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Article

Non-C2-Symmetric Bis-Benzimidazolium Salt Applied in the Synthesis of Sterically Hindered Biaryls

by
Yen-Hsin Chen
,
Shu-Jyun Huang
,
Tung-Yu Hsu
,
Pei-Yu Hung
,
Ting-Rong Wei
,
Dong-Sheng Lee
* and
Ta-Jung Lu
Department of Chemistry, National Chung Hsing University, Taichung 40227, Taiwan
*
Author to whom correspondence should be addressed.
Molecules 2021, 26(21), 6703; https://doi.org/10.3390/molecules26216703
Submission received: 12 October 2021 / Revised: 27 October 2021 / Accepted: 29 October 2021 / Published: 5 November 2021
(This article belongs to the Special Issue Applications of Palladium-Catalyzed in Organic Chemistry)
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Abstract

:
A novel non-C2-symmetric bis-benzimidazolium salt derived from (±)-valinol has been prepared by a simple and straightforward process in good yield. The structure of bis-benzimidazolium salt provided a bulky steric group on the ethylene bridge; which facilitates the catalytic efficacy in the C(sp2)–C(sp2) formation. Its catalytic activity in Suzuki–Miyaura cross-coupling reaction of unactivated aryl chlorides has been found to have high efficacy in 1 mol% Pd loading. This protocol demonstrated the potential on the synthesis of sterically hindered biaryls.

Graphical Abstract

1. Introduction

Sterically hindered biaryls are present in many natural products and pharmaceuticals, such as vancomycin [1,2,3,4], steganacin [5], and michellamines B [6,7]. The Pd-catalyzed Suzuki–Miyaura cross-coupling reaction (SMC) is one of the most practical protocols for the construction of biaryls [8,9,10,11,12,13,14,15,16]. Numerous successful examples using a combination of phosphine ligands with palladium have been reported [9,10,12,13]. However, the drawbacks of the phosphine ligands are difficult preparation, air sensitivity, expensiveness, and toxicity. Hence, the development of Pd catalysts with phosphine-free ligands has been receiving great attention. Over the past three decades, the replacement of phosphine ligands with N-heterocyclic carbenes (NHCs) has been a good choice [8,11,15,16].
Aryl chlorides, which are less expensive and more diverse relative to aryl bromides and iodides, are noticeably challenging partners in SMC reaction due to their low C–Cl bond reactivity. The in situ-formed bis-NHC/Pd catalytic systems are easy to handle and provide two strong carbene–metal bonds, making them more stable than monodentate NHC/Pd species. In comparison to the broad study and application of palladium/bis-NHC systems in the SMC reaction of aryl bromides or activated chlorides [17,18,19,20,21,22,23,24,25,26,27,28,29,30,31], much less attention has been paid to unactivated aryl chlorides and the synthesis of sterically hindered biaryls. In 2014, a 1,2-cyclohexane-bridged bis-NHC palladium catalyst has been synthesized by Zhang and co-workers [26]. This catalyst was also applied in the Pd-catalyzed SMC reaction of 1-bromo-2-alkoxynaphthalene and 1-napthylboronic acid at 65 °C to afford 45–83% yield. Although the coupling between 1-chloro-2-methoxynaphthalene and 1-napthylboronic acid was also examined, a 52% yield was obtained in the presence of 3 mol% Pd loading. In 2018, Shi et al. reported the development of bis-NHC dipalladium complexes and their application in Suzuki–Miyaura cross-coupling reactions 1-bromonaphthalene with 1-naphthaleneboronic acid [28]. Moderate yields (32–52%) were obtained at 100 °C. In 2020, Zhang and Yu developed fine-tunable bis-NHC palladium catalysts [30]. These catalysts were also applied in the Pd-catalyzed SMC reaction between 1-bromo-2-alkoxynapthalene and 1-naphthylboronic acid at 40 °C in the presence of 2.5 mol% Pd loading to achieve 50–71% conversions. The grave challenges, sterically hindered aryl chlorides coupled with sterically hindered arylboronic acids with low Pd loading, still exist.
We recently reported an in situ-generated Pd(OAc)2/L·2HX catalyst for the Suzuki–Miyaura reaction of aryl bromides or aryl chlorides with arylboronic acids in good to excellent yields [32,33,34]. Motivated by these results we continued our efforts to develop an efficient in situ–generated Pd(OAc)2/L·2HX catalytic system to catalyze the synthesis of biaryls. Herein, we describe the preparation of a new non-C2-symmetric bis-benzimidazolium salt (Figure 1) and its application in the coupling between sterically hindered aryl chlorides and arylboronic acids.

2. Results

2.1. Synthesis and Characterization of the Bis-Benzimidazolium Salts 3

Chiral valinol is often used to prepare chiral ligands, such as oxazolines [35], which are employed in asymmetric catalysis with excellent efficiency. (±)-Valinol is chosen as the starting material because it has a non-C2-symmetric ethylene skeleton, which can be used as a linker of non-C2-symmetric bis-benzimidazolium salt. In addition, the isopropyl group on the ethylene bridge could act as a bulky steric group which will facilitate the reductive elimination step in the catalytic cycle. The bis-benzimidazole 2 was synthesized by a simple and straightforward process from valinol. The bis-benzimidazolium salt 1 was obtained by the combination of 2 and two equivalents of benzyl bromide in acetonitrile at reflux in 91% yield (Scheme 1). The new salt was air- and moisture-stable both in the solid state and in solution. It was characterized by 1H- and 13C-NMR. The two benzimidazolium proton signals exhibit as sharp singlets at δ 12.51 and 12.25 ppm in the 1H-NMR spectrum, and two corresponding carbon resonances appear as a typical singlet in the 1H-decoupled mode at δ 143.7 and 142.3 ppm in the 13C-NMR spectrum.

