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

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.

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 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.

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 1 H-and 13 C-NMR. The two benzimidazolium proton signals exhibit as sharp singlets at δ 12.51 and 12.25 ppm in the 1 H-NMR spectrum, and two corresponding carbon resonances appear as a typical singlet in the 1 H-decoupled mode at δ 143.7 and 142.3 ppm in the 13 C-NMR spectrum.

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-C 2 -symmetric ethylene skeleton, which can be used as a linker of non-C 2 -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 1 H-and 13 C-NMR. The two benzimidazolium proton signals exhibit as sharp singlets at δ 12.51 and 12.25 ppm in the 1 H-NMR spectrum, and two corresponding carbon resonances appear as a typical singlet in the 1 H-decoupled mode at δ 143.7 and 142.3 ppm in the 13 C-NMR spectrum.

PEER REVIEW
3 of 13 Scheme 1. The synthesis of amino alcohol-derived bis-benzimidazolium salt 1.

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. Scheme 1. The synthesis of amino alcohol-derived bis-benzimidazolium salt 1.

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, K 3 PO 4 ·H 2 O 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-C 2 -symmetric bis-benzimidazolium salt, possessing high steric hindrance, and the Pd source demonstrated excellent catalytic capacity. It catalyzes the C(sp 2 )-C(sp 2 ) 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. reaction of 4-chloroanisole 3a with phenylboronic acid 4a with 1.0 mol% Pd loading was chosen to stud optimized reaction conditions ( Table 1). Solvents were evaluated firstly (entries 1-5), and 1,4-dioxane s 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) w examined, and the ratio of 1:3 was found to give the highest yield (87%) (entry 1). The base is usually a factor in this reaction (entries 1 and 9-15). Among commonly used bases, K 3 PO 4 ·H 2 O was found to be t base. Finally, various metal sources were investigated in SMC reaction (entries 1 and 16-21), and Pd(db metal source of choice for this reaction (entry 21, 83% isolated yield). A control reaction was also perfo absence of bis-benzimidazolium salt 1 (entry 22), which showed that no starting material was converted 5aa. 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-1,3dimethylbenzene, 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][9][10][11][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. symmetric bis-benzimidazolium salt, possessing high steric hindrance, and the Pd source demonstra catalytic capacity. It catalyzes the C(sp 2 )-C(sp 2 ) bond formation between deacitvated aryl chlorides phenylboronic acid under low Pd loading (1 mol%). In addition, this catalyst has superior tolerance of functional groups. symmetric bis-benzimidazolium salt, possessing high steric hindrance, and the Pd source demonstr catalytic capacity. It catalyzes the C(sp 2 )-C(sp 2 ) bond formation between deacitvated aryl chloride phenylboronic acid under low Pd loading (1 mol%). In addition, this catalyst has superior tolerance of functional groups. MeO symmetric bis-benzimidazolium salt, possessing high steric hindrance, and the Pd source demonstrate catalytic capacity. It catalyzes the C(sp 2 )-C(sp 2 ) bond formation between deacitvated aryl chlorides an phenylboronic acid under low Pd loading (1 mol%). In addition, this catalyst has superior tolerance to of functional groups. catalytic capacity. It catalyzes the C(sp 2 )-C(sp 2 ) bond formation between deacitvated aryl chloride phenylboronic acid under low Pd loading (1 mol%). In addition, this catalyst has superior tolerance of functional groups. MeO catalytic capacity. It catalyzes the C(sp 2 )-C(sp 2 ) bond formation between deacitvated aryl chlorides a phenylboronic acid under low Pd loading (1 mol%). In addition, this catalyst has superior tolerance to of functional groups. catalytic capacity. It catalyzes the C(sp 2 )-C(sp 2 ) bond formation between deacitvated aryl chlorides phenylboronic acid under low Pd loading (1 mol%). In addition, this catalyst has superior tolerance of functional groups. MeO catalytic capacity. It catalyzes the C(sp 2 )-C(sp 2 ) bond formation between deacitvated aryl chlorides an phenylboronic acid under low Pd loading (1 mol%). In addition, this catalyst has superior tolerance to of functional groups. catalytic capacity. It catalyzes the C(sp )-C(sp ) bond formation between deacitvated aryl chloride phenylboronic acid under low Pd loading (1 mol%). In addition, this catalyst has superior tolerance of functional groups. MeO catalytic capacity. It catalyzes the C(sp )-C(sp ) bond formation between deacitvated aryl chlorides an phenylboronic acid under low Pd loading (1 mol%). In addition, this catalyst has superior tolerance to of functional groups. phenylboronic acid under low Pd loading (1 mol%). In addition, this catalyst has superior tolerance of functional groups. MeO phenylboronic acid under low Pd loading (1 mol%). In addition, this catalyst has superior tolerance to a of functional groups. phenylboronic acid under low Pd loading (1 mol%). In addition, this catalyst has superior tolerance of functional groups. MeO phenylboronic acid under low Pd loading (1 mol%). In addition, this catalyst has superior tolerance to of functional groups.     