Pyridinium N-2 0 -pyridylaminide: radical cyclization in the synthesis of annulated 2-aminopyridines Ara ´nzazu Sa ´nchez, Araceli Nu ´n ˜ ez, Carolina Burgos * and Julio Alvarez-Builla * Departamento de Quı ´mica Orga ´ nica., Universidad de Alcala ´ , 28871 Alcala ´ de Henares, Madrid, Spain Received 17 July 2006; revised 14 September 2006; accepted 18 September 2006 Available online 9 October 2006 Dedicated to Professor Steven M. Weinreb on the occasion of his 65th birthday Abstract—The synthesis of annulated 2-aminopyridines by intramolecular radical pyridylation of the appropriate substrates, obtained from pyridinium N-2 0 -pyridylaminide, can be performed using TTMSS and AIBN. Ó 2006 Elsevier Ltd. All rights reserved. Substituted 2-aminopyridines and their annulated deriva- tives constitute an important class of organic compounds, widely represented in the molecules of pharmacological interest, in both therapeutic 1 and recognition agent fields. 2 In recent years, particular attention has been devoted to the development of synthetic methods that provide an entry into this class of compounds. Thus, 7-azaindoline I and 1,2,3,4-tetrahydro[1,8]naphthyridine II (Fig. 1) derivatives which have been described as therapeutically important compounds, 3 remain a somewhat inaccessible class of derivatives. Simple 7-azaindoline structures have been prepared by the sluggish hydrogenations of azain- doles. 4 More recently, a free radical-mediated aryl-ami- nation has been reported, whereby an aryl radical adds to the nitrogen of an azomethine bond to supply the required compound. 5 Alternatively, Wijtmans et al. 6 have described a new sequence based on Van der Plas’s reaction. 1,2,3,4-Tetrahydro[1,8]naphthyridines are usu- ally prepared by the selective catalytic hydrogenations of the corresponding precursors, either prepared by Skra- up, 7 Friedla ¨nder 1d,e,8 or Friedel–Crafts 6 approaches. Moreover, Palukcki and co-workers. 9 reported the prep- aration of 1,2,3,4-tetrahydro[1,8]naphthyridine frag- ments, using two different methods, one of which relied, again, on variations of Friedla ¨nder reaction, 9a the other being based in a double Suzuki–Miyaura reaction and Chichibabin cyclization. 9b,c Therefore, in addition to more specific methodologies, a universal synthetic method, which allows entry into these annu- lated systems would be highly desirable. Accordingly, Davies et al. 10 recently described how the ortho alkylation of Boc-protected 2-aminopyridines with a,x- dihaloalkanes, followed by in situ cyclization, results in the corresponding annulated pyridine derivatives in good yields. On the other hand, Zard and coworkers 11 reported the preparation of a series of compounds containing a 2- aminopyridine nucleus fused to a saturated ring (7-aza- oxindole, 7-azaindoline, tetrahydro[1,8]naphthyridine and tetrahydro-5H-pyrido[2,3-b]azepin-8-one), starting from various 2,6-dichloropyridines, through a radical xanthate-mediated cyclization. Although this approach is more general and flexible than previous traditional routes, initial studies starting from the suitable 2-amino- pyridines produced unwanted reactions on the cyclic nitrogen, as a result of its higher nucleophilicity. In this context, during the past few years our research group has been interested in the chemistry of pyridinium 0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved. doi:10.1016/j.tetlet.2006.09.092 * Corresponding authors. Tel.: +34 918854606; fax: +34 918854686 (C.B.); e-mail: carolina.burgos@uah.es N N N N I II 1 2 3 4 5 6 7 8 1 2 3 4 5 6 7 Figure 1. Compounds containing a pyridine nucleus fused to a saturated nitrogen-containing ring. I: 7-azaindoline; II: 1,2,3,4- tetrahydro[1,8]naphthyridine. Tetrahedron Letters 47 (2006) 8343–8346