A single step synthesis of 6-aminophenanthridines from anilines and 2-chlorobenzonitriles Fabienne Gug, a Ste ´phane Bach, b Marc Blondel, b Jean-Michel Vierfond, a Anne-Sophie Martin a and Herve ´ Galons a, * a Laboratoire de Chimie Organique, Universite ´ Rene ´ Descartes, 4 avenue de l’Observatoire, 75006 Paris, France b C.N.R.S., Station Biologique, Cell Cycle Laboratory, place G. Teissier, 29680 Roscoff, Bretagne, France Received 22 January 2004; revised 15 March 2004; accepted 19 March 2004 Abstract—Biologically active 6-aminophenanthridines were prepared in a single step procedure: Metal amides in liquid ammonia promoted the condensation of anilines with 2-chloro-benzonitriles. 6-Aminophenanthridines were isolated in moderate yield. q 2004 Elsevier Ltd. All rights reserved. 1. Introduction Prion deseases are neurodegenerative pathologies that include Creutzfeld – Jakob in human, bovine spongiform encephalopathie in cattle and scrapie in sheep. All these disorders are associated with an abnormal conformation of the normal host protein PrP. 1 Up to now no treatment has demonstrated clinical useful- ness. 2 Very recently, we have developed a rapid yeast-based assay to screen for antiprion drugs, which led to the discovery of phenanthridines as new prion inhibitors. In particular, 6-aminophenanthridines (6-AP) displayed the highest inhibition. 3 In our test, 6-APs were found more active than other previously reported inhibitors. 4 This prompts us to study the preparation of these heterocycles. Phenanthridines can be obtained by cyclisa- tion of various biphenyles: 2-formyl-2 0 -nitrobiphenyle, 5 2 0 iodo-2-isocyanobiphenyle. 6 Other syntheses include cyclisation of N-benzylanilides by reaction of hypervalent iodine, 7 condensation of Boc-aniline with 2-chlorobenzal- dimines under basic conditions 8 and annelation of tetra- hydroquinolin-4-one. 9 In contrast to the numerous approaches to phenanthridines, very few reports deal with 6-APs. The main routes start from phenanthridinones. Phenanthridinones can be obtained from phenanthridines via rearrangement of the N-oxide, 10 from fluorenones by the Schmidt reaction 11 and by Suzuki coupling of 2-Bocaminophenylboronic acid with 2-bromo- benzoates. 12 After conversion of phenanthridinone into 6-chlorophenanthridines, 13 6-AP could then be obtained upon reaction with ammonia. 14 Recently, a one step synthesis of 6-substituted-phenanthri- dine has been described. It is based on the condensation of 2 arynes generated from fluoroarenes with one equivalent of nitrile. However this approach does not allow the introduc- tion of various groups on the benzene rings and cannot be applied to the synthesis of unsubstituted 6-amino groups. 15 2. Results and discussion 2.1. Amination of 6-chlorophenanthridines At the onset of our work, we tried to prepare 6-APs via 6-chlorophenanthridine 16 using the above mentioned previously reported procedure: 6-chlorophenanthridine was obtained in an overall 48% yield from phenanthridine but exposure to a methanolic solution of ammonia produced only a minor trace of 6-AP. The amination was then successfully achieved by hydrogenation of 6-benzylamino- phenanthridine prepared by refluxing 6-chlorophenanthri- dine in benzylamine (Scheme 1). 2.2. Cyclization of 2-chlorophenylbenzamidine However, this classical approach was limited. We needed to prepare functionalised 6-APs in order to establish structure – activity relationships. This led us to investigate other routes. Taking into account that potassium amide in liquid ammonia allowed the cyclisation of the imine of 0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved. doi:10.1016/j.tet.2004.03.062 Tetrahedron 60 (2004) 4705–4708 * Corresponding author. Tel.: þ33-1-5373-9684; fax: þ33-1-4329-0592; e-mail address: herve.galons@univ-paris5.fr Keywords: Amidine; Prions; Phenanthridine; Heterocyclisation.