Intramolecular Pictet–Spengler Reaction of Cyclic Iminium ions: A Novel Access to Benzo[1,4]oxazepine‐Fused Tetrahydroisoquinoline and Tetrahydro‐β‐carboline Analogues

Abstract

A simple and efficient approach has been developed for the synthesis of benzo[1,4]oxazepino‐fused tetrahydroisoquinoline and tetrahydro‐β‐carboline derivatives via one‐pot cascade reaction sequence. This reaction involves the intramolecular Pictet–Spengler reaction of cyclic iminium ions, which were generated in situ via trifluoroacetic acid (TFA)‐mediated deprotection of an acetal derived from β‐arylethylamines and 2‐(2,2‐diethoxyethoxy)benzaldehyde. All reactions produced a novel library of complex fused polyheterocyclic compounds in good to excellent yields.

Convenient Synthesis of Alternatively Bridged Tryptophan Ketopiperazines and Their Activities against Trypanosomatid Parasites

“…The key step of the synthetic route was an intramolecular acidcatalyzed Pictet-Spengler condensation of aldehyde 7, proceeding through the intermediate imine 8 (Figure 2). While intramolecular Pictet-Spengler condensations have been previously reported, [14][15][16] they are typically implemented in the construction of comparatively less strained 1,2-bridged β-carboline and isoquinoline structures.…”

“…The mechanism is presumably similar to the well-reported acyl-iminium Pictet-Spengler condensations often applied in the synthesis of carboline structures. [14,17,18] This modification of reaction conditions would be valuable in cases where further modification of the scaffold is required, removing the need for additional steps to protect the reactive bridging amine.…”

Comprehensive Strategies for the Synthesis of Isoquinolines: Progress Since 2008

“…Again in 2017, Unnava et al reported intramolecular Pictet-Spengler reaction of cyclic iminium ions to access benzo [1,4]oxazepine fused tetrahydroisoquinoline derivatives 512 (Scheme 304). [303] Wang and Studer have reported annulation of αbenzylated tosylmethyl isocyanide 513 in presence of Togni reagent (339) as trifluoromethylating agent. The reaction follows a sequential double α-alkylation strategy (Scheme 305).…”

“…reported intramolecular Pictet‐Spengler reaction of cyclic iminium ions to access benzo[1,4]oxazepine fused tetrahydroisoquinoline derivatives 512 (Scheme 304). [303] …”

First synthesis of thiazepino[3,4‐a]isoquinolines, a facile new synthetic route to diazepino[3,4‐a]isoquinolines and assessment of their dopamine and σ receptor affinities

“…Here, construction of the tetracyclic framework 1a was effected via an intramolecular Pictet-Spengler reaction of an in situ generated cyclic acyliminium ion derived from 2 to generate racemic derivatives ( Figure 2). [35] We sought to engage a different retrosynthetic approach to the sulfur-containing thiazepino[3,4-a]isoquinoline framework as depicted in Figure 2. Accordingly, the thiazepino framework 1b was anticipated to be synthesized from the tetrahydroisoquinoline alcohol intermediate 5.…”