Catalytic and Chemodivergent Synthesis of 1-Substituted 9H-Pyrrolo[1,2-a]indoles via Annulation of β-CF₃ Enones with 3-Substituted Indoles

Abstract

Chemodivergent reactions are more advantageous in organic synthesis that yield diversely functionalized scaffolds from common starting materials. Herein, we report an efficient metal-free chemodivergent protocol for the synthesis of 1-substituted 9H-pyrrolo[1,2-a]indole derivatives in the presence of catalytic amounts of Lewis acid/Brønsted acid conditions using 3-substituted indoles and β-trifluoromethyl-α,β-unsaturated ketones. Fine-tuning of the catalyst and solvent system in the reaction conditions deliver the trifluoromethyl, trifluoroethylcarboxylate, or carboxylic acid substituents on the C1-position of 9H-pyrrolo[1,2-a]indole derivatives in situ. It is postulated that the solvent and LA/BA catalyst interaction was found to be crucial for the catalytic C–F activation in these transformations.

Synthesis of CF3-Substituted N-Heterocyclic Compounds Based on C–H Activation-Initiated Formal [2 + 3] Annulation Featuring with a Latent Nucleophilic Site

“…Among members of the pharmaceutically privileged indole family, pyrrolo­[1,2- a ]­indole derivatives are not only ubiquitous in nature but also endowed with powerful antitumor, antibacterial, anti-inflammatory, antinociceptive, and stomach disorder-relieving activities. , Some representative examples in this aspect are displayed in Figure . Meanwhile, the introduction of a trifluoromethyl (CF 3 ) unit often exerts significant influence on the permeability, lipophilicity, and metabolic stability of the parent compounds, thus substantially increasing the likelihood of creating novel lead compounds .…”

Iridium(iii)-catalyzed β-trifluoromethyl enone carbonyl-directed regioselective ortho-C(sp2)–H olefination

“…We first carried out the metal free reaction of 3aa with 3-methylindole ( 4 ) with a PTSA catalyst in TFE to afford the trifluoroethyl ester derivative of the corresponding tricyclic pyrroloindole scaffold ( 5aa ) in 40% yield. 10 In addition, we carried out the coupling of 1-(pyrimidin-2-yl)-1 H -indole ( 6 ) with 3aa as an electrophilic coupling partner under Rh( iii ) catalysis for C2 alkylation of indole as reported previously. 7 b We were delighted to see the reaction of indole C2 alkylated product ( 7aa ) occurring at the β-position of CF 3 enone.…”