4 -Methyl-2 -(quinolin-8-ylcarbamoyl)-biphenyl-4-carboxylic Acid Ethyl Ester

: In this short note communication, we report the synthesis of a novel amide 4 (cid:48) -methyl-2 (cid:48) -(quinolin-8-ylcarbamoyl)-biphenyl-4-carboxylic acid ethyl ester by the Ru-catalyzed C(sp 2 )-H bond arylation reaction. The catalytic C-H bond functionalization reaction was employed, amongst other reaction reagents and conditions, [RuCl 2 ( p -cymene)] 2 as a precatalyst and ( p -tol) 3 P as a ligand. The arylation product was characterized by various spectroscopic methods ( 1 H NMR, 13 C NMR, IR, GC-MS, and IR spectroscopy), and its composition was conﬁrmed by elemental analysis.


Introduction
Functionalization of C-H bonds has emerged as a powerful method for the construction of chemical bonds [1,2]. The strategy is centered on the functionalization of otherwise inert or nonreactive C-H bonds that are ubiquitous in nature. Therefore, C-H bond functionalization chemical science allows rapid access of target functional bonds or desired molecules from simple starting materials. Hence, it could reduce materials, reagents, conditions, and ultimately, the number of steps required to achieve target molecules using conventional methods, a demonstration of step economy. Given the abundance of C-H bonds in nature, functionalization science could result in a reduction of waste and a reduction of the emission of noxious substances into the environment. Therefore, functionalization of C-H bonds could be green and environmentally benign. Given the abundance of C-H bonds in molecules, controlling which C-H bond to be functionalized (or site-selectivity) remains a significant challenge for the scientific community. One approach is to control or circumvent the site-selectivity to use groups that can direct the functionalization of C-H bonds to occur at a specific site or position [3,4]. The essence of directing groups is the utilization of their Lewis basic properties toward the reaction with a Lewis acidic metal, by which the C-H bond functionalization is catalyzed. Lewis basic directing groups coordinate Lewis acidic metals, bringing them in proximity to C-H bonds to be functionalized. The regiocontrol provided by directing groups is determined by the thermodynamic stability of the reaction intermediate, cyclometalated complexes, or chelates [5]. The thermodynamic stability of an appropriately sized chelate or cyclometalated complex determines which C-H bond undergoes cleavage and thus C-H functionalization. The use of directing groups, via chelation assistance, is demonstrated by monodentate and bidentate directing groups via a mono-chelate or bis-chelate respectively [6][7][8].
C-H bond functionalization is typically catalyzed by transition metals with second row transition metals such as Pd [9,10], Rh [11,12], and Ru [13], which are established as metal catalysts for the reaction. The use of first row transition metals such as Ni [14,15], Fe [16], and Mn [17,18] is also established. The use of 8-aminoquinoline as a directing group in metal-catalyzed C-H bond functionalization is now well developed [7,8]. In 2013, Chatani et al. disclosed a pioneering Ru-catalyzed C(sp 2 )-H bond arylation using 8-aminoquionoline as a directing group [19]. In the reported work, [RuCl 2 (p-cymene)] 2 was used as a precatalyst and PPh 3 as a ligand. It is also reported that the latter was essential for the reaction as no reaction was observed without it [19]. In the continuation of our program [20][21][22][23] of the development of directed metal-catalyzed C-H bond functionalization, we wish to report herein the synthesis of a novel amide '4 -methyl-2 -(quinolin-8-ylcarbamoyl)-biphenyl-4-carboxylic acid ethyl ester' by the Ru-catalyzed C(sp 2 )-H bond arylation reaction. The functionalization method employed [RuCl 2 (p-cymene)] 2 as a precatalyst and (p-tol) 3 P as a ligand.

Results
The requisite starting amide, 3-methylbenzamide bearing 8-aminioquinoline as a directing group (1) was prepared according to literature procedures from the corresponding acid chloride [19,24]. The benzamide was then subjected to the Ru-catalyzed C-H bond arylation conditions. Thus, amide (1)  The Ru-catalyzed C(sp 2 )-H bond monoarylation successfully took place at the ortho position with respect to the amide, to afford the desired arylation product (3) in a decent 87% yield. No doublearylation product was observed. The aylation product (3) was then characterized by various spectroscopic methods ( 1 H NMR, 13 C NMR, GC-MS, and IR spectroscopy, supplementary materials). The elemental composition of the product was analyzed by elemental analysis.

