远程C–H键官能化在有机和药物化学研究中非常重要，但由于它们的配位能力弱，高反应活性和易于氧化，因此具有挑战性。在这里，我们首次报告了钯/仲胺共催化策略，该策略能够使位置在δ或ε处的远程C（sp ²）-H键与β/γ-芳基取代的脂族醛的醛基进行烯化。该策略的成功归因于原位产生的瞬态烯胺作为导向基团，经过α-palpalation后，可使较远的δ或ε芳族CH键易于活化。各种β/γ-芳基取代的脂肪族醛，包括天然产物和药物分子的衍生物，都可以有效地进行烯化。该策略的优点通过产品的放大合成和合成后修饰为各种有用的官能团得到证明。机理研究支持了我们关于烯胺α-palpalation参与C–H键激活步骤的假设。