2-Aminobenzaldehyde, a common precursor to acridines and acridones endowed with bioactivities

Abstract

By starting from a common substrate, 2-aminobenzaldehyde, both acridines and acridones were prepared. The former were generated in high yields by copper-catalyzed N-arylation followed by acid-mediated cyclization while the latter were obtained by double copper-catalyzed N-arylation followed by cyclization under the same reaction conditions. Moreover, acridine was subjected to deprotometalation by recourse to a lithium-zinc base and converted to the corresponding 4-iodo derivative, which was involved in copper-catalyzed couplings with pyrrolidinone and pyrazole. Finally, addition of pyrazole, indole and carbazole onto the 9 position of bare acridine was improved. While moderate biological activity was noticed in melanoma cells growth inhibition, the newly prepared compounds feature interesting photophysical properties which were evaluated in a preliminary study.

Introduction

Heteroaromatic units such as acridines and acridones play an important role in various molecules exhibiting biological properties as well as in organic materials for a wide range of applications (e.g. related to fluorescence) [1]. For example, N-(2-(dimethylamino)ethyl)acridine-4-carboxamide (DACA) and amsacrine (m-AMSA) are topoisomerase II inhibitors and, while the former has been used in trials for the treatment of lung cancer or brain and CNS tumors, the latter is also a potent intercalating antineoplastic agent used for the treatment of acute myeloid leukemia (Fig. 1, left) [1b].

Other biological activities can be found in acridone-based compounds. For example, 1,5,6-trimethoxyacridone is known for its ability to inhibit aromatase and glycosyltransferase, and its moderate cytotoxic activity against liver cancer cell line WRL-68 (IC₅₀ = 86 μM). Finally, citrusinine-I is a natural acridone reported as herbicide model due to its ability to inhibit photosynthesis (Fig. 1, right) [1b].

Acridines and acridones are traditionally prepared by using as key step copper-catalyzed C–N bond formation reactions between 2-halogenobenzoic acids and anilines [1]a), [1]b). Among other methods reported to access acridines [2], we can cite (i) the Bernthsen synthesis in which diphenylamine and carboxylic acids are heated in the presence of zinc chloride as catalyst to furnish 9-substituted acridines [3], (ii) palladium-catalyzed N-arylation/intramolecular Heck reaction of 2-bromostyrenes with 2-chloroanilines developed by Buchwald and co-workers [4], (iii) [4 + 2] annulation of 2-aminoaryl ketones with in situ formed arynes (by treating 2-(trimethylsilyl)aryl triflates with cesium fluoride) documented by Larock and co-workers to afford unsymmetrical acridines [5], (iv) palladium-catalyzed consecutive CC bond and C–N bond formations between 1,2-dibromobenzenes and N-tosyl hydrazones of 2-aminophenyl ketones reported by Wang and co-workers [6], (v) the appoach of Ellman and co-workers who employed aromatic azides with aromatic imines in a [3 + 3] annulation reaction (Rh(III)-catalyzed amination followed by intramolecular electrophilic aromatic substitution and aromatization) [7], (vi) palladium-catalyzed N-arylation/Friedel-Crafts reactions of anilines reported by Guo, Wang and co-workers from 2-formylphenyl triflates and anilines [8], and by Xu and co-workers from 2-bromobenzaldehydes [9], both in the presence of copper salts, (vii) tandem N-arylation/Friedel-Crafts reactions of 2-aminophenones with diaryliodonium salts [10] and arylboronic acids [11], (vii) Wang’s [12] and Wu’s [13] annulation-aerobic oxidative dehydrogenation and Deng’s palladium-catalyzed reaction [14] of 2-aminophenones with cyclohexanones, and (ix) Jiang’s nitrogen/iodine exchange of diaryliodonium salts with sodium azide [15] (Scheme 1).

Among a few other specific syntheses [16], the general ways to access acridones include (i) acid-induced cyclization of N-aryl anthranilic acids (or amides) [16]a), [17], (ii) hydrolysis of 9-chloroacridines [18] and oxidation of acridines [18,19] or acridinium salts [20], (iii) copper-catalyzed (first reported by Deng [21], Cheng [22], Xu [23], Zhu [23] and co-workers) or potassium tert-butoxide-mediated (reported by Zou and co-workers) [24] intramolecular N-arylation of N-substituted 2-aminobenzophenones [25], (iv) copper-catalyzed oxidative cyclization of 2-(phenylamino)acetophenones studied in parallel by Zhou [26], Fu [19], Zhang [27] and co-workers, as well as Yang’s scandium triflate-catalyzed [28] and Du/Zhao’s (diacetoxyiodo)benzene-mediated [29] dehydrogenative cyclization of 2-(phenylamino)benzaldehydes, (v) Chen’s tandem copper-catalyzed N-arylation/Friedel-Crafts reaction of methyl 2-aminobenzoates with diaryliodonium salts [10], (vi) reactions involving in situ generated arynes (from 2-(trimethylsilyl)aryl triflates) such as Jiang’s palladium-catalyzed multicomponent with 2-iodoanilines and carbon monoxide [30], and Larock’s cesium fluoride-mediated coupling with methyl 2-aminobenzoates [31], (vii) Lei’s palladium-copper co-catalyzed oxidative double C–H carbonylation of diphenylamines [16d], (vii) palladium-catalyzed carbonylation/C–H activation sequence developed by Song, Liu and co-workers from 2-bromodiarylamines [32], and (ix) Langer’s palladium-catalyzed double amination of bis(2-bromophenyl) ketones [33]. As far as N-arylated acridones are concerned, they can be obtained either by a suitable choice of the precursors [16]a), [21], [22], [25], [32], [33], or by post-functionalization of acridones [34] (Scheme 2).

In 2018, we reported an easy synthesis of N-aryl isatins or acridines, both involving a copper-catalyzed C–N bond formation from 2-aminophenones [35]. As part of our studies dedicated to the development of short syntheses to access aromatic heterocycles of biological interest [36], we here report our efforts to access both acridines and N-arylated acridones from a common precursor, 2-aminobenzaldehyde. We also document the photophysical properties of some of the prepared compounds, as well as their ability to inhibit the growth of melanoma cells.