Microwave-Assisted Syntheses of N-Heterocycles Using Alkenone-, Alkynone- and Aryl-carbonyl O-Phenyl Oximes: Formal Synthesis of Neocryptolepine Fernando Portela-Cubillo, † Jackie S. Scott, § and John C. Walton* ,† School of Chemistry, EaStChem, UniVersity of St. Andrews, St. Andrews, Fife KY16 9ST, U.K., and GlaxoSmithKline, New Frontiers Science Park, Third AVenue, Harlow, Essex CM19 5AW, U.K. jcw@st-and.ac.uk ReceiVed April 21, 2008 This research aimed to provide a new and “clean” synthetic method that would enable both known and novel N-heterocycles to be prepared efficiently. O-Phenyl oximes were found to be excellent precursors for iminyl radicals with a variety of acceptor side chains. Dihyropyrroles were made in good yields from O-phenyl oximes containing pent-4-ene acceptors. The analogous process with a hex-5-enyl acceptor did not yield a dihydropyridine, probably because the 6-exo-trig ring closure of the iminyl radical was too slow to compete with H-atom abstraction. The iminyl radical from a precursor with a pent-4-yne type side chain underwent ring closure followed by rearrangement to afford a pyrrole derivative. Suitably substituted iminyl radicals ring closed readily onto aromatic acceptors, thus enabling several polycyclic systems to be accessed. Quinolines were made from 3-phenylpropanones via their O-phenyl oximes. Syntheses of phenanthridines starting from 2-formylbiphenyls were particularly efficient, and this approach enabled the natural product trisphaeridine to be made. Starting from 2-phenylnicotinaldehyde derivatives, ring closures of the derived iminyl radicals onto the phenyl rings yielded benzo[h][1,6]naphthyridines. Similarly, ring closure onto a phenyl ring from a benzothiophene-based iminyl yielded a benzo[b- ]thieno[2,3-c]quinoline. By way of contrast, iminyl radical ring closure onto pyridine rings was not observed. However, iminyl radicals did cyclize onto indoles, enabling indolopyridines to be prepared. The latter route was exploited in a short formal synthesis of neocryptolepine starting from 2-((1H-indol-3-yl)methyl)cyclohexanone. Introduction Radical-mediated methods of preparing heterocycles are steadily entering mainstream organic synthesis because their experimental conditions are usually mild and neutral and because novel derivatives can be accessed in this way. 1 Ring closures of iminyl radicals (R 2 CdN • ) appear particularly promising because the products are convenient for further functional group manipulations. The literature on iminyl radical cyclizations is not extensive, but the most studied process is the 5-exo-trig closure of pent-4-enyl-iminyl types yielding 3,4-dihydro-2H- pyrroles. 2 It can be inferred from available kinetic data that the rate constant for this iminyl cyclization is only about a factor of 20 less than that of the archetype hex-5-enyl radical 3 and therefore the reaction is fast enough for incorporation into a variety of preparative sequences. 1a,2 An important objective has been to find ways of generating iminyls that are “clean”, flexible, † University of St. Andrews. § GSK Harlow. (1) For reviews, see: (a) Bowman, W. R.; Bridge, C. F.; Brookes, P. J. Chem. Soc. Perkin Trans. 1 2000, 1–14. (b) Stella, L. In Radicals in Organic Synthesis; Renaud, P., Sibi, M. P., Eds; Wiley-VCH: Weinheim, 2001; Vol. 1, p 317. (c) Walton, J. C. Top. Curr. Chem. 2006, 264, 163–200. (d) McCarroll, A. J.; Walton, J. C. Angew. Chem., Int. Ed. 2001, 40, 2224–2248. (e) Baguley, P. A.; Walton, J. C. Angew. Chem., Int. Ed. 1998, 37, 3072–3082. (2) Fallis, A. G.; Brinza, I. M. Tetrahedron 1997, 53, 17543–17594. (3) Le Tadic-Biadatti, M.-H.; Callier-Dublanchlet, A.-C.; Horner, J. H.; Quiclet-Sire, B.; Zard, S. Z.; Newcomb, M. J. Org. Chem. 1997, 62, 559–563. 10.1021/jo800847h CCC: $40.75  2008 American Chemical Society 5558 J. Org. Chem. 2008, 73, 5558–5565 Published on Web 06/13/2008