C-2 arylation of piperidines through directed transition-metal-catalyzed sp3 C-H activation.

The development of transition-metal-catalyzed methods for the direct functionalization of C H bonds has attracted much attention during the past decade. While the direct functionalization of sp C H bonds is an active field of research, the corresponding knowledge on sp C H bonds is still limited and remains one of the current challenges in organic chemistry. Within the area of sp C H activation, the transformation of a C H bond in the a-position to the nitrogen atom of saturated cyclic amines is of particular importance, since such heterocyclic motifs can be found in an impressive number of natural products and marketed drugs. The intermolecular, direct transition-metal-catalyzed functionalization of saturated cyclic amines adjacent to nitrogen offers a simple and efficient synthetic approach towards valuable building blocks. To the best of our knowledge, only six articles are hitherto published on this topic, wherein the main focus is on five-membered cyclic subACHTUNGTRENNUNGstrates. [6,7a] In 2006, Sames and co-workers reported the first direct arylation of saturated cyclic amines through transition-metal-catalyzed sp C H activation, involving arylboronate esters as a coupling partner. Pyrrolidines were successfully arylated adjacent to nitrogen by using a Ru-catalyzed C-H activation process, directed by a pyrroline group and mediated by ketone (used also as a solvent). The authors suggested that the key role of the ketone (pinacolone) is to allow a transmetalation by transforming the initially formed metal hydride species into a metal alkoxide intermediate. The pyrroline directing group could be removed by treatment of the a-arylated pyrrolidines with NH2NH2/ AcOH. One example of a piperidine substrate also appeared in this work, which was C-2 p-methoxyphenylated in moderate yield (38 %). The six-membered piperidine ring is inherently less reactive than its five-membered analogue (pyrrolidine) due to its chair conformation. Consequently, there are very few examples in the literature of direct functionalization of piperidines by means of a transition-metalcatalyzed, sp C H activation process. We report here a novel method for the direct C-2 arylation of piperidines with arylboronate esters, resulting from a mechanistic study of the transmetalation step of the catalytic cycle. As part of our interest in C-2 functionalized 4-substituted piperidines, we first applied the conditions described by Sames and co-workers to 1-(pyrrolin-2-yl)-4-piperidinone ethylene ketal (Scheme 1, 1). Unfortunately, the reaction of 1 with phenylboronic acid pinacol ester resulted in a low conversion to the arylated product, and directing group in[a] Dr. H. Prokopcov , Dr. S. D. Bergman, Dr. K. Aelvoet, V. Smout, Prof. Dr. B. U. W. Maes Organic Synthesis, University of Antwerp Groenenborgerlaan 171, 2020 Antwerp (Belgium) Fax: (+32) 32653233 E-mail : bert.maes@ua.ac. be [b] Prof. Dr. W. Herrebout, Prof. Dr. B. Van der Veken Cryospectroscopy, University of Antwerp Groenenborgerlaan 171, 2020 Antwerp (Belgium) [c] Dr. L. Meerpoel Johnson & Johnson Pharmaceutical Research & Development A Division of Janssen Pharmaceutica N.V. Turnhoutseweg 30, 2340 Beerse (Belgium) Supporting information for this article is available on the WWW under http://dx.doi. org/10.1002/chem.201001887. Scheme 1. 4-Piperidinone ethylene ketal bearing a pyrroline or pyridine directing group: substrates designed to explore the C-2 arylation process.