Bis-1,2,4-triazolo[4,3-a:3 0 ,4 0 -c]quinoxalines of pharmaceutical interest from 1,3-dipolar cycloaddition Antonino Lauria * , Annalisa Guarcello, Gaetano Dattolo, Anna Maria Almerico Dipartimento Farmacochimico, Tossicologico e Biologico, Universita ` di Palermo, Via Archirafi 32, 90123 Palermo, Italy Received 2 November 2007; revised 26 December 2007; accepted 9 January 2008 Available online 15 January 2008 Abstract Various derivatives of the heterocyclic system 1,12,12a,12b-tetrahydrobis-1,2,4-triazolo[4,3-a:3 0 ,4 0 -c]quinoxaline of pharmaceutical interest have been obtained by double site- and regio-selective 1,3-dipolar cycloaddition of arylnitrilimines to quinoxalines. No evidence for the formation of mono-adducts was obtained, at variance with literature reports. Specific studies to establish the exact stereo- chemistry of the bis-cycloadducts were undertaken. Ó 2008 Elsevier Ltd. All rights reserved. In common with other nitrogen heterocycles, quinoxa- lines, as well as their fused-ring bioisosteric analogs, show marked activity in many biological systems. A large num- ber of compounds incorporating these ring systems were found to possess antitumour and antibacterial activities. Thus, indolo[2,3-b]quinoxalines of type 1 represent an important series of DNA intercalating agents endowed with antiviral and cytotoxic activities (Fig. 1). For example, compound 2 (B-220) was found active against herpes virus 1,2 and also as chemopreventive agent in experimental tumour models. 3 The tetracyclic 1,6-diamino-bis-1,2,4- triazolo[4,3-a:3,4-c]quinoxaline (3) and 7-chloro-2-oxo- 2H-pyrimido[2 0 ,1 0 :5,1]-1,2,4-triazolo[4,3-a]quinoxalines of type 4 have shown moderate and high activity, respectively, against Gram-positive and Gram-negative micro- organisms. 4 Furthermore some 9H-bis-[1,2,4]triazolo[4,3-a:3 0 ,4 0 -d] [1,5]benzodiazepine derivatives of type 5, evaluated for antiproliferative activity against a panel of cell lines derived from either hematological or solid human tumours, showed antiproliferative activity against either or both leukemia- and lymphoma-derived cell lines in the low micromolar range. 5 On the basis of these data, we focused our studies on bis-triazoloquinoxaline derivatives of type 6, bioisosters of 5, to explore the effect of the ring contraction on biolog- ical activities. A useful synthetic strategy adopted to obtain various polyheterocyclic systems involves the use of 1,3-dipolar cycloaddition reactions. 6 To date in the literature no examples of this reaction applied to synthesize the bis- triazoloquinoxaline core structure have been reported. Quinoxalines, as other azine systems, act as dipolarophiles (2p component) in the dipolar 1,3-cycloadditions, thus 0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved. doi:10.1016/j.tetlet.2008.01.047 * Corresponding author. Tel.: +39 091 6161606; fax: +39 091 6169999. E-mail address: lauria@unipa.it (A. Lauria). N N N R R' R'' N N N N N N N N R' R N N R' R N N N N H 2 N N N H 2 N N N N N Cl N O R N N N N N N R R' R' 1 2 3 4 5 6 Fig. 1. Common heterocyclic quinoxalines and quinoxaline-like com- pounds with biological activity. Available online at www.sciencedirect.com Tetrahedron Letters 49 (2008) 1847–1850