Synthesis of New 2-Arylbenzo[b]furan Derivatives via Palladium-Catalyzed Suzuki Cross-Coupling Reactions in Aqueous Media

A series of novel benzofuran derivatives containing biaryl moiety were designed and synthesized by the Suzuki cross-coupling reactions. The reactions, performed in the presence of K2CO3, EtOH/H2O and Pd(II) complex as catalyst, gave the corresponding products in good to excellent yields. The methodology allows the facile production of heterobiaryl compounds, a unique architectural motif that is ubiquitous in medicinal chemistry.

known as the Suzuki cross-coupling reaction, is a versatile and highly utilized reaction for the selective formation of carbon-carbon bonds, in particular for the synthesis of biaryls [24][25][26][27][28]. This paper describes the Suzuki reaction applied to the synthesis of novel benzofuran derivatives containing biaryl moiety.

Results and Discussion
The designed novel benzofuran derivatives containing biaryl moiety (9) were prepared in two steps (Scheme 1). First, 2-(4-bromophenyl)benzofuran (7) was obtained following the method, Pd(II)/CuI/PPh3-co-catalyzed coupling-cyclization reaction of the commercially available 2iodophenol (5) with 4-bromo-1-ethynylbenzene (6) in the presence of NEt3 in water at 80 °C , reported by the Guo group [29]. Second, the optimal reaction conditions were studied by employing the Suzuki cross-coupling of 2-(4-bromophenyl)benzofuran (7) with 4-methoxyphenylboronic acid as model reaction for the synthesis of the 2-arylbenzo[b]furan derivatives. As can be seen in Table 1, we first examined the catalytic activity using common palladium salts PdCl2 or Pd(OAc)2 as catalyst in the presence of K2CO3 in EtOH/H2O (1:1) at 80 °C , only moderate yields of 55% or 61% were achieved ( Table 1, entries 1-2), but the reaction proceeded well in 91% yield in the presence of our newly developed Pd(II) complex catalyst (10) [30] (Table 1, entry 3). Compared to loading of catalyst 1 mol%-4 mol%, the yield was obviously enhanced to 97% when 3 mol% Pd(II) complex catalyst was used (Table 1, entry 5). The effects of base on the reaction were next examined. 28%, 40%, 53%, 78% and 63% yield of the desired product was obtained when using NEt3, NaF, NaHCO3, NaOH and Cs2CO3 as a base, respectively (  Motivated by the above-mentioned 2-arylbenzo[b]furan derivatives as valuable building blocks with a wide range of biological activities, to discover new potentially active agents, in this research, a series of novel benzofuran derivatives containing biaryl moiety were designed and synthesized. Biaryls are recurring functional groups in many natural products, pharmaceuticals and bioactive compounds [21][22][23]. Palladium-catalyzed cross-coupling of aryl halides with organoboronic acids, known as the Suzuki cross-coupling reaction, is a versatile and highly utilized reaction for the selective formation of carbon-carbon bonds, in particular for the synthesis of biaryls [24][25][26][27][28]. This paper describes the Suzuki reaction applied to the synthesis of novel benzofuran derivatives containing biaryl moiety.