In order to further extend the capacity of the catalytic system, the synthesis of sterically hindered scrutinized ( Table 3). Di-ortho-substituted aryl chlorides, such as 2-chloro-1-methyl-3-nitroben methoxy benzaldehyde, and 2-chloro-1,3-dimethylbenzene, were coupled with phenylboronic ac In order to further extend the capacity of the catalytic system, the synthesis of sterically hindered bi scrutinized ( Table 3). Di-ortho-substituted aryl chlorides, such as 2-chloro-1-methyl-3-nitrobenzen methoxy benzaldehyde, and 2-chloro-1,3-dimethylbenzene, were coupled with phenylboronic acid In order to further extend the capacity of the catalytic system, the synthesis of sterically hindered scrutinized ( Table 3). Di-ortho-substituted aryl chlorides, such as 2-chloro-1-methyl-3-nitrobenz methoxy benzaldehyde, and 2-chloro-1,3-dimethylbenzene, were coupled with phenylboronic ac corresponding products in 46-60% yields (entries 1-3). Di-ortho-substituted biaryls (5hb, 5ib, 5 In order to further extend the capacity of the catalytic system, the synthesis of sterically hindered bi scrutinized ( Table 3). Di-ortho-substituted aryl chlorides, such as 2-chloro-1-methyl-3-nitrobenzen methoxy benzaldehyde, and 2-chloro-1,3-dimethylbenzene, were coupled with phenylboronic acid t In order to further extend the capacity of the catalytic system, the synthesis of sterically hindered scrutinized ( Table 3). Di-ortho-substituted aryl chlorides, such as 2-chloro-1-methyl-3-nitrobenz methoxy benzaldehyde, and 2-chloro-1,3-dimethylbenzene, were coupled with phenylboronic ac corresponding products in 46-60% yields (entries 1-3). Di-ortho-substituted biaryls (5hb, 5ib, 5 In order to further extend the capacity of the catalytic system, the synthesis of sterically hindered bi scrutinized ( Table 3). Di-ortho-substituted aryl chlorides, such as 2-chloro-1-methyl-3-nitrobenzen methoxy benzaldehyde, and 2-chloro-1,3-dimethylbenzene, were coupled with phenylboronic acid corresponding products in 46-60% yields (entries 1-3). Di-ortho-substituted biaryls (5hb, 5ib, 5pb  could be successfully generated in the presence of 1 mol% 1/Pd(OAc) 2 with 50-85% yields (entries 8 Unfortunately, the product 5nc bearing tetra-ortho-substituents proved difficult to obtain (entry 13). S successfully demonstrated the synthesis of tri-ortho-substituted biaryls in the presence of 1 mol% in s 1/Pd(OAc) 2 catalytic system. Unfortunately, the product 5nc bearing tetra-ortho-substituents proved difficult to obtain (entry 13 successfully demonstrated the synthesis of tri-ortho-substituted biaryls in the presence of 1 mol% i 1/Pd(OAc) 2 catalytic system. Unfortunately, the product 5nc bearing tetra-ortho-substituents proved difficult to obtain (entry 13). So successfully demonstrated the synthesis of tri-ortho-substituted biaryls in the presence of 1 mol% in sit 1/Pd(OAc) 2 catalytic system. Unfortunately, the product 5nc bearing tetra-ortho-substituents proved difficult to obtain (entry 13). So fa successfully demonstrated the synthesis of tri-ortho-substituted biaryls in the presence of 1 mol% in situ-1/Pd(OAc) 2 catalytic system. Unfortunately, the product 5nc bearing tetra-ortho-substituents proved difficult to obtain (entry 13) successfully demonstrated the synthesis of tri-ortho-substituted biaryls in the presence of 1 mol% i 1/Pd(OAc) 2 catalytic system. Unfortunately, the product 5nc bearing tetra-ortho-substituents proved difficult to obtain (entry 13). So successfully demonstrated the synthesis of tri-ortho-substituted biaryls in the presence of 1 mol% in si 1/Pd(OAc) 2 catalytic system. Unfortunately, the product 5nc bearing tetra-ortho-substituents proved difficult to obtain (entry 13). So fa successfully demonstrated the synthesis of tri-ortho-substituted biaryls in the presence of 1 mol% in situ-f 1/Pd(OAc) 2 catalytic system.  could be successfully generated in the presence of 1 mol% 1/Pd(OAc) 2 with 50-85% yields (entries 8 Unfortunately, the product 5nc bearing tetra-ortho-substituents proved difficult to obtain (entry 13). S successfully demonstrated the synthesis of tri-ortho-substituted biaryls in the presence of 1 mol% in s 1/Pd(OAc) 2 catalytic system.