2.2. The Suzuki–Miyaura Cross-Coupling Reaction

Continuing our previous studies on the application of in situ-formed catalyst to SMC reaction [32,33,34], the SMC reaction of 4-chloroanisole 3a with phenylboronic acid 4a with 1.0 mol% Pd loading was chosen to study the optimized reaction conditions (Table 1). Solvents were evaluated firstly (entries 1–5), and 1,4-dioxane showed that 5aa had a good GC yield (entry 1, 87%). Secondly, the Pd/1 ratio from 1:0.5 to 1:3 (entries 1 and 6–8) were examined, and the ratio of 1:3 was found to give the highest yield (87%) (entry 1). The base is usually an important factor in this reaction (entries 1 and 9–15). Among commonly used bases, K3PO4·H2O was found to be the best base. Finally, various metal sources were investigated in SMC reaction (entries 1 and 16–21), and Pd(dba)2 was the metal source of choice for this reaction (entry 21, 83% isolated yield). A control reaction was also performed in the absence of bis-benzimidazolium salt 1 (entry 22), which showed that no starting material was converted to biaryl 5aa.
After the optimized reaction conditions were secured, the scope of SMC reaction of aryl chlorides was studied (Table 2). Unactivated aryl chlorides 3a and 3b were successfully coupled with phenylboronic acid in the presence of 1.0 mol% Pd loading with moderate to good yields (entries 1 and 2). Functionalized aryl chlorides were successfully coupled with phenylboronic acid with good to excellent yields (entries 3–6, 87–99%) except 5fa (entry 7, 63%). o-Monosubstituted aryl chlorides could couple with phenylboronic acid to achieve corresponding biaryls in 66–85% yields (entries 8–11). Our results clearly show that the catalytic system formed by this non-C2-symmetric bis-benzimidazolium salt, possessing high steric hindrance, and the Pd source demonstrated excellent catalytic capacity. It catalyzes the C(sp2)–C(sp2) bond formation between deacitvated aryl chlorides and phenylboronic acid under low Pd loading (1 mol%). In addition, this catalyst has superior tolerance to a wide range of functional groups.
In order to further extend the capacity of the catalytic system, the synthesis of sterically hindered biaryls was scrutinized (Table 3). Di-ortho-substituted aryl chlorides, such as 2-chloro-1-methyl-3-nitrobenzene, 2-chloro-3-methoxy benzaldehyde, and 2-chloro-1,3-dimethylbenzene, were coupled with phenylboronic acid to afford the corresponding products in 46–60% yields (entries 1–3). Di-ortho-substituted biaryls (5hb, 5ib, 5pb, and 5kb) were derived from 1-naphthylboronic acid and aryl chlorides bearing o-functional groups, such as ketone, ester, and aldehyde in 20–92% yields (entries 4–7). Most of the tri-ortho-substituted biaryls (5ob, 5od, 5nb, 5ne, and 5nf) could be successfully generated in the presence of 1 mol% 1/Pd(OAc)2 with 50–85% yields (entries 8–12). Unfortunately, the product 5nc bearing tetra-ortho-substituents proved difficult to obtain (entry 13). So far, we have successfully demonstrated the synthesis of tri-ortho-substituted biaryls in the presence of 1 mol% in situ-formed a 1/Pd(OAc)2 catalytic system.

3. Materials and Methods

3.1. General Methods

Unless otherwise stated, commercially available materials were received from Aldrich and Acros (New Taipei City, Taiwan) and used without further purification. Acetonitrile was distilled over calcium hydride prior to its use. Toluene, 1,4-dioxane, and t-BuOH were distilled over sodium prior to its use. Reactions were monitored using pre-coated silica gel 60 (F-254) plates. The products were purified by column chromatography (silica gel, 0.040–0.063 μm), eluting with n-hexane/ethyl acetate. 1H- and 13C-NMR spectra were recorded using an Agilent Mercury 400 spectrometer (Agilent Technologies, Inc., Santa Clara, CA, USA), with the J-values given in Hz. Chemical shifts (δ) were referenced to CDCl3 (δ = 7.26 ppm) in the 1H-NMR spectra and CDCl3 (δ = 77.0 ppm) in the 13C-NMR spectra. Copies of 1H- and 13C-NMR spectra of all compounds are provided as Supplementary Materials. Melting points were determined using a Thermo 1001D digital melting point apparatus and are uncorrected. GC-FID was recorded using a Shimadzu GC-2014 spectrometer (Shimadzu Co., Kyoto, Japan) equipped with a capillary column (SPB®-5, 60 m × 0.25 mm × 0.25 μm). The conversion yields, GC yields, and ratios were determined using undecane as an internal standard. High-resolution mass spectra were recorded using a Finnigan/Thermo Quest MAT 95XL mass spectrometer (Finnigan MAT LCQ, San Jose, CA, USA) via either atmospheric-pressure chemical ionization (APCI) or electrospray ionization (ESI) methods.

