Ruthenium‐Catalyzed Oxidative Annulation by Cleavage of CH/NH Bonds

Abstract

Oxidative transition-metal-catalyzed C H bond functionalizations have attracted significant recent interest, because these methods avoid the multi-step preparation of preactivated starting materials, and hence allow for an overall streamlining of organic synthesis. Pioneering reports by the research groups of Miura and Satoh, Fagnou, and Jones revealed that particularly rhodium catalysts enabled effective dehydrogenative annulation reactions of alkynes through chelation assistance, which have set the stage for very recently developed rhodium-catalyzed isoquinolone syntheses. On the contrary, the use of less-expensive ruthenium catalysts for oxidative annulations through cleavage of C H bonds has thus far not been reported. During studies on oxidative ruthenium-catalyzed homodehydrogenative arylations, we observed unprecedented ruthenium-catalyzed direct annulations of alkynes through the chemoand site-selective functionalization of both C H and N H bonds, and we wish to disclose our results herein. At the outset of our studies, we explored the effect of different reaction parameters on the oxidative annulation of alkyne 2a by amide 1a, which included the use of representative ruthenium precursors, solvents, oxidants, and additives (Table 1, and Table S1 in the Supporting Information). Among a variety of ruthenium complexes, optimal yields of product 3a were obtained with [{RuCl2(p-cymene)}2], along with Cu(OAc)2·H2O as the terminal oxidant, and tAmOH (tAm= tert-amyl) as the solvent. On the contrary, the use of silver(I) salts as stoichiometric oxidants resulted in decreased catalytic efficacy. As to the reaction mechanism (see below), the formation of compound 4a in apolar solvents is noteworthy. With an optimized catalytic system in hand, we explored its scope in C H bond functionalizations by employing differently substituted benzamides 1 (Scheme 1). Owing to its remarkable chemoselectivity the ruthenium catalyst proved tolerant of valuable electrophilic functional groups, such as fluoro, chloro, or ester substituents. Furthermore, amides 1 bearing different groups on the nitrogen atom, such as N-alkyl, N-benzyl, or N-aryl derivatives, were efficiently reacted, with the latter being chemoselectively converted into isoquinolones 3k and 3 l, without the formation of any indole by-products. Likewise, the successful use of a heteroaromatic benzamide turned out to be viable. The catalytic system was not restricted to the use of tolane (2a), but also allowed for efficient oxidative annulations of aryl-, alkenylor alkyl-substituted alkynes 2 (Scheme 2). Importantly, the annulation process occurred with high regioselectivity even when using unsymetrically substituted aryl/alkyl or alkenyl/alkyl alkynes 2. Given the remarkable activity of the novel catalytic system, we became interested in understanding its mode of action. Thus, intramolecular competition experiments with meta-substituted substrates were largely controlled by steric interactions, thus delivering isoquinolones 3m and 3n as the sole products (Scheme 1). In contrast, the use of substrates 1b and 1c, which have electronegative heteroatoms in metaposition, gave significant amounts of products 3w and 3y, respectively, through C H bond functionalizations at the 2[*] Prof. Dr. L. Ackermann, Dr. A. V. Lygin, Dipl.-Chem. N. Hofmann Institut f r Organische und Biomolekulare Chemie Georg-August-Universit t Tammannstrasse 2, 37077 G ttingen (Germany) Fax: (+49)551-39-6777 E-mail: lutz.ackermann@chemie.uni-goettingen.de Homepage: http://www.org.chemie.uni-goettingen.de/ackermann/