One-pot α-arylation of β-carboline with Indole and Naphthol Derivatives

Abstract

4,9-Dihydro-3H-β-carboline and 6-methoxy-4,9-dihydro-3H-β-carboline were subjected to catalyst-free onepot α-arylation with 1 or 2-naphthol, 6-hydroxyquinoline or 5-hydroxyisoquinoline as N-containing analogues via direct aza-Friedel-Crafts reactions. The procedure was then extended to other electron-rich aromatic compounds, such as indole or indole-2-carboxylic acid, to yield new indole γ-amino acid derivatives containing β-carboline skeleton. All the reactions were performed both under neat conditions and with microwave irradiation. The reaction of 2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole and benzaldehyde with 1-naphthol as nucleophile led to the formation of the N-alkylated compound as a single product, whereas the reaction with 2-resulted in the two possible α-arylated/N-alkylated products, in a ratio depending on the reaction conditions.

Solvent-Free C-3 Coupling of Azaindoles with Cyclic Imines

“…In our initial experiments, 7-azaindole (compound 1 ) was reacted with 1.5 equivalent of 3,4-dihydroisoquinoline (compound 2 ), which was synthesized using a method from the literature (Scheme 1) [18]. The reaction between compounds 1 and 2 was performed in solvent-free conditions by classical heating (oil bath) at 60 °C ( i ).…”

“…The starting cyclic imines 3,4-dihydroisoquinoline ( 2 ) [18]; 3,4-dihydro-β-carboline ( 4 ) [19]; 6,7-dihydrothieno[3,2- c ]pyridine ( 5 ) [20]; and 4,5-dihydro- 3H -benz[ c ]azepine ( 6 ) [21,22] were synthesized according to the literature.…”

“…In this case, the synthesis of 1-(7-azaindol-3-yl)-1,2,3,4-tetrahydroisoquinoline involves the coupling of 7-azaindole with N-protected tetrahydroisoquinoline under iron and copper catalysis [15,16]. The catalyst-free direct coupling of partially-saturated cyclic amines and indole as an electron-rich aromatic compound, via a modified aza -Friedel-Crafts reaction, has recently been published by our research group [17,18]. The reaction has been extended by using indole-2-carboxylic acid as a substrate, leading to the formation of γ-amino acid derivatives [17].…”

High‐performance liquid chromatographic and subcritical fluid chromatographic separation of α‐arylated ß‐carboline, N‐alkylated tetrahydroisoquinolines and their bioisosteres on polysaccharide‐based chiral stationary phases

“…Analyte 1 was synthesized by the catalyst‐free direct coupling of 4,9‐dihydro‐3 H ‐ß‐carboline and 1‐naphthol . For the synthesis of analytes 2 and 3 , 1‐naphthol was reacted with secondary cyclic amines, such as 2,3,4,5‐tetrahydro‐1 H ‐benz[ d ]azepine or 2,3,4,5‐tetrahydro‐1 H ‐benz[ c ]azepine in the presence of benzaldehyde, leading to the formation of 2 and 3 .…”