3.2. Experimental Procedures and Spectral Data

3.2.1. Synthesis of Non-C2-Symmetric Bis-Benzimidazolium Salt 1

Procedure for 3-methyl-2-(2-nitrophenylamino)-butan-1-ol (S1) [36]. To a solution of 1-fluoro-2-nitrobenzene (1.10 equiv), valinol (0.10 g 0.97 mmol) and potassium carbonate (1.10 equiv) in DMSO (10 mL) was stirred for 2 h at 60 °C. The reaction mixture was cooled to room temperature and diluted with water (20 mL). The mixture was stirred for several minutes, then extracted with EtOAc (80 mL × 1). The organic layer was washed with saturated NaCl(aq) (20 mL × 3), dried over Na2SO4, and then filtered. The filtrate was concentrated under reduced pressure to afford crude product. The residual was purified by chromatography to obtain S1 in a 66% yield (0.14 g). 1H-NMR (CDCl3, 400 MHz): δ 8.21 (br, 1H, NH), 8.17 (dd, J = 8.0, 1.2 Hz, 1H), 7.41 (t, J = 8.0 Hz, 1H), 6.99 (d, J = 8.0 Hz, 1H), 6.63 (t, J = 8.0 Hz, 1H), 3.85–3.81 (m, 1H), 3.77–3.72 (m, 1H), 3.64–3.60 (m, 1H), 2.06 (octect, J = 6.8 Hz, 1H), 1.66 (br, 1H, OH), 1.03 (d, J = 6.8 Hz, 3H), 1.02 (d, J = 6.8 Hz, 3H); 13C-NMR (CDCl3, 100 MHz): δ 146.1, 136.2, 131.9, 127.0, 115.3, 114.4, 63.1, 59.8, 29.7, 19.4, 18.3. Spectroscopic data was consistent with the literature [36].
Procedure for 2-[(2-aminophenyl)amino]-3-methylbutan-1-ol (S2) [36]. Saturated NH4Cl(aq) (25 mL) was added to a mixture of Fe powder (10 equiv) and compound S1 (0.12 g, 0.53 mmol) in EtOH (25 mL). After refluxing for 2 h, the resulting mixture was filtered. The filtrate was concentrated under reduced pressure. The residual was treated with H2O (20 mL) and EtOAc (30 mL). The aqueous layer was extracted with EtOAc (30 mL×3). The combined organic layers were dried over anhydrous Na2SO4 and then filtered. The filtrate was concentrated to afford black solid S2 in 96% yield (0.20 g), which was subjected to the next reaction without any purification. 1H-NMR (CDCl3, 400 MHz): δ 6.81 (t, J = 7.6 Hz, 1H), 6.75 (d, J = 7.6 Hz, 1H), 6.72 (d, J = 7.6 Hz, 1H), 6.68 (t, J = 7.6 Hz, 1H), 3.78 (dd, J = 10.8, 4.0 Hz, 1H), 3.59 (dd, J = 10.8, 6.4 Hz, 1H), 3.37 (br, 2H, NH2), 3.31 (dd, J = 10.8, 6.4 Hz 1H), 1.97 (octect, J = 6.8 Hz, 1H), 1.12 (d, J = 6.8 Hz, 3H), 0.97 (d, J = 6.8 Hz, 3H); 13C-NMR (CDCl3, 100 MHz): δ 137.6, 134.1, 121.0, 118.7, 117.6, 113.3, 61.9, 60.4, 29.6, 19.3, 18.8. Spectroscopic data was consistent with the literature [36].
Procedure for 2-(1H-benzo[d]imidazol-1-yl-3-methylbutan-1-ol (S3) [36]. To a mixture of S2 (0.20 g, 1.03 mmol), triethyl orthoformate (3.0 equiv) and sulfamic acid (0.05 equiv) in MeOH (20 mL) was stirred for 16 h at room temperature. After removal of MeOH, the resulting solution was treated with H2O (20 mL) and EtOAc (30 mL). The aqueous layer was extracted with EtOAc (30 mL × 3). The combined organic layers were dried over Na2SO4 and then filtered. The filtrate was concentrated on a rotary evaporator. The residual was purified by column chromatography to obtain S3 in a 97% yield (0.20 g). 1H-NMR (CDCl3, 400 MHz): δ 7.93 (s, 1H), 7.65 (d, J = 7.6 Hz, 1H), 7.38 (d, J = 7.6 Hz, 1H), 7.24 (t, J = 7.6 Hz, 1H), 7.19 (t, J = 7.6 Hz, 1H), 4.17 (dd, J = 12.4, 7.6 Hz, 1H), 4.04–3.99 (m, 2H), 2.47–2.41 (m, 1H), 1.15 (d, J = 6.8 Hz, 3H), 0.76 (d, J = 6.8 Hz, 3H); 13C-NMR (CDCl3, 100 MHz): δ 141.9, 133.8, 122.7, 122.1, 119.7, 110.1, 65.2, 62.0, 29.3, 20.2, 19.7. Spectroscopic data was consistent with the literature [36].
