Diversity-oriented synthesis of indole-fused scaffolds and bis(indolyl)methane from tosyl-protected tryptamine

• Published in: Organic & biomolecular chemistry Vol. 22; no. 14; pp. 2824 - 2834
• Main Authors: Wang, Liang, Song, Xiaopei, Guo, Fengxia, Xu, Lubin, Hu, Fangzhi, Guo, Feng-Wei, Li, Shuai-Shuai
• Format: Journal Article
• Language: English
• Published: CAMBRIDGE Royal Soc Chemistry 03.04.2024; Royal Society of Chemistry
• Subjects: Alkylation; Amines; Benzodiazepines; Catalysts; Chemistry; Chemistry, Organic; Dehydration; Hydrides; Indoles; Physical Sciences; Reagents; Scaffolds; Science & Technology; Synthesis; Tryptamine; Tryptamines; FUNCTIONALIZATION; BIS-INDOLE; CYTOTOXICITY; ALKALOIDS
• ISSN: 1477-0520; 1477-0539
• DOI: 10.1039/d4ob00099d

An efficient, diversity-oriented synthesis of indole-1,2-fused 1,4-benzodiazepines, tetrahydro-β-carbolines, and 2,2′-bis(indolyl)methanes was established starting from tosyl-protected tryptamine. These diverse privileged skeletons were controllably constructed by adjusting different hydride donors and Brønsted acids. A variety of indole-1,2-fused 1,4-benzodiazepines were facilely accessed using benzaldehydes bearing cyclic amines as hydride donors via a cascade N -alkylation/dehydration/[1,5]-hydride transfer/Friedel-Crafts alkylation sequence. The reaction site could be switched when benzaldehydes bearing an alkoxy moiety as hydride donors were used for the generation of tetrahydro-β-carbolines. On the other hand, the switchable synthesis of 2,2′-bis(indolyl)methanes could be achieved as well by applying p -TsOH·H 2 O as a catalyst. The reactions feature mild conditions, simple and practical operation, excellent efficiency and the use of EtOH as a green solvent. Using the concept of diversity-oriented, reagent-based synthesis, the inexpensive feedstock tryptamine was efficiently converted to three different types of privileged scaffolds, which facilitates rapid compound library synthesis for accelerating drug discovery. Diversity-oriented synthesis of indole-1,2-fused 1,4-benzodiazepines, tetrahydro-β-carbolines, and 2,2′-bis(indolyl)methanes is presented by control of reaction sites.