Discussion
While the reported Ru-catalyzed C(sp 2 )-H arylation reaction by Chatani et al. employed [RuCl2(p-cymene)]2 as a precatalyst and PPh3 as a standard phosphine ligand, the present Rucatalyzed C(sp 2 )-H bond arylation reaction, reported herein (Scheme 1), employed (p-tol)3P as a ligand with [RuCl2(p-cymene)]2. This is a demonstration that substituted triphenylphosphines can also promote the reaction. The electron-rich phosphine ligand has proven to be successful and efficient in promoting the Ru-catalyzed arylation reaction presented. Given the fact that the arylation product (3) obtained was new, there was no direct comparison with literature reports given herein. However, Chatani et al. reported that the 3-mehylbenzamide bearing 8-aminoquinoline (1) underwent Ru-catalyzed C(sp2)-H bond arylation with bromobenzene using [RuCl2(p-cymene)]2 as a precatalyst and PPh3 as a ligand, to give the corresponding arylation product in a 74% yield [19]. A similar electron-deficient aryl bromide, methyl 4-bromobenzoate under Ru-catalyzed C-H arylation reaction with a 3-phenylbenzamide bearing 8-aminoquinoline, was also reported by Chatani et al. [19]. The arylation product was obtained in a 78% yield [19].

General Methods
All chemicals, reagents, and solvents were purchased from chemical companies (Sigma-Aldrich Chemie GmbH, Taufkirchen, Germany) and were used as received without prior purification. The Ru-catalyzed C(sp 2 )-H bond monoarylation successfully took place at the ortho position with respect to the amide, to afford the desired arylation product (3) in a decent 87% yield. No double-arylation product was observed. The aylation product (3) was then characterized by various spectroscopic methods ( 1 H NMR, 13 C NMR, GC-MS, and IR spectroscopy, Supplementary Materials). The elemental composition of the product was analyzed by elemental analysis.

Discussion
While the reported Ru-catalyzed C(sp 2 )-H arylation reaction by Chatani et al. employed [RuCl 2 (p-cymene)] 2 as a precatalyst and PPh 3 as a standard phosphine ligand, the present Ru-catalyzed C(sp 2 )-H bond arylation reaction, reported herein (Scheme 1), employed (p-tol) 3 P as a ligand with [RuCl 2 (p-cymene)] 2 . This is a demonstration that substituted triphenylphosphines can also promote the reaction. The electron-rich phosphine ligand has proven to be successful and efficient in promoting the Ru-catalyzed arylation reaction presented. Given the fact that the arylation product (3) obtained was new, there was no direct comparison with literature reports given herein. However, Chatani et al. reported that the 3-mehylbenzamide bearing 8-aminoquinoline (1) underwent Ru-catalyzed C(sp2)-H bond arylation with bromobenzene using [RuCl 2 (p-cymene)] 2 as a precatalyst and PPh 3 as a ligand, to give the corresponding arylation product in a 74% yield [19]. A similar electron-deficient aryl bromide, methyl 4-bromobenzoate under Ru-catalyzed C-H arylation reaction with a 3-phenylbenzamide bearing 8-aminoquinoline, was also reported by Chatani et al. [19]. The arylation product was obtained in a 78% yield [19].

General Methods
All chemicals, reagents, and solvents were purchased from chemical companies (Sigma-Aldrich Chemie GmbH, Taufkirchen, Germany) and were used as received without prior purification. Reactions that required dry conditions were performed in an inert atmosphere with Ar gas. Syringes and needles for the transfer of reagents were oven dried and cooled in a desiccator over silica gel before use. The reaction's progress was monitored by thin-layer chromatography (TLC) on glass plates pre-coated with Merck silica gel. TLC plates were examined under UV lamplight (UVGL-58 Handheld 254/365 nm). Büchi-USA rotary evaporators were used to evaporate solvents using appropriate temperatures. Flash column chromatography was performed using silica gel (Kieselgel) (70-230) mesh as an adsorbent. The purified products were characterized using NMR ( 1 H NMR, 13 C NMR), IR, mass spectra, and melting point analyses. Melting points were recorded on the GallenKamp-MPd350.bm2.5 melting point apparatus (Gallenkamp, Kent, U.K.). Attenuated total-reflectance IR spectra were recorded on pure samples on Agilent Technologies Cary 630 FTIR (Agilent, Santa Clara, CA, USA). 1 H NMR spectra were recorded in CDCl 3 on JEOL ECX-400 spectrometers (JEOL Ltd., Tokyo, Japan). 1 H NMR chemical shifts (δ) were assigned in parts per million (ppm) downfield using an internal standard trimethylsilane (TMS) and were referenced to CDCl 3 , δ = 7.24. Abbreviations s, d, t, q, quin, sept, and m refer to singlet, doublet, triplet, quartet, quintet, septet, and multiplet, respectively. Chemical shifts in 13
( 1 H NMR, 13 C NMR, GC-MS, and IR spectroscopy), and its composition was confirmed by elemental analysis measurements.

Supplementary Materials:
The following are available online, Figure S1: 1 H NMR of the title compound, Figure S2: 13 C NMR of the title compound, Figure S3: IR of the title compound, Figure S4: GC-MS of the title compound.