Synthesis of 3-Alkenyl-1-azaanthraquinones via Diels-Alder and Electron Transfer Reactions

A convenient route to 3-alkenyl-1-azaanthraquinones via a hetero Diels-Alder reaction between an azadiene and naphthoquinone, a free radical chlorination and an electron transfer reaction is reported.


Introduction
The anthracyclines (doxorubicin, daunorubicin) play an important role in the treatment of many human lymphomas, leukemia and solid tumors [1,2]. However, their clinical use is limited mainly by two major problems, namely their cumulative cardiotoxicity and the appearance of intrinsic and acquired drug resistance. The search for new analogues having better therapeutic efficacy led us to synthesize 3 -alkenyl-1azaanthraquinone derivatives.
By performing the reaction in acetonitrile at room temperature for 24 hours and using 2 equivalents of naphthoquinone, Serckx-Poncin [4] obtained, in an one pot synthesis, the aromatized adduct 2 in 92% yield. Lee [5] modified this process by replacing the excess naphthoquinone with stirring in the presence of silica gel to effect the oxidation. Compound 2 was then obtained in 51% yield. Using the Serckx-Poncin procedure with a slight excess (1.2 eq.) of napthoquinone we only obtained compound 1 in 55% yield, resulting from the cycloaddition followed by the elimination of dimethylamine, instead of the 3-methyl-1-azaanthraquinone (2). Oxidation was performed by stirring in refluxing ethanol as described for the reaction with 5hydroxynaphthoquinone [6]. Derivative 2 was isolated in 95% yield after purification by chromatography. In order to optimize this reaction we have treated directly the crude residue, after acetonitrile removal, with boiling ethanol. A simple recrystallization from ethanol led to 2 in 90% yield. The advantage of such a procedure lies in the fact that you don't have to use a 2 eq. excess of naphthoquinone, in one hand and you can obtain 2 without any purification by column chromatography, on the other hand.
The 3-methyl group was then halogenated according to the Newkome procedure [7]. (Scheme 2). Various experimental conditions, using N-chlorosuccinimide as reactant, were tried in an attempt to increase the yield of the reaction. The best yield of 3 was 31% along with the starting material 2 (47%) and trace amounts of the dihalogenated derivative were also isolated.

Conclusions
A first key-step has been optimized, providing 3-methyl-1-azaanthraquinone (2) in high yield after an easier work-up than those previously described in the literature. Thus, this work has shown that such a pathway is a convenient route for the synthesis of 3-alkenyl-1-azaanthraquinones and it is currently being extended to various anions to produce a new series of azaanthraquinones which will be assessed for biological activity towards various tumor cell lines.

Acknowledgments
We are grateful to the Centre National de la Recherche Scientifique for its financial support. We also wish to express our thanks to Gilles Lanzada for his technical collaboration.

General
Melting points were determined on a Büchi B-540 apparatus and are uncorrected. Elemental analyses were performed by the Centre de Microanalyses of the University of Aix-Marseille 3. Both 1 H-and 13 C-NMR spectra were determined on a Bruker ARX 200 spectrometer. The 1 H-chemical shifts were reported as parts per million downfield from tetramethylsilane (Me 4 Si) and the 13 C-chemical shifts were referenced to the CDCl 3 solvent peak (76.9 ppm). Silica gel 60 (Merck, 230-400 mesh) was used for column chromatography. Thin-layer chromatography was performed with silica gel Merck 60F-254 (0.25 mm layer thickness).