Ruthenium（Ⅱ）-Catalyzed Highly Stereoselective Trans-Alkenylation Of Indole C₂-h Bonds With Alkynes

Alkenyl-substituted indoles and their derivatives are the important nucleus which can be found in many natural products, and these alkenyl-substituted indoles are also the useful precursors for synthesizing biologically active molecules. Generally, most of coupling reactions involving indoles occur at the C3-position of indole. Transition metal-catalyzed functional group-directed C-H bond activation strategy provides a possible access to highly regioselective Csp2-Csp2 coupling at C2-position of indole ring. Therefore, this dissertation explored the Ru(II)-catalyzed alkenylation reaction of indole/pyrrole C2-H bonds with alkynes to construct 2-alkenyl group-substituted indole derivatives, in which pyrimidyl group was employed as a directing group.Initially, we designed and synthetized the indole substrates employing pyridyl group as a directing group. Then we systematically investigated the effect of reaction parameters such as Ru catalysts, additives, solvents and temperature et al on the coupling reaction of indole/pyrrole C2-H bonds with alkynes, and find that [RuCl2(p-cymene)]2(7 mol %) could efficiently catalyze the alkenylation of N-(2-pyridyl)indole with diphenylacetylene using AcOH(1.0 eq) as proton source in DMF under Ar atmosphere to furnished the desired C2-H alkenylation indoles in 98% yield. The further substrate expansion indicated that the new approach tolerates variety arenes which contain electron-withdrawing or electron-donation groups, and also tolerate electron-poor internal alkynes and acyl- or alkyl-substituted terminal alkynes which have not been easily accessible through existing synthetic methods. More importantly, the present reaction system allows for the rapid assembly of C2-trans-alkenylated indoles in good to excellent yield with high regioselectivity and stereoselectivity.To further investigate the mechanism, we conducted the experiments of H/D exchange and kinetic isotope effect(KIE). The corresponding results clearly revealed that the first step of Csp2-H bond activation is a reversible process and is not the rate-limiting step of the reaction. By the way, the pyridyl group of the alkenylation products could be effectively removed and afford free(N-H) C2-alkenylation indoles under mild basic conditions.