Palladium-catalyzed CeN bond formation via direct CeH bond functionalization. Recent developments in heterocyclic synthesis Egle M. Beccalli a , Gianluigi Broggini b, * , Andrea Fasana b , Micol Rigamonti b a DISMAB, Sezione di Chimica Organica “A. Marchesini”, Università di Milano, Via Venezian 21, 20133 Milano, Italy b Dipartimento di Scienze Chimiche e Ambientali, Università dell’Insubria, via Valleggio 11, 22100 Como, Italy article info Article history: Received 29 July 2010 Received in revised form 10 September 2010 Accepted 14 September 2010 Available online 18 November 2010 Keywords: CeH bond functionalization Palladium catalyst Heterocycles Oxidative coupling Amination abstract The formation of carbonenitrogen bonds by reaction between a nitrogen atom and an unactivated carbonehydrogen bond is a highly atom-economical process that attracted the attention of the chemists in the last two decades. The widely useful amination and hydroamination reactions, which furnish acyclic or cyclic products, give access to various nitrogen-containing basic and fine chemicals. This review highlights recent progress in the development of palladium-catalyzed reactions that occur by direct functionalization of simple carbonehydrogen bonds to give heterocyclic products. Pd(0)- and Pd(II)- catalyzed reactions are described separately, emphasizing the different behavior of the metal in these two oxidation states. Ó 2010 Published by Elsevier B.V. 1. Introduction The synthesis of nitrogen-containing heterocycles continues to attract attention by synthetic chemists, as these structures are found in the cores of thousands of natural products and synthetic drugs. Among the several methods to build such rings, transition- metal-promoted reactions have become one of the most versatile a chemist can dispose of in his quest [1]. In this field, palladium has undoubtedly found a wide utility, since it is effective in mild conditions and tolerates a variety of common functional groups, thus avoiding protection group chemistry. Moreover, most Pd-promoted reactions show high regio- and stereoselectivities and can be run catalytically, offering one of the most efficient tool in this plethora of synthetic ways [2]. Recently, a number of different protocols has enormously widened the application of Pd-catalyzed reactions, promoting a shift from a general interest in cross-coupling processes towards new and more challenging direct CeH functionaliza- tion studies on unactivated substrates [3]. In fact, new proce- dures that pave the way to minimal waste production, thus meaning cheaper and improved atom economic reactions, are welcome. Herein we cover the recent developments in Pd-catalyzed reactions which form a heterocyclic core formally replacing a CeH bond by a CeN bond. Although several accounts on the use of transition metals in heterocyclic synthesis have been published, thus witnessing their importance, an overview on this specific area has not been given so far. Pd(0)- and Pd(II)-catalyzed reactions will be treated separately, reflecting the different behavior shown by these two oxidation states, which are the most commonly involved in organic chemistry [4]. Due to the heterocyclic ring formation, intramolecular processes are the main subject of this account. 2. Palladium(0)-catalyzed reactions In this chapter we consider protocols in which the catalytic cycle is triggered by a Pd(0)-complex, regardless of the oxidation state of the reagent or the key metallic intermediates. The need for this limitation comes from the facile interconversion between the three different oxidation states palladium can adopt, even in the same reaction. In front of such a varied panorama, it seems more clear to name these processes with the cycle-starting species. 2.1. Involving ethylenic CeH bonds 2.1.1. Amination reactions Usually, amination reactions proceed by mechanisms that claim for the formation of a p-allyl- [5] or a p-olefin Pd complex [6]. * Corresponding author. E-mail address: gianluigi.broggini@uninsubria.it (G. Broggini). Contents lists available at ScienceDirect Journal of Organometallic Chemistry journal homepage: www.elsevier.com/locate/jorganchem 0022-328X/$ e see front matter Ó 2010 Published by Elsevier B.V. doi:10.1016/j.jorganchem.2010.09.078 Journal of Organometallic Chemistry 696 (2011) 277e295