Cu Mediated C-H Functionalization Of Indoles Assisted By Pyrimidine Group

Indole derivatives, important heterocyclic compounds which usually presented in natural products and bio-active molecular, found wide applications in biological medicine, functional materials, pesticide and dyestuff ambit. However, the functionalization of indoles often occurred in C3 position, and it was challenging to achieve the C2 activation due to its weak reactivity. C-H activation catalyzed by transition metals made great progress in recent years, compared with conventional synthetic strategy, this synthetic method was atom-economical because the starting materials could be used directly without pre-functionalization. Besides, high chemo-selectivity and regio-selectivity could be achieved with the assistance of directing group. Therefore, the C-H activation method became the hotspots among synthetic scientists.Initially, we tried to realize the Cu mediated C2 functionalization of indoles assisted by the pyrimidine group. After optimizing reaction conditions, finally, we achieved the selective C2 homocoupling and nitration. Our job mainly include three parts:Synthesis of 1-(pyrimidin-2-yl)-1H-indolesWe summarized the C-H activation of indoles and found that the pyrimidine group was frequently used as the directing group, then we introduced this group to indoles using the procedure that reported:indoles served as the substrates and NaH acted as the base reagent reacted in 0℃ for 40 minutes, then add 2-colropyrimidine and heated to 130℃ for 24 hours, consequently, a series of 1-(pyrimidin-2-yl)-1H-indole and substituted 1-(pyrimidin-2-yl)-1 H-indoles were synthesized to be the starting materials of C-H activation reactions.Cu mediated C2 C-H homocoupling of indoles assisted by pyrimidine groupWith 1-(pyrimidin-2-yl)-1H-indole substrate in hand, we designed reaction conditions, especially we investigated the impact of solvent, temperature and additive/oxidant, and finally we screened the optimal conditions and realized C2 homocoupling (optimal conditions: Cu(OAc)2(1 equiv.), AgNO3(1.2 equiv.), toluene,130℃,24h). The substituted substrates reacted well with the same conditions, some products yielded more than 80%. This reaction conditions exhibited broad substrate scopes, good functional group tolerability, high selectivity and obtained excellent yield. Then, we removed the pyrimidine group and got the 2,2’-biindoles, which can be used to synthesize anti-tumor active indolocarbazoles.Cu mediated C2 C-H nitration of indoles assisted by pyrimidine groupWith 1-(pyrimidin-2-yl)-1H-indole substrate in hand, we screened the reactions and got a better yield, then we optimized the solvent, amount of Cu(NO3)2.3H2O, nitrating reagent, amount of nitrating reagent and temperature, eventually, under the optimal conditions: Cu(NO3).3H2O (2 equiv.), AgNO3(1.2 equiv.), CH3CN,110℃,16h, we achieved the C2 nitration with a good yield.