Construction of indole- and isoquinoline-fused nitrogen-containing heterocycles through copper-catalyzed multi-component reaction.
A copper-catalyzed synthesis of 2-(aminomethyl)indole through domino three-component coupling-cyclization has been developed. This reaction proceeds through Mannich-type coupling of 2-ethynylanilines, aldehydes, and secondary amines, followed by hydroamination. This indole formation was applicable to the synthesis of 4-methylene-2,3,4,9-tetrahyro-1H-pyrido[3,4-b]indoles and 5,6,7,8-tetrahydrobenzo[e]indolo[2,3-c]azepines via palladium-catalyzed C-H functionalization at the 3-position of indole. A combination of the three-component indole formation with nucleophilic cyclization promoted by t-BuOK or MsOH provides an effective access to beta-carboline scaffolds. Indole-fused 1,4-diazepines were also synthesized through deprotection/N-arylation at the nitrogen atom of indole by one-pot addition of MeONa after the formation of 2-(aminomethyl)indoles. In relation to the three-component indole formation, a novel four-component synthesis of isoquinolines has been developed. This isoquinoline formation includes Mannich-type reaction of 2-ethynylbenzaldehyde with (HCHO)(n) and secondary amine, imine formation with t-BuNH(2), isoquinoline formation, and elimination of t-butyl group to directly afford 3-(aminomethyl)isoquinolines in good yields. By the use of an alkane diamine instead of t-BuNH(2), fused 3-(aminomethyl)isoquinoline derivatives were obtained by cascade cyclization and oxidation.
Ohta
Yusuke
Y
Graduate School of Pharmaceutical Sciences, Kyoto University, Yoshidashimoadachi-cho, Sakyo-ku, Kyoto, Japan. yusukebe0108@f01.mbox.media.kyoto-u.ac.jp
D000473:Alkanes; D002384:Catalysis; D003300:Copper; D003500:Cyclization; D003959:Diamines; D015195:Drug Design; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry; D007546:Isoquinolines / Q000138:chemical synthesis* / Q000737:chemistry; D009584:Nitrogen; D010084:Oxidation-Reduction
D000473:Alkanes; D003959:Diamines; D007211:Indoles; D007546:Isoquinolines; D003300:Copper; C039109:isoquinoline; D009584:Nitrogen