Results and Discussion
The designed novel benzofuran derivatives containing biaryl moiety (9) were prepared in two steps (Scheme 1). First, 2-(4-bromophenyl)benzofuran (7) was obtained following the method, Pd(II)/CuI/PPh 3 -co-catalyzed coupling-cyclization reaction of the commercially available 2-iodophenol (5) with 4-bromo-1-ethynylbenzene (6) in the presence of NEt 3 in water at 80 • C, reported by the Guo group [29]. Second, the optimal reaction conditions were studied by employing the Suzuki cross-coupling of 2-(4-bromophenyl)benzofuran (7) with 4-methoxyphenylboronic acid as model reaction for the synthesis of the 2-arylbenzo[b]furan derivatives. As can be seen in Table 1, we first examined the catalytic activity using common palladium salts PdCl 2 or Pd(OAc) 2 as catalyst in the presence of K 2 CO 3 in EtOH/H 2 O (1:1) at 80 • C, only moderate yields of 55% or 61% were achieved (Table 1, entries 1-2), but the reaction proceeded well in 91% yield in the presence of our newly developed Pd(II) complex catalyst (10) [30] (Table 1, entry 3). Compared to loading of catalyst 1 mol%-4 mol%, the yield was obviously enhanced to 97% when 3 mol% Pd(II) complex catalyst was used (Table 1, entry 5). The effects of base on the reaction were next examined. 28%, 40%, 53%, 78% and 63% yield of the desired product was obtained when using NEt 3 , NaF, NaHCO 3 , NaOH and Cs 2 CO 3 as a base, respectively ( Then, under the best conditions, the use of different arylboronic acid for efficient synthesis of new 2-arylbenzo[b]furan derivatives was examined. The desired products were obtained in good to excellent yields (92%-98%) with substrates that contained electron-withdrawing and donating groups ( Table 2, entries 1-4). The effect of steric hindrance was also tested with ortho-substituted boronic acid showing slightly lower yield (85%) ( Then, under the best conditions, the use of different arylboronic acid for efficient synthesis of new 2-arylbenzo[b]furan derivatives was examined. The desired products were obtained in good to excellent yields (92%-98%) with substrates that contained electron-withdrawing and donating groups ( Table 2, entries 1-4). The effect of steric hindrance was also tested with ortho-substituted boronic acid showing slightly lower yield (85%) ( Then, under the best conditions, the use of different arylboronic acid for efficient synthesis of new 2-arylbenzo[b]furan derivatives was examined. The desired products were obtained in good to excellent yields (92%-98%) with substrates that contained electron-withdrawing and donating groups ( Table 2, entries 1-4). The effect of steric hindrance was also tested with ortho-substituted boronic acid showing slightly lower yield (85%) ( Table 2, entry 5).

General Information
Commercial reagents employed in the synthesis were analytical grade, obtained from Alfa Aesar (Ward Hill, MA, USA) and used as received without any prior purification. Silica gel GF254 (Qingdao Haiyang Chemical Co., Ltd., Qingdao, China) was used for analytical thin-layer chromatography (TLC) (glass coating 0.25 mm thick) using hexane and dichloromethane as the eluent. 1 H-NMR, 13 C-NMR spectra were recorded on a BRUKER DRX (400 MHz) spectrometer (Billerica, MA, USA) using tetramethylsilane as the internal standard and CDCl3 or CD2Cl2 as the solvent. Low-resolution massspectra were recorded on an Agilent gas chromatography mass spectrometry 7890A-5795C instrument. High-resolution mass spectra (HRMS) were obtained using Agilent 6210 ESI/TOF mass spectrometer (Santa Clara, CA, USA). Melting points were determined using a Mettler

General Information
Commercial reagents employed in the synthesis were analytical grade, obtained from Alfa Aesar (Ward Hill, MA, USA) and used as received without any prior purification. Silica gel GF254 (Qingdao Haiyang Chemical Co., Ltd., Qingdao, China) was used for analytical thin-layer chromatography (TLC) (glass coating 0.25 mm thick) using hexane and dichloromethane as the eluent. 1 H-NMR, 13 C-NMR spectra were recorded on a BRUKER DRX (400 MHz) spectrometer (Billerica, MA, USA) using tetramethylsilane as the internal standard and CDCl3 or CD2Cl2 as the solvent. Low-resolution massspectra were recorded on an Agilent gas chromatography mass spectrometry 7890A-5795C instrument. High-resolution mass spectra (HRMS) were obtained using Agilent 6210 ESI/TOF mass spectrometer (Santa Clara, CA, USA). Melting points were determined using a Mettler

