& CÀ H Activation Amidines for Versatile Ruthenium(II)-Catalyzed Oxidative CÀ H Activations with Internal Alkynes and Acrylates Jie Li, Michael John, and Lutz Ackermann* [a] Abstract: Cationic ruthenium complexes derived from KPF 6 or AgOAc enabled efficient oxidative C ÀH functionalizations on aryl and heteroaryl amidines. Thus, oxidative annulations of diversely decorated internal alkynes provided expedient access to 1-aminoisoquinolines, while catalyzed C ÀH activa- tions with substituted acrylates gave rise to structurally novel 1-iminoisoindolines. The powerful ruthenium(II) cata- lysts displayed a remarkably high site-, regio- and, chemose- lectivity. Therefore, the catalytic system proved tolerant of a variety of important electrophilic functional groups. De- tailed mechanistic studies provided strong support for the cationic ruthenium(II) catalysts to operate by a facile, reversi- ble C ÀH activation. Introduction Aminoisoquinolines and isoindolines are important structural motifs of various compounds with activities of relevance to biology or medicinal chemistry, [1, 2] as found in nonbenzamidine factor VIIa inhibitors against nonthromboembolic cardiovascu- lar disease. [3] Therefore, there is a continued strong demand for efficient and selective syntheses of these heterocyclic scaf- folds. In recent years, metal-catalyzed C ÀH-bond activation has been recognized as an increasingly viable tool for the prepara- tion of substituted heterocycles. [4] These methods avoid the synthesis and use of prefunctionalized starting materials and thereby improve the atom- and step-economy of organic syn- theses. While rhodium and palladium catalysts were frequently utilized for oxidative C ÀH-bond functionalizations, [4] in recent years, less expensive [5] ruthenium complexes have attracted considerable attention as versatile catalysts for oxidative C ÀH- bond activations. [6, 7] One of the key obstacles in the develop- ment of practically useful intermolecular C ÀH-bond functionali- zations is represented by achieving site selectivity. [4] Directing- group assistance has proven to be one of the most powerful strategies for ensuring site selectivity in stoichiometric and cat- alytic C ÀH-bond transformations. [8] While various Lewis-basic directing groups were previously exploited for C ÀH-bond acti- vations, [4] ubiquitous amidines [9] have, to the best of our knowledge, not been exploited in oxidative ruthenium(II)-cata- lyzed C ÀH-bond activation so far. This lack of available meth- ods is likely owing to the excellent binding properties of ben- zamidines as bidentate ligands, [10, 11] rendering these NH-acidic compounds particularly challenging substrates for catalytic C À H-bond functionalization. As part of our program on catalyzed C ÀH-bond activation for sustainable synthesis, [12] we herein report on the first ruthenium-catalyzed oxidative C ÀH-bond functionalizations with benzamidines 1. Notably, our strategy proved to be widely applicable and enabled annulations of al- kynes 2 and alkenes 4 to provide expedient access to diversely substituted 1-aminoisoquinolines 3 and novel 1-iminoisoindo- lines 5, respectively (Scheme 1). Results and Discussion Oxidative alkyne annulation Optimization studies We initiated our studies by testing different reaction conditions for the desired oxidative annulation of tolane (2a) and benza- midine 1a. Preliminary experiments identified [RuCl 2 (p- cymene)] 2 as the ideal metal source and KPF 6 as the cocatalytic additive of choice. Among a set of representative solvents, DME provided optimal results (Table 1, entries 1–5 and 8). Scheme 1. Ruthenium-catalyzed C ÀH activation on amidines 1. [a] J. Li, Dr. M. John, Prof. Dr. L. Ackermann Institut für Organische und Biomolekulare Chemie Georg-August-Universität Tammannstrasse 2, 37077 Gçttingen (Germany) Fax: (+ 49) 551-39-6777 E-mail : Lutz.Ackermann@chemie.uni-goettingen.de Supporting information for this article is available on the WWW under http ://dx.doi.org/10.1002/chem.201304944. Chem. Eur. J. 2014, 20, 5403 – 5408  2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 5403 Full Paper DOI: 10.1002/chem.201304944