Procedure for 2-(1H-benzo[d]imidazol-1-yl)-3-methylbutyl 4-methyl benzenesulfonate (S4). To a solution of S3 (1.00 mmol) in pyridine (2 mL) was added p-toluenesulfonyl chloride (3.00 mmol) in one portion at 0 °C. The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with EtOAc (30 mL) and then washed with saturated sodium bicarbonate (10 mL) and brine (10 mL). The organic layer was dried over Na2SO4 and filtered. The filtrate was concentrated on a rotary evaporator. The residual was purified by column chromatography to obtain S4 in an 82% yield (0.72 g). Mp = 123–125 °C; 1H-NMR (CDCl3, 400 MHz): δ 7.82 (s, 1H), 7.75 (d, J = 8.0 Hz, 1H), 7.43 (d, J = 8.0 Hz, 1H), 7.26–7.17 (m, 3H), 7.07 (d, J = 8.0 Hz, 2H), 4.45 (dd, J = 10.8, 7.6 Hz, 1H), 4.36 (dd, J = 10.8, 3.2 Hz, 1H), 4.15–4.09 (m, 1H), 2.47–2.41 (m, 1H), 2.33 (s, 3H), 1.13 (d, J = 6.8 Hz, 3H), 0.74 (d, J = 6.8 Hz, 3H); 13C-NMR (CDCl3, 100 MHz): δ 145.1, 143.7, 141.9, 133.1, 131.5, 129.8, 127.4, 122.9, 122.2, 120.6, 109.8, 68.3, 61.8, 29.2, 21.6, 19.9, 19.5; MS–ESI (m/z) (relative intensity) 359.1 (M + H+, 100); HRMS–ESI (m/z) [M + H+]: calcd. for C19H23N2O3S: 359.1424, found: 359.1430.
Procedure for 1,1′-(3-methylbutane-1,2-diyl)bis(1H-benzo[d]imidazole) (2). The flask was charged with benzimidazole (1.10 equiv), KOtBu (2.20 equiv). The solution of compound S4 (0.22 g, 0.61 mmol) in DMF (6 mL) was added into the flask at room temperature at 0.5 mL/h. The reaction mixture was stirred at room temperature overnight and then treated with H2O (100 mL). The reaction mixture was extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine, dried over Na2SO4, and filtered. The filtrate was concentrated on a rotary evaporator. The residual was purified by column chromatography to afford 2 (0.13 g, 68% yield). Mp = 190–195 °C; 1H-NMR (CDCl3, 400 MHz): δ 7.78 (d, J = 8.0 Hz, 1H), 7.77–7.13 (m, 1H), 7.55 (s, 1H), 7.26–7.13 (m, 7H), 4.80 (dd, J = 14.8, 3.6 Hz, 1H), 4.65 (dd, J = 14.8, 10.0 Hz, 1H), 4.27 (ddd, J = 14.8, 10.0, 3.6 Hz, 1H), 2.62–2.54 (m, 1H), 1.37 (d, J = 6.8 Hz, 3H), 0.85 (d, J = 6.8 Hz, 3H); 13C-NMR (CDCl3, 100 MHz): δ 143.0, 142.6, 141.8, 141.3, 132.3, 132.1, 122.4, 121.7, 121.6, 121.4, 119.7, 119.5, 109.2, 108.2, 62.5, 45.4, 29.5, 19.6, 18.6; MS–ESI (m/z) (relative intensity) 305.1 (M + H+, 100); HRMS–ESI (m/z) [M + H+]: calcd. for C19H21N4: 305.1761, found: 305.1770.
Procedure for 1,1′-(3-methylbutane-1,2-diyl)bis(3-benzyl-1H-benzo[d]imidazol-3-ium) dibromide (1). A mixture of 1,1′-(3-methylbutane-1,2-diyl)bis(1H-benzo[d]imidazole) (2) (0.7 g, 2.3 mmol) and benzyl bromide (5.1 mmol) was refluxed in acetonitrile (24.0 mL) for 13 h. The resulting mixture was filtered, and the residue was the bis-benzimidazolium salt 1 (1.3 g, 91%) as a white solid. 1H-NMR (CDCl3, 400 MHz): δ 12.51 (s, 1H), 12.25 (s, 1H), 8.92–8.88 (m, 1H), 8.80–8.78 (m, 1H), 7.49–7.20 (m, 16H,), 6.53 (s, 1H), 6.05–5.99 (m, 1H), 5.70–5.51 (m, 4H), 3.00–2.92 (m, 1H), 1.42 (d, J = 6.4 Hz, 3H), 0.97 (d, J = 6.8 Hz, 3H); 13C-NMR (CDCl3, 100 MHz): δ 143.7, 142.3, 132.0, 132.0, 129.8, 129.7, 129.4, 128.3, 128.2, 128.0, 127.8, 127.5, 127.4, 115.2, 114.9, 112.8, 64.7, 51.7, 49.3, 32.5, 19.8, 19.1; MS–ESI (m/z) (relative intensity) 243.4 (79), 395.4 (68), 485.4 (61), 565.2 (M + H+, 100), 567.3 (89); HRMS–ESI (m/z) [M−Br−] calcd. for C33H34N4Br: 565.1961, found 565.1944.