General Information
Commercial reagents employed in the synthesis were analytical grade, obtained from Alfa Aesar (Ward Hill, MA, USA) and used as received without any prior purification. Silica gel GF254 (Qingdao Haiyang Chemical Co., Ltd., Qingdao, China) was used for analytical thin-layer chromatography (TLC) (glass coating 0.25 mm thick) using hexane and dichloromethane as the eluent. 1 H-NMR, 13 C-NMR spectra were recorded on a BRUKER DRX (400 MHz) spectrometer (Billerica, MA, USA) using tetramethylsilane as the internal standard and CDCl3 or CD2Cl2 as the solvent. Low-resolution massspectra were recorded on an Agilent gas chromatography mass spectrometry 7890A-5795C instrument. High-resolution mass spectra (HRMS) were obtained using Agilent 6210 ESI/TOF mass spectrometer (Santa Clara, CA, USA). Melting points were determined using a Mettler

General Information
Commercial reagents employed in the synthesis were analytical grade, obtained from Alfa Aesar (Ward Hill, MA, USA) and used as received without any prior purification. Silica gel GF254 (Qingdao Haiyang Chemical Co., Ltd., Qingdao, China) was used for analytical thin-layer chromatography (TLC) (glass coating 0.25 mm thick) using hexane and dichloromethane as the eluent. 1 H-NMR, 13 C-NMR spectra were recorded on a BRUKER DRX (400 MHz) spectrometer (Billerica, MA, USA) using tetramethylsilane as the internal standard and CDCl3 or CD2Cl2 as the solvent. Low-resolution massspectra were recorded on an Agilent gas chromatography mass spectrometry 7890A-5795C instrument. High-resolution mass spectra (HRMS) were obtained using Agilent 6210 ESI/TOF mass spectrometer (Santa Clara, CA, USA). Melting points were determined using a Mettler

General Information
Commercial reagents employed in the synthesis were analytical grade, obtained from Alfa Aesar (Ward Hill, MA, USA) and used as received without any prior purification. Silica gel GF254 (Qingdao Haiyang Chemical Co., Ltd., Qingdao, China) was used for analytical thin-layer chromatography (TLC) (glass coating 0.25 mm thick) using hexane and dichloromethane as the eluent. 1 H-NMR, 13 C-NMR spectra were recorded on a BRUKER DRX (400 MHz) spectrometer (Billerica, MA, USA) using tetramethylsilane as the internal standard and CDCl3 or CD2Cl2 as the solvent. Low-resolution massspectra were recorded on an Agilent gas chromatography mass spectrometry 7890A-5795C instrument. High-resolution mass spectra (HRMS) were obtained using Agilent 6210 ESI/TOF mass spectrometer (Santa Clara, CA, USA). Melting points were determined using a Mettler

General Information
Commercial reagents employed in the synthesis were analytical grade, obtained from Alfa Aesar (Ward Hill, MA, USA) and used as received without any prior purification. Silica gel GF254 (Qingdao Haiyang Chemical Co., Ltd., Qingdao, China) was used for analytical thin-layer chromatography (TLC) (glass coating 0.25 mm thick) using hexane and dichloromethane as the eluent. 1 H-NMR, 13 C-NMR spectra were recorded on a BRUKER DRX (400 MHz) spectrometer (Billerica, MA, USA) using tetramethylsilane as the internal standard and CDCl3 or CD2Cl2 as the solvent. Low-resolution massspectra were recorded on an Agilent gas chromatography mass spectrometry 7890A-5795C instrument. High-resolution mass spectra (HRMS) were obtained using Agilent 6210 ESI/TOF mass spectrometer (Santa Clara, CA, USA). Melting points were determined using a Mettler

General Information
Commercial reagents employed in the synthesis were analytical grade, obtained from Alfa Aesar (Ward Hill, MA, USA) and used as received without any prior purification. Silica gel GF254 (Qingdao Haiyang Chemical Co., Ltd., Qingdao, China) was used for analytical thin-layer chromatography (TLC) (glass coating 0.25 mm thick) using hexane and dichloromethane as the eluent. 1 H-NMR, 13 C-NMR spectra were recorded on a BRUKER DRX (400 MHz) spectrometer (Billerica, MA, USA) using tetramethylsilane as the internal standard and CDCl3 or CD2Cl2 as the solvent. Low-resolution massspectra were recorded on an Agilent gas chromatography mass spectrometry 7890A-5795C instrument. High-resolution mass spectra (HRMS) were obtained using Agilent 6210 ESI/TOF mass spectrometer (Santa Clara, CA, USA). Melting points were determined using a Mettler

