Oxidative coupling of acridinones: Synthesis of new C₂‐symmetry atropisomers

Abstract

The preparation of symmetric 2,2'-dimethoxy-10,10'-biacridinyl-9,9'-dione atropisomers were obtained by the oxidative coupling of 9(10H)-acridinone with 1,3-dibromo-5,5-dimethyl-imidazolidine-2,4-dione J. Heterocyclic Chem., 45, 67 (2008).Acridine derivatives are well known therapeutic agents due to their wide range of pharmacological and biological activities [1], and many C 2 -symmetry derivatives have been reported in the literature [2]. We reported previously the prep artion of symmetrical heterocyclic host compounds related to bianthryl [3] using unsubstituted 9,9-biacridinyl [4]; but no inclusion compounds were observed with these derivatives. On the other hand 2,2'-dimethoxy-9,9'-biacridines atropisomers proved useful in molecular recognition showing a 'scissor-like' host conformation and guest inclusion of chloroform in their crystalline structure [5]. Recently we obtained the first chiral (aR)-(-)-9,9'-biacridinyl-2,2'-diol atropisomer enantiomerically pure by derivatization and recrystallisation [6]. Hence we were interested in the preparation of new C 2 symmetry derivatives bridged at positions 10,10' and report now the synthesis of 2,2'-dimethoxy-10,10'-biacridinyl-9,9'-diones using the corresponding methoxy-9(10H)-acridinones 4a and 4b.Our approach towards this synthesis was based on the preparation of the 2-methoxy-and 2-methoxy-7-methyl-9(10H)-acridinones (4a) and (4b) followed by oxidative coupling to yield the desired acridinone dimers.First, 4'-methoxyphenyl-N-anthranilic acid (3a) and 5-methoxy-4'-methyl-N-phenylanthranilic acid (3b) were prepared by Ullmann's reaction between 2-bromo-benzoic acid and 4-alkylanilines (2a) and (2b). Compound 3a was obtained by a modified procedure of Krishnegowda using EtOH as solvant and 2-bromobenzoïc acid [7]; while use of dimethoxyethane instead of 1-pentanol under reflux yielded 3b [8] (Scheme 1). The cyclization of 3a,b could be performed by FriedelCrafts acylation in polyphosphoric acid or in sulfuric acid but the best yields were obtained in polyphosphoric acid after purification leading to 2-methoxy-9(10H)-acridinone (4a) and 2-methoxy-7-methyl -9(10H)-acridinone (4b) in 65 % and 95 % yield respectively. Demethylation was also observed performing the cyclization of anthranilic acid (3b) in sulfuric acid; leading to the hydroxy derivative 2-hydroxy-7-methyl-acridin-9(10H)-one (5) in 89 % yield (Scheme 2). Then, we tried the oxidative homocoupling of 2-methoxy-9(10H)-acridinone (4a) and 2-methoxy-7-methyl-9(10H)-acridinone (4b), according to Graebe's procedure with sodium bichromate in acetic acid [9] successfully used in the laboratory for the preparation of 10,10'-biacridinyl-9,9'-dione derivatives, [4] and also with tris(acetyl-acetonato)cobalt(III), in deuteriodimethyl-

Synthesis of Acridines by the [4 + 2] Annulation of Arynes and 2-Aminoaryl Ketones

“…Another commonly used method for preparing acridines involves the reduction of acridones . However, until our recent report (eq ), the syntheses of acridones have also required high temperatures and strongly acidic conditions to affect intramolecular electrophilic aromatic substitution of N -phenylanthranilic acids. , Also published recently were the annulations of 2-oxoaryl azides and 2-azidobenzenecarbonitrile by benzene, giving rise to a variety of acridines, including 9-aminoacridine …”