Bu 3 SnH-mediated radical cyclisation onto azoles Steven M. Allin a, * , William R.S. Barton a , W. Russell Bowman a, * , Emma Bridge (ne ´ e Mann) a , Mark R.J. Elsegood a , Tom McInally b , Vickie McKee a a Department of Chemistry, Loughborough University, Loughborough, Leicestershire LE113TU, United Kingdom b AstraZeneca R&D Charnwood, Bakewell Road, Loughborough LE11 5RH, United Kingdom article info Article history: Received 14 March 2008 Received in revised form 21 May 2008 Accepted 5 June 2008 Available online 10 June 2008 Keywords: Radical cyclisation Homolytic aromatic substitution Bu 3 SnH Imidazole Pyrrole Pyrazole abstract Alkyl radicals have been cyclised onto pyrroles, imidazoles and pyrazoles, and acyl radicals cyclised onto pyrroles, using Bu 3 SnH-, (TMS) 3 SiH- and Bu 3 GeH-mediated aromatic homolytic substitution for the synthesis of bicyclic N-heterocycles. The reactions yield intermediate p-radicals that lose hydrogen in the rearomatisation step of the aromatic homolytic substitution. Mechanistic studies of these rear- omatisation steps indicate aromatic homolytic substitution in which the initiator or breakdown products from the inhibitor are responsible for the H-abstraction step. Ó 2008 Elsevier Ltd. All rights reserved. 1. Introduction Synthesis using aromatic homolytic substitution has advanced rapidly in the last 20 years with the development of modern free radical chemistry and the application of Bu 3 SnH and (Me 3 Sn) 2 as reagents. The use of aromatic homolytic substitution in synthesis has been recently reviewed in detail. 1,2 One of the recent synthetic advances has been the cyclisation of radicals onto azole moieties as shown in Scheme 1 . The application of N-(u-phenylselenyl)-alkyl and N-(u-bromo)alkyl building blocks have been used for aromatic homolytic substitution with loss of hydrogen for the cyclisation of N-(u-alkyl)-radicals onto a range of azole rings, which include pyrroles, 3–5 indoles, 5–7 imidazoles, 3,8 benzimidazoles, 3 pyrazoles 8,9 and 1,2,3-triazoles. 10 These building blocks contain a radical leaving group and another leaving group that can be used to facilitate attachment to azoles by N-alkylation. Different chain lengths can be incorporated but in general only five-, six-, and seven-membered ring cyclisations give useful yields. The cyclisations are most successful when electron-withdrawing substituents are present on the azole rings, i.e., nucleophilic alkyl radicals prefer to attack electron deficient rings. These reactions are therefore the umpolung of the normal Friedel–Crafts alkylation onto electron rich azoles and have useful synthetic application. These intramolecular radical reactions are regioselective, which facilitate the design of syntheses to desired target molecules. Aromatic homolytic ipso substitution with loss of S-centred radicals (phenyl-sulfonyl, -sulfoxyl and -thiyl leaving groups) has provided another avenue of synthesis and has been reported for indoles, 11 imidazoles 12 and benzimidazoles. 12,13 N-Alkyl(u-acyl) radicals have also been cyclised onto pyrroles 14,15 and indoles. 15 Isoelectronic N-alkyl(u-imidoyl) radicals have also been cyclised onto pyrroles and indoles. 16 Buildings blocks, which generate aryl N X – (H•) N Y n Bu 3 SnH N N Y n N N Y n H N n N Y exo cyclisation Scheme 1. Aromatic homolytic substitution on azoles with loss of hydrogen. * Corresponding authors. Tel.: þ44 1509 222569; fax: þ44 1509 223925. E-mail address: w.r.bowman@lboro.ac.uk (W. Russell Bowman). Contents lists available at ScienceDirect Tetrahedron journal homepage: www.elsevier.com/locate/tet 0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved. doi:10.1016/j.tet.2008.06.014 Tetrahedron 64 (2008) 7745–7758