3.2.2. General Procedures for Suzuki–Miyaura Cross-Coupling Reactions under N2

All manipulations were carried out under nitrogen using dried solvent. Pd(dba)2 (1 mol%), salt 1 (3 mol%) and 1,4-dioxane (3 mL), aryl chloride 3 (1.0 mmol), arylboronic acid 4 (1.5 mmol), and K3PO4·H2O (3.0 mmol) were charged to the Schlenk tube. After stirring for 24 h at 110 °C, the reaction was quenched by water (3.0 mL). The aqueous layer was extracted with EtOAc (3.0 mL × 3). The combined organic layers were dried over anhydrous Na2SO4 and then filtered. The solvent was evaporated under reduced pressure, and the corresponding product was purified by chromatography.
4-Methoxybiphenyl (5aa) [33]. 1H-NMR (CDCl3, 400 MHz): δ 7.57–7.51 (m, 4H), 7.42 (t, J = 7.6 Hz, 2H), 7.30 (t, J = 7.2 Hz, 1H), 7.98 (d, J = 8.8 Hz, 2H), 3.86 (s, 1H); 13C-NMR (CDCl3, 100 MHz): δ 159.1, 140.8, 133.7, 128.7, 128.1, 126.7, 126.6, 114.1, 55.3.
4-Methylbiphenyl (5ba) [34]. 1H-NMR (CDCl3, 400 MHz): δ 7.58 (d, J = 7.8 Hz, 2H), 7.50 (d, J = 8.0 Hz, 2H), 7.37 (t, J = 7.6 Hz, 2H), 7.32 (t, J = 7.6 Hz, 1H), 7.25 (d, J = 7.6 Hz, 2H), 2.40 (s, 1H); 13C-NMR (CDCl3, 100 MHz): δ 141.1, 138.3, 137.0, 129.5, 128.7, 127.0, 21.1.
4-Acetylbiphenyl (5ca) [33]. 1H-NMR (CDCl3, 400 MHz): δ 8.04 (d, J = 8.8 Hz, 2H), 7.69 (d, J = 8.8 Hz, 2H), 7.63 (d, J = 7.2 Hz, 2H), 7.48 (t, J = 7.2 Hz, 2H), 7.40 (t, J = 7.2 Hz, 1H), 2.65(s, 3H); 13C-NMR (CDCl3, 100 MHz): δ 197.7, 145.7, 139.8, 135.8, 128.9, 128.9, 128.2, 127.2, 127.2, 26.6.
4′-Phenylpropiophenone (5da) [33]. 1H-NMR (CDCl3, 400 MHz): δ 8.04 (d, J = 8.8 Hz, 2H), 7.69 (d, J = 8.8 Hz, 2H), 7.63 (d, J = 7.2 Hz, 2H), 7.47 (t, J = 7.2 Hz, 2H), 7.40 (t, J = 7.2 Hz, 1H), 3.45 (q, J = 7.2 Hz, 1H), 1.26 (t, J = 7.2 Hz, 3H); 13C-NMR (CDCl3, 100 MHz): δ 200.4, 145.5, 139.9, 135.6, 128.9, 128.5, 128.1, 127.23, 127.19, 31.8, 8.3.
4-Nitrobiphenyl (5ea) [34]. 1H-NMR (CDCl3, 400 MHz): δ 8.30 (d, J = 8.8 Hz, 2H), 7.74 (d, J = 8.8 Hz, 2H), 7.63 (d, J = 6.8 Hz, 2H), 7.52–7.45 (m, 3H); 13C-NMR (CDCl3, 100 MHz): δ 147.5, 147.0, 138.7, 129.1, 128.9, 127.7, 127.3, 124.0.
4-Cyanobiphenyl (5fa) [34]. 1H-NMR (CDCl3, 400 MHz): δ 7.73 (d, J = 8.8 Hz, 2H), 7.69 (d, J = 8.8 Hz, 2H), 7.59 (d, J = 7.2 Hz, 2H), 7.49 (t, J = 8.0 Hz, 2H), 7.43 (t, J = 7.2 Hz, 1H); 13C-NMR (CDCl3, 100 MHz): δ 145.6, 139.1, 132.5, 129.1, 128.6, 127.7, 127.2, 118.9, 110.9.
[1,1′-Biphenyl]-4-carbaldehyde (5ga) [33]. 1H-NMR (CDCl3, 400 MHz): δ 10.06 (s, 1H), 7.96 (d, J = 8.0 Hz, 2H), 7.76 (d, J = 8.4 Hz, 2H), 7.64 (d, J = 7.2 Hz, 2H), 7.49 (t, J = 7.2 Hz, 2H), 7.42 (t, J = 7.2 Hz, 1H); 13C-NMR (CDCl3, 100 MHz): δ 191.9, 147.2, 139.7, 135.2, 130.3, 129.0, 128.5, 127.7, 127.4.
2-Acetylbiphenyl (5ha) [34]. 1H-NMR (CDCl3, 400 MHz): δ 7.57–7.53 (m, 1H), 7.52–7.49 (m, 1H), 7.46–7.38 (m, 2H), 7.36–7.34 (m, 5H), 2.01 (s, 3H); 13C-NMR (CDCl3, 100 MHz): δ 204.9, 140.9, 140.7, 140.5, 130.7, 130.2, 128.8, 128.7, 127.9, 127.4, 30.4.
Methyl [1,1′-biphenyl]-2-carboxylate (5ia) [37]. 1H-NMR (CDCl3, 400 MHz): δ 7.83 (d, J = 8.0 Hz, 1H), 7.55–7.3 (m, 1H), 7.39–7.31 (m, 7H), 3.63 (s, 3H); 13C-NMR (CDCl3, 100 MHz): δ 169.1, 142.5, 141.1, 131.2, 130.9, 130.7, 129.8, 128.3, 128.0, 127.2, 127.1, 51.9.
2-Nitrobiphenyl (5ja) [34]. 1H-NMR (CDCl3, 400 MHz): δ 7.86 (d, J = 8.0 Hz, 1H) 7.62 (t, J = 7.2 Hz 1H), 7.51–7.40 (m, 5H), 7.34–7.32 (m, 2H); 13C-NMR (CDCl3, 100 MHz): δ 149.1, 137.2, 136.1, 132.1, 131.8, 128.5, 128.0, 127.7, 123.9.
2-Methyl-1,1′-biphenyl (5ka) [34]. 1H-NMR (CDCl3, 400 MHz): δ 7.42–7.39 (m, 2H), 7.36–7.31 (m, 3H), 7.27–7.26 (m, 1H), 7.25–7.23 (m, 3H), 2.28, (s, 1H); 13C-NMR (CDCl3, 100 MHz): δ 141.9, 135.2, 130.2, 129.7, 129.1, 128.0, 127.2, 126.7, 125.7, 20.4.
2-Methyl-6-nitro-1,1′-biphenyl (5ma) [38]. 1H-NMR (CDCl3, 400 MHz): δ 7.66 (d, J = 8.8 Hz, 1H), 7.49 (d, J = 7.6 Hz, 1H) 7.45–7.36 (m, 4H), 7.19 (d, J = 7.2 Hz, 2H), 2.14 (s, 3H); 13C-NMR (CDCl3, 100 MHz): δ 150.4, 139.1, 136.0, 135.3, 133.7, 128.5, 128.4, 127.9, 127.8, 121.0, 20.6.
