The Scripps Research Institute , 10550 North Torrey Pines Road, La Jolla, California 92037, United States.
School of Pharmacy, Xinxiang Medical University , Xinxiang Shi, Henan Province 453003, People's Republic of China.
J Am Chem Soc. 2017 Aug 9;139(31):10702-10714. doi: 10.1021/jacs.7b03296. Epub 2017 Jul 27.
A conformationally flexible template for the meta-C-H olefination of benzoic acids was designed through both experimental and computational efforts. The newly designed template favors a silver-palladium heterodimer low barrier transition state, and demonstrates that it is feasible to lengthen templates so as to achieve meta-selectivity when the distance between the functional handle of the native substrate and target C-H bond decreases. Analysis of the ortho-, meta-, and para-C-H cleavage transition states determined that the new template conformation optimizes the interaction between the nitrile and palladium-silver dimer in the meta-transition state, enabling palladium to cleave meta-C-H bonds with moderate-to-good yields and generally high regioselectivity. Regioselectivity is governed exclusively by the template, and kinetic experiments reveal that there is a 4-fold increase in rate in the presence of monoprotected amino acid ligands. Using a Boltzmann distribution of all accessible C-H activation transition states, it is possible to computationally predict meta-selectivity in a number of investigated templates with reasonable accuracy. Structural and distortion energies reported may be used for the further development of templates for meta-C-H activation of hitherto unexplored arene substrates.
通过实验和计算努力，设计了一种用于苯甲酸的间-C-H 烯烃化的构象柔性模板。新设计的模板有利于银钯杂二聚体低能垒过渡态，并证明当天然底物的功能基团和目标 C-H 键之间的距离减小时，可以通过延长模板来实现间选择性。对邻位、间位和对位 C-H 断裂过渡态的分析表明，新模板构象优化了腈和钯银二聚体在间过渡态中的相互作用，使钯能够以中等至良好的收率和普遍较高的区域选择性断裂间 C-H 键。区域选择性完全由模板控制，动力学实验表明，在存在单保护氨基酸配体的情况下，速率增加了 4 倍。使用所有可及的 C-H 活化过渡态的玻尔兹曼分布，可以以合理的精度计算出许多研究模板的间选择性。报道的结构和变形能可用于进一步开发迄今尚未探索的芳基底物间-C-H 活化的模板。
