One‐Step Direct Functionalization of Tetrahydroisoquinolines under Copper and Acid Catalysis

Abstract

A facile, one‐step, direct functionalization of the C1 and N positions of tetrahydroisoquinolines was developed. Unprotected tetrahydroisoquinolines, indoles, and benzaldehydes could be used as starting materials. The different substituted indoles and benzaldehydes were investigated in detail and the scope proved to be broad.

Condensation-Based Methods for the C–H Bond Functionalization of Amines

“…92 Yi, Zhang and coworkers developed redox-arylations of THIQs using indoles as nucleophiles, catalyzed by a combination of copper(I) bromide/triphenylphosphine, and acetic acid (Scheme 48). 93 Side products derived from Friedel-Crafts reactions between indole and aromatic aldehydes are formed in the absence of triphenylphosphine and inferior yields of products 100 are obtained with either no or higher amounts of acetic acid. Luo, Lv and coworkers later reported very similar reactions catalyzed by a Lewis acidic tritylium salt.…”

“…92 In 2015 Yi, Zhang, and co-workers developed redox-arylations of THIQs using indoles as nucleophiles, catalyzed by a combination of copper(I) bromide/triphenylphosphine, and acetic acid (Scheme 48). 93 Side products derived from Friedel-Crafts reactions between indole and aromatic aldehydes are formed in the ab-…”

Metal‐Free Multicomponent Construction of Tetrahydroisoquinoline‐Indole Derivatives via In Situ Generated ortho‐Quinonoid Intermediate

“…In the present research work, we envisaged that MCR between ortho ‐hydroxybenzaldehydes, THIQs and indoles can lead to a metal‐free entry for the construction of THIQ‐indole derivatives via simultaneous N ‐benzylation and C(1)‐substitution. It was noticed that Zhang and coworkers [14] have not studied the hydroxybenzaldehydes as substrates under their developed reaction conditions ( i.e CuBr/PPh 3 /AcOH), as AcOH can promote the competitive cyclization of ortho‐ hydroxybenzaldehydes with THIQs towards benzo[ e ][1,3]‐oxazines (polycyclic N,O ‐acetals) [16] …”

“…In the present research work, we envisaged that MCR between ortho-hydroxybenzaldehydes, THIQs and indoles can lead to a metal-free entry for the construction of THIQ-indole derivatives via simultaneous N-benzylation and C(1)-substitution. It was noticed that Zhang and coworkers [14] have not studied the hydroxybenzaldehydes as substrates under their developed reaction conditions (i.e CuBr/PPh 3 /AcOH), as AcOH can promote the competitive cyclization of ortho-hydroxybenzaldehydes with THIQs towards benzo[e] [1,3]-oxazines (polycyclic N,Oacetals). [16] In continuation of our research work towards developing ecofriendly approaches for the synthesis of diverse biologically active molecules, [15,17] we herein describe metal-and ligand-free multicomponent coupling for the synthesis of THIQ-indole derivatives (Scheme 1c) under solvent-free conditions.…”

Catalytic C3 aza-alkylation of indoles

“…, an interesting modification to the copper-catalysed indole aza-alkylation was reported two years later by Zhang et al, taking advantage of a mixture of catalysts to promote the one-step direct functionalization of tetrahydroisoquinolines 30. The reaction mechanism (Scheme 4b) was promoted by the use of CuBr catalyst, PPh3 ligand and AcOH as co-catalysts.…”