General Information
Commercial reagents employed in the synthesis were analytical grade, obtained from Alfa Aesar (Ward Hill, MA, USA) and used as received without any prior purification. Silica gel GF254 (Qingdao Haiyang Chemical Co., Ltd., Qingdao, China) was used for analytical thin-layer chromatography (TLC) (glass coating 0.25 mm thick) using hexane and dichloromethane as the eluent. 1 H-NMR, 13 C-NMR spectra were recorded on a BRUKER DRX (400 MHz) spectrometer (Billerica, MA, USA) using tetramethylsilane as the internal standard and CDCl3 or CD2Cl2 as the solvent. Low-resolution massspectra were recorded on an Agilent gas chromatography mass spectrometry 7890A-5795C instrument. High-resolution mass spectra (HRMS) were obtained using Agilent 6210 ESI/TOF mass spectrometer (Santa Clara, CA, USA). Melting points were determined using a Mettler

General Information
Commercial reagents employed in the synthesis were analytical grade, obtained from Alfa Aesar (Ward Hill, MA, USA) and used as received without any prior purification. Silica gel GF254 (Qingdao Haiyang Chemical Co., Ltd., Qingdao, China) was used for analytical thin-layer chromatography (TLC) (glass coating 0.25 mm thick) using hexane and dichloromethane as the eluent. 1 H-NMR, 13 C-NMR spectra were recorded on a BRUKER DRX (400 MHz) spectrometer (Billerica, MA, USA) using tetramethylsilane as the internal standard and CDCl3 or CD2Cl2 as the solvent. Low-resolution massspectra were recorded on an Agilent gas chromatography mass spectrometry 7890A-5795C instrument. High-resolution mass spectra (HRMS) were obtained using Agilent 6210 ESI/TOF mass spectrometer (Santa Clara, CA, USA). Melting points were determined using a Mettler

General Information
Commercial reagents employed in the synthesis were analytical grade, obtained from Alfa Aesar (Ward Hill, MA, USA) and used as received without any prior purification. Silica gel GF254 (Qingdao Haiyang Chemical Co., Ltd., Qingdao, China) was used for analytical thin-layer chromatography (TLC) (glass coating 0.25 mm thick) using hexane and dichloromethane as the eluent. 1 H-NMR, 13 C-NMR spectra were recorded on a BRUKER DRX (400 MHz) spectrometer (Billerica, MA, USA) using tetramethylsilane as the internal standard and CDCl3 or CD2Cl2 as the solvent. Low-resolution massspectra were recorded on an Agilent gas chromatography mass spectrometry 7890A-5795C instrument. High-resolution mass spectra (HRMS) were obtained using Agilent 6210 ESI/TOF mass spectrometer (Santa Clara, CA, USA). Melting points were determined using a Mettler

General Information
Commercial reagents employed in the synthesis were analytical grade, obtained from Alfa Aesar (Ward Hill, MA, USA) and used as received without any prior purification. Silica gel GF254 (Qingdao Haiyang Chemical Co., Ltd., Qingdao, China) was used for analytical thin-layer chromatography (TLC) (glass coating 0.25 mm thick) using hexane and dichloromethane as the eluent. 1 H-NMR, 13 C-NMR spectra were recorded on a BRUKER DRX (400 MHz) spectrometer (Billerica, MA, USA) using tetramethylsilane as the internal standard and CDCl3 or CD2Cl2 as the solvent. Low-resolution massspectra were recorded on an Agilent gas chromatography mass spectrometry 7890A-5795C instrument. High-resolution mass spectra (HRMS) were obtained using Agilent 6210 ESI/TOF mass spectrometer (Santa Clara, CA, USA). Melting points were determined using a Mettler

