Published: February 28, 2011 r2011 American Chemical Society 3780 dx.doi.org/10.1021/ja111670s | J. Am. Chem. Soc. 2011, 133, 3780–3783 COMMUNICATION pubs.acs.org/JACS Rh(NHC)-Catalyzed Direct and Selective Arylation of Quinolines at the 8-Position Jaesung Kwak, Min Kim, and Sukbok Chang* Department of Chemistry and Molecular Level Interface Research Center, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 305-701, Republic of Korea b S Supporting Information ABSTRACT: A new catalytic protocol for the regioselec- tive direct arylation of quinoline derivatives at the 8-posi- tion has been developed. The reaction is catalyzed by a Rh(NHC) system, and the choice of the NHC ligand was most important for achieving high reactivity and selectivity. R ecent progress on the catalytic C-H bond functionalization methods has opened new possibilities for an ideal chemical synthesis enabling straightforward formation of C-C or C-X bonds from cheap and simple molecules. 1 However, it is still difficult to control the position of activated C-H bonds if the substrates have more than one reacting site. Therefore, the development of site-selective C-H bond activation is highly desirable to achieve regioselective C-C or C-X bond formation in subsequent steps. 2 Quinoline, which is a prominent structural motif found in a wide range of natural products of interesting biological activity, 3 has been derivatized often via transition-metal-catalyzed ap- proaches (Scheme 1). 4-9 In such transformations, high regios- electivity at the 2-position was readily obtained by converting quinolines into their N-oxides. 5b,c,6 More recently, catalytic C-2 arylation of unmodified quinolines was achieved by utilizing nickel (Tobisu and Chatani), 7 silver (Baran), 8 or rhodium catalysts (Bergman and Ellman). 9 In addition, Yu developed a novel method of arylation at the 3- or 4-position based on a chelation- assisted strategy, thus requiring an amido group in the 4- or 3-position of quinolines to direct the regioselectivity. 5d In spite of the above important contributions, no direct catalytic arylation method has been developed to functionalize quinolines at the 8-position. 10 In fact, the conventional method requires the de novo synthesis of 8-halogenated quinolines followed by cross-coupling. 11 In this context, there is a strong desire for the development of a direct catalytic functionalization of unmodified quinolines at the 8-postion. Described herein is the Rh(NHC)-catalyzed direct 8-arylation of quinolines, represent- ing the first example of complete regiocontrol to the best of our knowledge. Recently, we have demonstrated that N-heterocyclic carbene (NHC) ligands can play a crucial role in Rh-catalyzed reactions, thus dramatically improving both reactivity and selectivity. 12 During the course of our research aimed at an efficient C-H bond functionalization of heteroarenes, 13 we were intrigued by the feasible effects of NHC ligands on the resultant Rh-NHC catalytic system ultimately to influence the catalytic activity and regioselectivity in the direct arylation of quinoline (Table 1). While Rh 2 (OAc) 4 species (5 mol %) exhibited only negligible activity in the absence of ligands (entry 1), the addition of the IMes•HCl ligand (1 equiv) significantly improved the arylation efficiency (entry 2). Importantly, a careful analysis of the obtained products revealed that the arylation took place almost exclusively at the 8-postion of quinoline to afford 8-(p-tolyl)quinoline (2b) albeit in moderate yield under the employed conditions. 14 Other NHC ligands examined exhibited much lower effects on the catalytic activity, but the selectivity still remained high in favor of 8-arylation over the 2-position (entries 3-5). Interestingly, regioselectivity was diminished upon the use of a bulky NHC ligand (e.g., IAd) although the catalytic activity was improved moderately (entry 6). In addition, no beneficial effect was observed when a phosphine ligand was employed (entry 7). The structure of an isolated Rh 2 (OAc) 4 (IMes) complex was characterized, 15 and it was confirmed that this pregenerated catalyst performs the arylation with similar reactivity when compared to that obtained under the in situ conditions (compare entries 8 and 2). With the use of 2 equiv of quinoline relative to bromoarene, the reaction proceeded more smoothly to afford a synthetically acceptable yield even using a lesser amount of catalyst (entry 9). A dramatic NHC effect was also observed with other sources of Rh catalysts such as RhCl(PPh 3 ) 3 , [Rh(coe) 2 Cl] 2 , or Rh(acac) 3 species (entries 10-13). 16 Our result is highly significant in that the Bergman-Ellman Rh-catalyst system for the arylation of quinolines gives only 2-arylated products via Rh-quinoline “carbene” intermediates. 9c,d Therefore, our Rh-NHC system is an extremely useful and complementary route to obtain regioisomeric 8-arylquinolines. For operational convenience, the protocol of generating a Rh-NHC catalyst in situ was set up as the optimized conditions. Scheme 1. Selectivity Controlled Direct Arylation of Quinolines Received: December 28, 2010