6-Methoxy-[1,1′-biphenyl]-2-carbaldehyde (5na) [39]. 1H-NMR (CDCl3, 400 MHz): δ 9.74 (s, 1H), 7.63 (d, J = 7.6 Hz,1H), 7.48–7.42 (m, 4H), 7.33 (d, J = 6.4 Hz, 2H), 7.20 (d, J = 8.4 Hz, 1H), 3.79 (s, 1H); 13C-NMR (CDCl3, 100 MHz): δ 157.0, 135.4, 134.9, 133.1, 131.0, 128.7, 128.0, 127.9, 119.1, 115.9, 56.0.
2,6-Dimethyl-1,1′-biphenyl (5oa) [33]. 1H-NMR (CDCl3, 400 MHz): δ 7.43 (t, J = 7.4 Hz, 2H), 7.35 (d, J = 7.4 Hz, 1H), 7.18–7.11 (m, 5H), 2.04 (s, 6H); 13C-NMR (100 MHz, CDCl3): δ 141.8, 141.1, 136.0, 129.0, 128.4, 127.2, 127.0, 126.6, 20.8.
1-(2-(Naphthalen-1-yl)phenyl)ethan-1-one (5hb) [40]. 1H-NMR (CDCl3, 400 MHz): δ 7.92–7.89 (m, 2H), 7.75 (d, J = 6.8 Hz, 1H), 7.62 (d, J = 8.4 Hz, 1H), 7.60–7.49 (m, 4H), 7.43 (t, J = 7.6 Hz, 2H), 7.34 (d, J = 6.8 Hz, 1H), 1.79 (s, 3H); 13C-NMR (CDCl3, 100 MHz): δ 203.0, 141.2, 139.0, 138.6, 133.5, 131.8, 131.6, 130.8, 128.3, 128.3, 128.2, 127.7, 127.3, 126.5, 126.0, 125.6, 125.3.
Methyl 2-(naphthalen-1-yl)benzoate (5ib) [41]. 1H-NMR (CDCl3, 400 MHz): δ 8.03 (d, J = 7.6 Hz, 1H), 7.90–7.85 (m, 2H), 7.61 (t, J = 7.2 Hz, 1H), 7.54–7.31 (m, 7H), 3.36 (s, 3H,); 13C-NMR (CDCl3, 100 MHz): δ 167.9, 141.3, 139.6, 133.2, 132.0, 131.9, 131.6, 131.5, 130.0, 128.2), 127.5, 126.0, 125.9, 125.6, 125.5, 125.1, 51.7.
2-(Naphthalen-1-yl)benzaldehyde (5pb) [42]. 1H-NMR (CDCl3, 400 MHz): δ 79.63 (s, 1H), 8.12 (d, J = 7.6 Hz, 1H), 7.96–7.93 (m, 2H), 7.70 (t, J = 7.2 Hz, 1H), 7.61–7.41 (m, 7H); 13C-NMR (CDCl3, 100 MHz): δ 191.9, 144.1, 135.3, 134.7, 133.5, 133.3, 132.6, 131.6, 128.5, 128.3, 128.1, 127.0 (C6), 126.7, 126.1, 125.7, 124.9.
1-(o-Tolyl)naphthalene (5kb) [42]. 1H-NMR (CDCl3, 400 MHz): δ 7.91 (d, J = 8.4 Hz, 1H), 7.87 (d, J = 8.4 Hz, 1H) 7.55–7.51 (m, 1H), 7.50–7.45 (m, 2H), 7.40–7.33 (m, 5H), 7.32–7.28 (m, 1H), 2.03 (s, 3H); 13C-NMR (CDCl3, 100 MHz): δ 140.2, 139.8, 136.8, 133.5, 132.0, 130.3, 129.8, 128.2, 127.5, 127.4, 126.6, 126.1, 125.9, 125.7, 125.5, 125.4, 20.0.
1-(2,6-Dimethylphenyl)naphthalene (5ob) [43]. 1H-NMR (CDCl3, 400 MHz): δ 7.90 (d, J = 8.4 Hz, 1H), 7.86 (d, J = 8.4 Hz, 1H), 7.56–7.52 (m, 1H), 7.49–7.45 (m, 1H), 7.35–7.33 (m, 2H), 7.28–7.26 (m, 1H), 7.26–7.17 (m, 3H), 1.90 (s, 6H); 13C-NMR (CDCl3, 100 MHz): δ 139.6, 138.7, 137.0, 133.7, 131.7, 128.3, 127.3, 127.2, 127.2, 126.4, 126.0, 125.8, 125.7, 125.4, 20.4.
2,2′,6-Trimethyl-1,1′-biphenyl (5od) (=5kc) [44]. 1H-NMR (CDCl3, 400 MHz): δ 7.30–7.26 (m, 3H), 7.26–7.15 (m, 3H), 7.12–7.10 (m, 1H), 1.97 (s, 3H), 1.95 (s, 6H); 13C-NMR (CDCl3, 100 MHz): δ 140.5, 135.8, 135.6, 129.9, 129.8, 128.8, 127.2, 127.0, 126.9, 126.0.
3-Methoxy-2-(naphthalen-1-yl)benzaldehyde (5nb). 1H-NMR (CDCl3, 400 MHz): δ 9.47 (s, 1H), 7.95–7.91 (m, 2H), 7.71 (d, J = 8.8 Hz, 1H), 7.56 (t, J = 8.0 Hz, 2H), 7.51–7.48 (m, 1H), 7.41–7.38 (m, 3H), 7.28–7.26 (m, 1H), 3.70 (s, 3H); 13C-NMR (CDCl3, 100 MHz): δ 192.2, 157.8, 136.1, 133.3, 133.2, 132.9, 131.3, 129.2, 128.8, 128.5, 128.3, 126.4, 126.0, 125.9, 125.0, 118.9, 116.0, 56.0; MS–ESI (m/z) (relative intensity) 245.2 (70), 263.2 (M + H+, 100); HRMS–ESI (m/z) [M + H+] calcd. for C18H15ON2: 263.1067, found 263.1064.
4′,6-Dimethoxy-2′-methyl-[1,1′-biphenyl]-2-carbaldehyde (5ne). 1H-NMR (CDCl3, 400 MHz): δ 9.64 (s, 1H), 7.61 (d, J = 7.6 Hz, 1H), 7.45 (t, J = 8.4 Hz, 1H), 7.18 (d, J = 8.0 Hz, 1H), 7.04 (d, J = 8.4 Hz, 1H), 6.86 (s, 1H), 6.81 (d, J = 8.0 Hz, 1H), 3.85 (s, 3H), 3.79 (s, 3H), 2.05 (s, 3H), 13C-NMR (CDCl3, 100 MHz): δ 192.7, 159.4, 157.3, 138.7, 135.6, 134.4, 131.9, 128.6, 125.1, 118.9, 115.8, 115.4, 110.8, 55.9, 55.1, 20.3; MS–ESI (m/z) (relative intensity) 279.2 (M + Na+, 100); HRMS–ESI (m/z) [M + Na]+ calcd. for C16H16O3Na: 279.0992, found 279.0986.
2′-Formyl-6′-methoxy-2-methyl-[1,1′-biphenyl]-4-carbonitrile (5nf). 1H-NMR (CDCl3, 400 MHz): δ 9.61 (s, 1H) 7.65–7.61 (m, 2H), 7.57–7.51 (m, 2H), 7.25–7.24 (m, 1H), 7.23–7.22 (m, 1H), 3.78 (s, 3H), 2.09 (s, 3H); 13C-NMR (CDCl3, 100 MHz): δ 191.1, 156.6, 140.3, 139.0, 134.7, 133.2, 131.9, 131.4, 129.8, 129.2, 120.0, 118.8, 116.1, 112.1, 56.0, 19.8; MS–APCI (m/z) (relative intensity) 252.2 (M + H+, 100); HRMS–APCI (m/z) [M + H+] calcd. for C16H14O2N: 252.1019, found 252.1017.

