Copper-Catalyzed Selective Oxidative Cross-Coupling of Tryptophols and Tryptamines To Access Heterocyclic 3a,3a′-Bisindolines

Abstract

The first example of cyclization cross-coupling of tryptophols and tryptamines has been realized by copper catalysis with air or oxone as the terminal oxidant, resulting in the direct construction of a new class of heterocyclic 3a,3a′-bisindolines in moderate to good yields with high chemoselectivities. A series of mechanistic control experiments were also conducted, indicating that the copper catalyst selectively coordinates with the nitrogen moiety of the tryptamine to initiate the oxidation, and a nucleophilic-alkylation process is proposed for the carbon−carbon bond-forming in the reaction. The novel synthetic strategies and molecular skeletons outlined in this work provide new ideas and concepts for the design of other useful reaction and potential drugs.

Copper-Catalyzed Aerobic Selective Oxidation of Tetrahydrocarbolines

“…To gain mechanistic insight into our system, controlled radical trapping and H 2 18 O tracking experiments (see Supporting Information 3.1–3.5 for details) were performed. A plausible reaction pathway that is consistent with the results of these experiments and those of previous studies , is depicted in Scheme . First, the Cu II species oxidizes the THβC/THC to form radical cation intermediate A .…”

“…The pioneering studies in this area are mainly focused on the selective oxidation of N -free indoles or tryptamines to generate free radicals in the presence of base . Accordingly, several novel synthetic methods and total syntheses of complex indole-based natural products have been accomplished using radical processes. , However, the application of copper catalysis to the oxidation of THCs and THβCs is comparatively underresearched. This may be attributed to their inherent oxidation resistance and the steric hindrance affecting substitutions at C2 and C3 …”

“…When 10 mol % of the metal salt CuBr 2 was employed as the catalyst in ethanol (EtOH) under open air conditions, the desired product 2a was obtained in 30% yield (Table , entry 1). Considering that nitrogen-containing ligands showed the most influence on reaction efficiency in our previous relevant indole-oxidation research, we then turned our attention to ligand optimization. The use of bisbenzoxazoline L1 and bisbenzothiazoline L2 failed to improve the yield (Table , entries 2–3).…”

“…Subsequent nucleophilic attack by the alcohol gives product 5a . Simultaneously, Cu I species are oxidized to Cu II by O 2 in the catalytic cycle . The reaction pathways for 5a to 6a proceed from 1a to 2a .…”

Copper-catalyzed cascade reaction of tryptamines with diazo compounds to access hexahydropyrroloindoline derivatives

“…5 Recently, the oxidative-coupling strategy has been applied to achieve bisindolines by Tu’s group 6 and Ren’s group. 7…”