General Methods
Unless otherwise stated, commercially available materials were received from Aldrich and Acros ( Taiwan) and used without further purification. Acetonitrile was distilled over calcium hydride prio Toluene, 1,4-dioxane, and t-BuOH were distilled over sodium prior to its use. Reactions were mon coated silica gel 60 (F-254) plates. The products were purified by column chromatography (silica g μm), eluting with n-hexane/ethyl acetate. 1 H-and 13 C-NMR spectra were recorded using an Agilen spectrometer (Agilent Technologies, Inc., Santa Clara, CA, USA), with the J-values given in Hz. C (δ) were referenced to CDCl 3 (δ = 7.26 ppm) in the 1 H-NMR spectra and CDCl 3 (δ = 77.0 ppm) in spectra. Copies of 1 H-and 13 C-NMR spectra of all compounds are provided as Supplementary Ma points were determined using a Thermo 1001D digital melting point apparatus and are uncorrected recorded using a Shimadzu GC-2014 spectrometer (Shimadzu Co., Kyoto, Japan) equipped with a (SPB ® -5, 60 m × 0.25 mm × 0.25 μm). The conversion yields, GC yields, and ratios were determin undecane as an internal standard. High-resolution mass spectra were recorded using a Finnigan/Th 95XL mass spectrometer (Finnigan MAT LCQ, San Jose, CA, USA) via either atmospheric-pressu ionization (APCI) or electrospray ionization (ESI) methods.

General Methods
Unless otherwise stated, commercially available materials were received from Aldrich and Acros (New Taiwan) and used without further purification. Acetonitrile was distilled over calcium hydride prior to Toluene, 1,4-dioxane, and t-BuOH were distilled over sodium prior to its use. Reactions were monitore coated silica gel 60 (F-254) plates. The products were purified by column chromatography (silica gel, μm), eluting with n-hexane/ethyl acetate. 1 H-and 13 C-NMR spectra were recorded using an Agilent M spectrometer (Agilent Technologies, Inc., Santa Clara, CA, USA), with the J-values given in Hz. Chem (δ) were referenced to CDCl 3 (δ = 7.26 ppm) in the 1 H-NMR spectra and CDCl 3 (δ = 77.0 ppm) in the spectra. Copies of 1 H-and 13 C-NMR spectra of all compounds are provided as Supplementary Mater points were determined using a Thermo 1001D digital melting point apparatus and are uncorrected. GC recorded using a Shimadzu GC-2014 spectrometer (Shimadzu Co., Kyoto, Japan) equipped with a capi (SPB ® -5, 60 m × 0.25 mm × 0.25 μm). The conversion yields, GC yields, and ratios were determined u undecane as an internal standard. High-resolution mass spectra were recorded using a Finnigan/Therm 95XL mass spectrometer (Finnigan MAT LCQ, San Jose, CA, USA) via either atmospheric-pressure c ionization (APCI) or electrospray ionization (ESI) methods.

General Methods
Unless otherwise stated, commercially available materials were received from Aldrich and Acros (New Ta Taiwan) and used without further purification. Acetonitrile was distilled over calcium hydride prior to its u Toluene, 1,4-dioxane, and t-BuOH were distilled over sodium prior to its use. Reactions were monitored u coated silica gel 60 (F-254) plates. The products were purified by column chromatography (silica gel, 0.04 μm), eluting with n-hexane/ethyl acetate. 1 H-and 13 C-NMR spectra were recorded using an Agilent Mercu spectrometer (Agilent Technologies, Inc., Santa Clara, CA, USA), with the J-values given in Hz. Chemica (δ) were referenced to CDCl 3 (δ = 7.26 ppm) in the 1 H-NMR spectra and CDCl 3 (δ = 77.0 ppm) in the 13 Cspectra. Copies of 1 H-and 13 C-NMR spectra of all compounds are provided as Supplementary Materials points were determined using a Thermo 1001D digital melting point apparatus and are uncorrected. GC-FI recorded using a Shimadzu GC-2014 spectrometer (Shimadzu Co., Kyoto, Japan) equipped with a capillar (SPB ® -5, 60 m × 0.25 mm × 0.25 μm). The conversion yields, GC yields, and ratios were determined usin undecane as an internal standard. High-resolution mass spectra were recorded using a Finnigan/Thermo Q 95XL mass spectrometer (Finnigan MAT LCQ, San Jose, CA, USA) via either atmospheric-pressure chem ionization (APCI) or electrospray ionization (ESI) methods.

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. 1 H-and 13 C-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 CDCl 3 (δ = 7.26 ppm) in the 1 H-NMR spectra and CDCl 3 (δ = 77.0 ppm) in the 13 C-NMR spectra. Copies of 1 H-and 13 C-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.