4. Conclusions

In conclusion, we have successfully prepared a new non-C2-symmetric bis-benzimidazolium salt 1 from racemic valinol in 6 steps in good yields. The high catalytic ability of this in situ-generated Pd catalyst allowed it to expedite the Pd-catalyzed tri-ortho-substituted biaryl syntheses under 1 mol% Pd catalyst loading and 110 °C in 50–85% yields. In addition, this catalytic system provided, in many cases, better results than the present bis-NHC/Pd system for Suzuki–Miyaura cross-coupling of unactivated aryl chlorides and excellent functional group tolerance, e.g., methoxy, ketone, ester, and aldehyde groups. This method provides an alternative synthetic pathway for constructing sterically hindered biaryls.

Supplementary Materials

The following are available online, 1H- and 13C-NMR spectra are available online.

Author Contributions

Conceptualization, D.-S.L.; methodology, Y.-H.C. and S.-J.H.; validation, Y.-H.C., S.-J.H., T.-Y.H., P.-Y.H. and T.-R.W.; formal analysis, Y.-H.C. and S.-J.H.; investigation, Y.-H.C., S.-J.H., T.-Y.H., P.-Y.H. and T.-R.W.; data curation, Y.-H.C., T.-Y.H., P.-Y.H. and T.-R.W.; writing—original draft preparation, D.-S.L.; writing—review and editing, T.-J.L.; supervision, D.-S.L.; project administration, D.-S.L.; funding acquisition, D.-S.L. All authors have read and agreed to the published version of the manuscript.

Funding

This research was funded by the Ministry of Science and Technology of the Republic of China, grant number 109WFA0510134.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Data are contained within the article and the Supplementary Materials.

Acknowledgments

We thank to National Center for High-performance Computing (NCHC) for providing computational and storage resources, the Instrument Center of National Chung Hsing University for help with measurements of the high-resolution mass spectrometer, and Dao-Wen Luo for help with the X-ray analysis.

Conflicts of Interest

The authors declare no conflict of interest.

Sample Availability

Samples of the compounds are not available from the authors.

