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Paper | Special issue | Vol 86, No. 1, 2012, pp.233-244
Published online, 17th April, 2012
DOI: 10.3987/COM-12-S(N)4
Synthesis, Cyclization, and Evaluation of the Anticancer Activity against HeLa S-3 Cells of Ethyl 2-Acetylamino-3-ethynylazulene-1-carboxylates

Marie Hyoudou, Hajime Nakagawa, Takahiro Gunji, Yoshino Ito, Yu Kawai, Reiko Ikeda, Takeo Konakahara, and Noritaka Abe*

*Department of Pure and Applied Chemistry, Faculty of Science and Technology, Tokyo University of Science, 2641 Yamazaki, Noda, Chiba 278-8510, Japan


Reaction of ethyl 2-aminoazulene-1-carboxylate with NIS in CHCl3 gave 2,2’-diamino-3,3’-diethoxycarbonyl-1,1’-biazulene (3) and a terazulene derivative. The coupling of azulenes was catalyzed by acid. Operation of the reaction in the presence of Et3N in CH2Cl2 for 7 min at -7 °C retarded the coupling of the azulene nuclei to give ethyl 2-amino-3-iodoazulene-1-carboxylate (1a) in 95% yield. Sonogashira cross-coupling of ethyl 2-acetylamino-3-iodoazulene-1-carboxylate (1b) gave ethyl 2-acetylamino-3-ethynylazulene-1-carboxylates (5a and 5b) in good yields. Cyclization of ethyl 2-acetylamino-3-phenylethynylazulene-1-carboxylate with Pd-catalyst gave azuleno[2,1-b]pyrrole derivatives. Compounds (3 and 5b) showed potent cytotoxic activity against HeLa S-3 cells (IC50 [μM] : 3: 2.9 ± 0.2, 5b: 13.4 ± 1.1).