National Institute of Advanced Industrial Science and Technology, Tsukuba Central 5, 1-1-1 Higashi, Tsukuba, Ibaraki 305-8565, Japan.
Org Biomol Chem. 2020 Mar 18;18(11):2063-2075. doi: 10.1039/c9ob02495f.
Base-catalyzed, C-alkylation of potassium (K) enolates with styrenes (CAKES) has recently emerged as a highly practical and convenient method for elaboration or synthesis of pharmaceutically-relevant cores. K enolate-type precursors such as alkyl-substituted heterocycles (pyridines, pyrazines and thiophenes), ketones, imines, nitriles and amides undergo C-alkylation reactions with styrene in the presence of KOtBu or KHMDS. Surprisingly, no studies have probed the reaction mechanism beyond the likely initial formation of a K enolate. Herein, a synergistic approach of computational (DFT), kinetic and deuterium labelling studies rationalizes various experimental observations and supports a metal-ene-type reaction for amide CAKES. Moreover, our approach explains experimental observations in other reported C-alkylation reactions of other enolate-type precursors, thus implicating a general mechanism for CAKES.
最近，钾（K）烯醇盐与苯乙烯（CAKES）的基底催化 C-烷基化已成为一种非常实用和方便的方法，可用于药物相关核心的精细化或合成。K 烯醇盐型前体（如烷基取代的杂环（吡啶、吡嗪和噻吩）、酮、亚胺、腈和酰胺）在 KOtBu 或 KHMDS 的存在下与苯乙烯发生 C-烷基化反应。令人惊讶的是，除了可能最初形成 K 烯醇盐之外，没有研究探究反应机制。在此，通过计算（DFT）、动力学和氘标记研究的协同方法合理化了各种实验观察结果，并支持酰胺 CAKES 的金属-烯型反应。此外，我们的方法解释了其他报道的 K 烯醇盐型前体的其他 C-烷基化反应的实验观察结果，因此暗示了 CAKES 的一般机制。
