C-2 Halogenations Of Indoles Via C-H Activation

Aryl halides are important starting materials in chemical reactions and key structural motifs in numerous natural products and manufactured drugs. Meanwhile, C-H activation method has emerged rapidly as a economic, straightforward and efficient synthetic pro-tocol. Direct C-H halogenation catalyzed by transition metals has attracted considerable attention of the chemical community and have become one of the significant subject of study. In this paper, direct C-2 halogenations of indoles via a directing group were inves-tigated. The method is not disclosed in the literature.Firstly, the pyrimidine group was attached on indoles to avoid the C-3 electrophilic substitutions and get the C-2 halogenation products. The substrates with directing group were obtained by reaction of indoles and 2-Cl-pyrimidine. Then, optimization studies were conducted to get the C-2 chloroindoles with good yields and regioselectivities and the optimal conditions involve Cu(OAc)2 and CuCl2 in DCE at 100℃ for 12h.Secondly, With the optimized reaction conditions in hand, the reaction with a range of substrates with different functional groups on C-4,5,6,7 of indoles were extended which obtained C-2 chlorination products with high yields and regioselectivities respec-tively. The chlorination protocol could also be applied to the efficient synthesis of 2,3-dihaloindoles by two-step sequence. The first step got the C-3 halogenation indoles and the second step got the 2,3-dihaloindoles with high yields. The indole scopes con-firmed the functional group tolerance under optimized conditions.Finally, the gram scale synthesis and deprotection were conducted. When other con-ditions were unchanged besides increased time to ensure its completation, the C-2 chlo-rination reaction can be carried out on a gram scale without a decrease in yield and selec-tivity. The deprotection was also conducted to remove the pyrimidine group with high yield. Furthermore, based on the experiments’results and recent studies, a possible mechanism was proposed.Meanwhile, other halogenations of C-2 indoles were also investigated. However, the C-2 haloindoles can not been obtained under the equivalent conditions.