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May 10, 2017 - hindered coupling partners only afforded the meta-function- alized products with ruthenium catalyst. In order to develop a more synthet...
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Ligand-Enabled Regioselectivity in the Oxidative CrossCoupling of Arenes and Alkanes Using Ruthenium Catalysts: Tuning the Site-Selectivity from the Ortho to Meta-Positions Guobao Li, Dongze Li, Jingyu Zhang, Da-Qing Shi, and Yingsheng Zhao ACS Catal., Just Accepted Manuscript • Publication Date (Web): 10 May 2017 Downloaded from http://pubs.acs.org on May 10, 2017

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ACS Catalysis

Ligand-Enabled Regioselectivity in the Oxidative Cross-Coupling of Arenes with Toluenes and Cycloalkanes using Ruthenium Catalysts: Tuning the Site-selectivity from the ortho to meta-Positions Guobao Li, Dongze Li, Jingyu Zhang, Da-Qing Shi* and Yingsheng Zhao* Key Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry, Chemical Engineering and Materials Science Soochow University, Suzhou 215123 (PR China)ll Supporting Information ABSTRACT: A Ru-catalyzed 1,1'-binaphthyl-2,2'diylhydrogenphosphate (BNDHP) enabled meta-C-H benzylation under the assistance of ferrocene using less sterically hindered toluene derivatives as the coupling partners has been developed. Various arenes bearing pyridyl, pyridmidyl and pyrazolyl directing groups can be selectively coupled with toluenes at the meta positions in moderate to good yield. A mechanistic study clearly showed the site selectivity at the ortho or meta-position is completely controlled by the ligand of BNDHP and catalyst precursor.

ortho- or meta-site selectivity may be shifted upon modifying the ligands in the coordination center of ruthenium.

1. INTRODUCTION Recently, ruthenium complexes have been disclosed to have versatile catalytic performance by means of chelation-assisted cycloruthenation, which not only promotes the ortho arene C-H functionalization1, but also the challenging meta-arene C-H transformation2-5. For example, several meta-C-H functionalizations have been explored, including the sulfonation2, alkylation3, bromination4 and nitration5. Interestingly, all these coupling partners only afforded coupling products in either the ortho or meta position. For example, primary6 and secondary alkyl halides3 can be regioselectively transformed into the ortho and meta-alkylated 2-pyridylbenzene products respectively, as reported by the Ackermann’s group (Scheme 1a). It was proposed that the steric interaction of the substrates greatly affect the site selectivity in the ruthenium catalyzed alkylation reactions. To date, the site selectivity at the ortho or meta positions7-12, which is completely influenced by the catalyst, has still not been realized. Herein, we report the ruthenium(III) chloride catalyzed 1,1'binaphthyl-2,2'-diylhydrogenphosphate (BNDHP) enabled metabenzylation/alkylation of aryl pyridines using toluene/alkane derivatives as the coupling partners and ferrocene as an additive. While the ortho-benzylation/alkylation of aryl pyridines can be accomplished by employing tris(triphenylphosphine)ruthenium(II) dichloride as the catalyst. Various ortho- or meta-benzylated arenes have been selectively obtained. A mechanistic study revealed that ferrocene facilitated the formation of alkyl radicals and BNDHP greatly affected the regioslelectivity during the catalytic cycle. The diarylmethane moiety is present as a key structural unit in numerous biological compounds13. The most straightforward method for preparing various diarylmethane moieties is a cross dehydrogenative coupling (CDC) reaction employing toluene derivatives as the substrates14. Recently, the benzyl radical has been applied in various coupling reactions as the efficient coupling partners15. Inspired by these discoveries and Ackermann’s reports3a, we speculated the benzyl radical may be directly coupled with arylpyridine using a ruthenium catalyst. The

Scheme 1. Ruthenium-catalyzed C-H alkylation 2. RESULTS AND DISCUSSION With this hypothesis in mind, we initially explored plenty of additives in the direct benzylation of 2-phenylpyridine using [RuCl2(p-cymene)]2 as the catalyst, o-xylene as the solvent and DTBP as the oxidant at 130 °C for 24 h (Table1, entry 1). The ortho-benzylated product 4a was observed in 51% yield, along with recovered 1a. Several ligands were further screened (entry 24). Piv-Val-OH and MesCOOH as the additives only afforded the ortho-benzylated product 4a in good yield. To our surprise, when PPh3 was used, the ortho-benzylated 4a was obtained in 41% yield accompanied with 3a in 14% yield. Further screening the ruthenium precursor revealed that both ruthenium(III) chloride and triruthenium dodecacarbonyl provided the meta-benzylated 3a as the major product along with 4a in 80% yield and the ortho-benzylated product 4a in