Regioselective Synthesis of 4-Substituted Indoles via C–H Activation: A Ruthenium Catalyzed Novel Directing Group Strategy

Abstract

A highly regioselective functionalization of indole at the C-4 position by employing an aldehyde functional group as a directing group, and Ru as a catalyst, under mild reaction conditions (open flask) has been uncovered. This strategy to synthesize 4-substituted indoles is important, as this class of privileged molecules serves as a precursor for ergot alkaloids and related heterocyclic compounds.

Unexpected regioselective carbon–hydrogen bond activation/cyclization of indolyl aldehydes or ketones with alkynes to benzo-fused oxindoles

“…1b). Aldehydes often exhibit a poor directing effect and thus examples are still significantly underrepresented [15][16][17] . Usually, (in situ) conversion to imines can solve this problem [18][19][20] .…”

“…In an effort to explore the rhodium-catalyzed annulation of indolyl-3-aldehydes with internal alkynes to construct cyclopenta[b]indol-1-one or cyclopenta[b]indol-1-ol derivatives through the more reactive C2-H cleavage of indole, the benzo-fused oxindoles were obtained unexpectedly through the C4-H activation of indole (Fig. 1c) 17,30,31 , which were confirmed by single crystal X-ray diffraction analysis ( Supplementary Figs 42 and 43). This tandem reaction was disclosed to involve an apparent oxygen transposition via dehydration-rehydration from the indolyl-3-carbonyl group to the pyrrole C2-position to forge a new carbonyl bond [32][33][34] .…”

Advance in C-H Arylation of Indoles

“…反应条件也同样适用于 3-乙酰基苯并噻吩的 C4 位氟代 烷基化. Prabhu 课题组 [32] 通过在吲哚的 C3 位引入醛基, 在其导向下选择性地实现 Ru 催化下的吲哚 C4 位 C-H 烯基化(Eq. 10).…”

Ru-catalysed C–H silylation of unprotected gramines, tryptamines and their congeners

“…Partial C-H/D exchange was observed at C2 in 19 and the C3-methylene/methyl positions of 2e and 19, as well as the C4 and C7 positions in both. Catalytic indole C4-H activation is very rare 22 and reported only for electrophilic metal species. 40% of C4-D incorporation was observed in product 2e obtained from the reaction between 1a-d and D-SiEt3 (Scheme 3A).…”