General Information
Commercial reagents employed in the synthesis were analytical grade, obtained from Alfa Aesar (Ward Hill, MA, USA) and used as received without any prior purification. Silica gel GF254 (Qingdao Haiyang Chemical Co., Ltd., Qingdao, China) was used for analytical thin-layer chromatography (TLC) (glass coating 0.25 mm thick) using hexane and dichloromethane as the eluent. 1 H-NMR, 13 C-NMR spectra were recorded on a BRUKER DRX (400 MHz) spectrometer (Billerica, MA, USA) using tetramethylsilane as the internal standard and CDCl3 or CD2Cl2 as the solvent. Low-resolution massspectra were recorded on an Agilent gas chromatography mass spectrometry 7890A-5795C instrument. High-resolution mass spectra (HRMS) were obtained using Agilent 6210 ESI/TOF mass spectrometer (Santa Clara, CA, USA). Melting points were determined using a Mettler FP5 melting point apparatus (Columbus, OH, USA) in open capillaries and were uncorrected. The 1 H-NMR, 13

General Information
Commercial reagents employed in the synthesis were analytical grade, obtained from Alfa Aesar (Ward Hill, MA, USA) and used as received without any prior purification. Silica gel GF254 (Qingdao Haiyang Chemical Co., Ltd., Qingdao, China) was used for analytical thin-layer chromatography (TLC) (glass coating 0.25 mm thick) using hexane and dichloromethane as the eluent. 1 H-NMR, 13 C-NMR spectra were recorded on a BRUKER DRX (400 MHz) spectrometer (Billerica, MA, USA) using tetramethylsilane as the internal standard and CDCl3 or CD2Cl2 as the solvent. Low-resolution massspectra were recorded on an Agilent gas chromatography mass spectrometry 7890A-5795C instrument. High-resolution mass spectra (HRMS) were obtained using Agilent 6210 ESI/TOF mass spectrometer (Santa Clara, CA, USA). Melting points were determined using a Mettler FP5 melting point apparatus (Columbus, OH, USA) in open capillaries and were uncorrected. The 1 H-NMR, 13

General Information
Commercial reagents employed in the synthesis were analytical grade, obtained from Alfa Aesar (Ward Hill, MA, USA) and used as received without any prior purification. Silica gel GF254 (Qingdao Haiyang Chemical Co., Ltd., Qingdao, China) was used for analytical thin-layer chromatography (TLC) (glass coating 0.25 mm thick) using hexane and dichloromethane as the eluent. 1 H-NMR, 13 C-NMR spectra were recorded on a BRUKER DRX (400 MHz) spectrometer (Billerica, MA, USA) using tetramethylsilane as the internal standard and CDCl3 or CD2Cl2 as the solvent. Low-resolution massspectra were recorded on an Agilent gas chromatography mass spectrometry 7890A-5795C instrument. High-resolution mass spectra (HRMS) were obtained using Agilent 6210 ESI/TOF mass spectrometer (Santa Clara, CA, USA). Melting points were determined using a Mettler FP5 melting point apparatus (Columbus, OH, USA) in open capillaries and were uncorrected. The 1 H-NMR, 13 C-NMR and HRMS for all the synthesized compounds are available in the supplementary materials.

General Information
Commercial reagents employed in the synthesis were analytical grade, obtained from Alfa Aesar (Ward Hill, MA, USA) and used as received without any prior purification. Silica gel GF254 (Qingdao Haiyang Chemical Co., Ltd., Qingdao, China) was used for analytical thin-layer chromatography (TLC) (glass coating 0.25 mm thick) using hexane and dichloromethane as the eluent. 1 H-NMR, 13 C-NMR spectra were recorded on a BRUKER DRX (400 MHz) spectrometer (Billerica, MA, USA) using tetramethylsilane as the internal standard and CDCl 3 or CD 2 Cl 2 as the solvent. Low-resolution mass-spectra were recorded on an Agilent gas chromatography mass spectrometry 7890A-5795C instrument. High-resolution mass spectra (HRMS) were obtained using Agilent 6210 ESI/TOF mass spectrometer (Santa Clara, CA, USA). Melting points were determined using a Mettler FP5 melting