Homophtalonitrile for Multicomponent Reactions: Syntheses and Optical Properties of o‐Cyanophenyl‐ or Indol‐3‐yl‐Substituted Chromeno[2,3‐c]isoquinolin‐5‐Amines

Abstract

Malononitrile is a useful reagent for multicomponent reactions with hundreds of methods developed. In this paper, we suggest α‐(cyano)‐o‐tolunitrile (homophtalonitrile) to work as a vinylogous malononitrile. Thus, a organocatalytic pseudo‐three‐component reaction of homopthalonitrile (2 equiv) and o‐hydroxybenzaldehyde, leading to the diastereoselective formation of 5‐amino‐12H‐chromeno[2,3‐c]isoquinolin‐12‐yl)(cyano)methyl)benzonitriles, was discovered. The possibility to employ other nucleophiles was demonstrated for indoles, and a sequential three‐component reaction of homophtalonitrile, o‐hydroxybenzaldehyde, and (aza)indole, giving 12‐(1H‐Indol‐3‐yl)‐12H‐chromeno[2,3‐c]isoquinolin‐5‐amines, was developed. The photophysical properties of the synthesized compounds have been studied, revealing high fluorescence quantum yields (42–70 %) for indol‐3‐yl substituted 12H‐chromeno[2,3‐c]isoquinolin‐5‐amines and reversible fluorescence quenching under acidic conditions.

The Chromenopyridine Scaffold: A Privileged Platform in Drug Design

“…The use of homophtalonitrile 14 instead of malononitrile or derivates, as a precursor in the synthesis of chromenopyridines, has also been studied in the past years. Two recent publications [57,58] describe the experimental conditions to prepare chromenopyridines 15, 17 and 18 by a multicomponent reaction involving 14, salicylaldehydes 1 and different nucleophiles (Scheme 3A,B). The proposed methodologies are conceptually similar to those involving other active methylene compounds and are also based on the formation of an adduct from Knoevenagel condensation, followed by a tandem intramolecular cyclization promoted by Michael addition of a nucleophile, leading to the formation of the chromenopyridine scaffold.…”

Multicomponent synthesis of chromophores – The one-pot approach to functional π-systems

“…The sequential three-component synthesis of homophthalonitrile, o-hydroxybenzaldehyde, and a nucleophile gives rise to chromenoisoquinolines (Festa et al, 2017). If (aza) indole acts as the nucleophile, 12-(1H-indol-3-yl)12H-chromeno [2,3-c]isoquinolin-5-amines 103 are obtained in the sense of the chromophore approach (Supplementary Material S37) (Festa et al, 2019).…”

ZnCl2-Promoted Three-Component Reaction of 2-Aminochromenones, Aromatic Aldehydes, and Quinone Monoketals: Access to 5,6-Dihydro-12H-chromeno[2,3-c]isoquinolin-12-one Derivatives

“…Voskressensky and co-workers provided an effective preparative multicomponent synthesis of 12-nitromethyl-12 H -chromeno­[2,3- c ]­isoquinolin-5-amines via sequential reactions of salicylaldehydes with homophthalo­nitrile and then with nitromethane under MW irradiation (Scheme ). Soon afterward, the same group reported the preparation of 12-(1 H -indol-3-yl)-12 H -chromeno­[2,3- c ]­isoquinolin-5-amines, 12-nitromethyl-12 H -chromeno­[2,3- c ]­isoquinolin-5-amines, and 12-pyrrolyl-substituted chromeno­[2,3- c ]­isoquinolin-5-amines via the similar microwave-assisted sequential three-component reaction . An alternative pathway involved the base-promoted domino reactions of 2-methyl-4-oxo-4 H -chromene-3-carbonitrile and ( E )-3-(3-(4-nitrophenyl)-3-oxoprop-1-en-1-yl)-4 H -chromen-4-one which gave a product 12 H -chromeno­[2,3- c ]­isoquinolin-12-one in 62% yield (Scheme ).…”