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Molecules 26 06703 g001 550
Figure 1. Structures of new non-C2-symmetric bis-benzimidazolium salt 1.
Figure 1. Structures of new non-C2-symmetric bis-benzimidazolium salt 1.
Molecules 26 06703 g001
Molecules 26 06703 sch001 550
Scheme 1. The synthesis of amino alcohol-derived bis-benzimidazolium salt 1.
Scheme 1. The synthesis of amino alcohol-derived bis-benzimidazolium salt 1.
Molecules 26 06703 sch001
Table
Table 1. Screening the optimized reaction conditions of in situ-formed catalyst 1.
Table 1. Screening the optimized reaction conditions of in situ-formed catalyst 1.
Molecules 26 06703 i001
EntryPd Source1 (mol%)SolventBase3a (%)25aa (%) 2
1Pd(OAc)23.01,4-DioxaneK3PO4·H2O1187
2Pd(OAc)23.0TolueneK3PO4·H2O7717
3Pd(OAc)23.0CH3CNK3PO4·H2O866
4Pd(OAc)23.0t-BuOHK3PO4·H2O7017
5Pd(OAc)23.0tBuOH/H2O 3K3PO4·H2O933
6Pd(OAc)22.01,4-DioxaneK3PO4·H2O4253
7Pd(OAc)21.01,4-DioxaneK3PO4·H2O7424
8Pd(OAc)20.51,4-DioxaneK3PO4·H2O7918
9Pd(OAc)23.01,4-DioxaneKOtBu804
10Pd(OAc)23.01,4-DioxaneKOAc990
11Pd(OAc)23.01,4-DioxaneK3PO46532
12Pd(OAc)23.01,4-DioxaneK2CO38214
13Pd(OAc)23.01,4-DioxaneCs2CO38710
14Pd(OAc)23.01,4-DioxaneCsF8018
15Pd(OAc)23.01,4-DioxaneKF8117
16PdCl23.01,4-DioxaneK3PO4·H2O6631
17PdCl2(PPh3)23.01,4-DioxaneK3PO4·H2O945
18PdCl2(CH3CN)23.01,4-DioxaneK3PO4·H2O2866
19[PdCl(C3H5)]23.01,4-DioxaneK3PO4·H2O2074
20Pd2(dba)33.01,4-DioxaneK3PO4·H2O488
21Pd(dba)23.01,4-DioxaneK3PO4·H2O390 (83) 4
22Pd(dba)2–1,4-DioxaneK3PO4·H2O>990
1 All reactions were carried out on a 1.0 mmol scale under a N2 atmosphere. 2 Determined by GC-FID using n-undecane as an internal standard. 3 t-BuOH/H2O = 9/1. 4 Isolated yield in parentheses.
Table
Table 2. In situ-generated catalyst catalyzed Suzuki–Miyaura cross-coupling reaction of aryl chlorides 1.
Table 2. In situ-generated catalyst catalyzed Suzuki–Miyaura cross-coupling reaction of aryl chlorides 1.
Molecules 26 06703 i002
EntryArCl 3Product 5Yield (%)2
1 Molecules 26 06703 i003 Molecules 26 06703 i00483
2 Molecules 26 06703 i005 Molecules 26 06703 i00667
3 Molecules 26 06703 i007 Molecules 26 06703 i00895
4 Molecules 26 06703 i009 Molecules 26 06703 i01099
5 Molecules 26 06703 i011 Molecules 26 06703 i01291
6 Molecules 26 06703 i013 Molecules 26 06703 i01487
7 Molecules 26 06703 i015 Molecules 26 06703 i01663
8 Molecules 26 06703 i017 Molecules 26 06703 i01875
9 Molecules 26 06703 i019 Molecules 26 06703 i02066
10 Molecules 26 06703 i021 Molecules 26 06703 i02281
11 Molecules 26 06703 i023 Molecules 26 06703 i02485
1 All reactions were carried out on a 1.0-mmol scale under a N2 atmosphere. Isolated yield was reported.
Table
Table 3. Poly-ortho-substituted biaryl synthesis using in situ-generated catalyst 1.
Table 3. Poly-ortho-substituted biaryl synthesis using in situ-generated catalyst 1.
Molecules 26 06703 i025
EntryArCl 3 ArB(OH)2 4Product 5Yield (%)2
1 Molecules 26 06703 i026 Molecules 26 06703 i027 Molecules 26 06703 i02850
2 Molecules 26 06703 i029 Molecules 26 06703 i030 Molecules 26 06703 i03146
3 Molecules 26 06703 i032 Molecules 26 06703 i033 Molecules 26 06703 i03460
4 Molecules 26 06703 i035 Molecules 26 06703 i036 Molecules 26 06703 i03746
5 Molecules 26 06703 i038 Molecules 26 06703 i039 Molecules 26 06703 i04020
6 Molecules 26 06703 i041 Molecules 26 06703 i042 Molecules 26 06703 i04375
7 Molecules 26 06703 i044 Molecules 26 06703 i045 Molecules 26 06703 i04692
8 Molecules 26 06703 i047 Molecules 26 06703 i048 Molecules 26 06703 i04985
9 Molecules 26 06703 i050 Molecules 26 06703 i051 Molecules 26 06703 i05251
10 Molecules 26 06703 i053 Molecules 26 06703 i054 Molecules 26 06703 i05584
11 Molecules 26 06703 i056 Molecules 26 06703 i057 Molecules 26 06703 i05858
12 Molecules 26 06703 i059 Molecules 26 06703 i060 Molecules 26 06703 i06150
13 Molecules 26 06703 i062 Molecules 26 06703 i063 Molecules 26 06703 i064ND 2
1 All reactions were carried out on a 1.0-mmol scale under a N2 atmosphere. Isolated yield was reported. 2 ND = no detected.
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Chen, Y.-H.; Huang, S.-J.; Hsu, T.-Y.; Hung, P.-Y.; Wei, T.-R.; Lee, D.-S.; Lu, T.-J. Non-C2-Symmetric Bis-Benzimidazolium Salt Applied in the Synthesis of Sterically Hindered Biaryls. Molecules 2021, 26, 6703. https://doi.org/10.3390/molecules26216703

AMA Style

Chen Y-H, Huang S-J, Hsu T-Y, Hung P-Y, Wei T-R, Lee D-S, Lu T-J. Non-C2-Symmetric Bis-Benzimidazolium Salt Applied in the Synthesis of Sterically Hindered Biaryls. Molecules. 2021; 26(21):6703. https://doi.org/10.3390/molecules26216703

Chicago/Turabian Style

Chen, Yen-Hsin, Shu-Jyun Huang, Tung-Yu Hsu, Pei-Yu Hung, Ting-Rong Wei, Dong-Sheng Lee, and Ta-Jung Lu. 2021. "Non-C2-Symmetric Bis-Benzimidazolium Salt Applied in the Synthesis of Sterically Hindered Biaryls" Molecules 26, no. 21: 6703. https://doi.org/10.3390/molecules26216703

APA Style

Chen, Y. -H., Huang, S. -J., Hsu, T. -Y., Hung, P. -Y., Wei, T. -R., Lee, D. -S., & Lu, T. -J. (2021). Non-C2-Symmetric Bis-Benzimidazolium Salt Applied in the Synthesis of Sterically Hindered Biaryls. Molecules, 26(21), 6703. https://doi.org/10.3390/molecules26216703

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