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A Facial Protocol for the Synthesis of Benzofuran Derivatives by the Reaction of o-Hydroxy Aryl Ketone, Amine and Chloroacetyl Chloride

  • Xia, Shuai (College of Pharmaceutical Sciences, Southwest University) ;
  • Wang, Xiu-Hua (College of Pharmaceutical Sciences, Southwest University) ;
  • Liu, Ji-Qiang (College of Pharmaceutical Sciences, Southwest University) ;
  • Liu, Chang (College of Pharmaceutical Sciences, Southwest University) ;
  • Chen, Jian-Bin (College of Pharmaceutical Sciences, Southwest University) ;
  • Zuo, Hua (College of Pharmaceutical Sciences, Southwest University) ;
  • Xie, Yong-Sheng (Department of Chemistry, Changwon National University) ;
  • Dong, Wen-Liang (Department of Chemistry, Changwon National University) ;
  • Shin, Dong-Soo (Department of Chemistry, Changwon National University)
  • Received : 2013.12.01
  • Accepted : 2014.02.18
  • Published : 2014.06.20
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Abstract

A facile and effective method has been developed for the synthesis of a novel series of benzofuran derivatives via N-acylation, O-alkylation and intramolecular condensation reactions, starting from readily available substituted o-hydroxy aryl ketone, and chloroacetyl arylamides. This metal-free transition process is characterized by mild reaction conditions, atom economy, short reaction time and a high yield with a decreased amount of by-products.

Keywords

Introduction

Benzofuran moiety is abundant in both natural and arti-ficial molecules. Substituted benzofurans are pharmaceuti-cally important heterocycles that display numerous bio-logical activities such as antimicrobial,1,2 antifungal,3 anti-tubercular,3,4 antiprotozoal,5 anti-HIV-1, anticancer,6,7 anti--malarial,7 antiretroviral,8 antioxidant,9 cytotoxic,10 anticonvulsant,11 anti-inflammatory12 activities. They have also been exhibited some properties as steroidogenic inhibitors,13 MMP-13 inhibitors,14 cathepsin K inhibitors,15 local anes-thetic,16 monoamine oxidase inhibitors,17 dual 5-HT1A receptor agonists, and serotonin reuptake inhibitors.18 In addition, several benzo[b]furan ring systems bearing various substituents are widely distributed in nature, e.g., ailanthoidol,1 (–)-concentricolide,19 (+)-frondosin B20 and the eupomatenoid family.21

Owing to their important applications in medicinal chemistry, it is of great significance to develop systematic and novel approaches to benzofurans. The conventional strategies for the construction of furan rings are via the conversion of various arene derivatives,22,23 through C-O bond formation24,25 or with the assistance of expensive tran-sition- metal catalyzed reactions,26-36 most of which suffer from the limitations such as the requirement of expensive metal reagents, multi-step processes, harsh reaction condi-tions, and unavailability of starting materials. Furthermore, there are still no typical efficient protocols for the pre-paration of benzofuran skeleton, making it urgent for searching new methods.

Herein, in the interest of the impressive results of various benzofuran series and in continuation of our previous work in the synthesis of heterocycles,37-39 we reported an efficient protocol for the synthesis of a novel variety of benzofuran derivatives using readily available o-hydroxy aryl ketones, chloroacetyl chloride and amines via N-acylation, O-alkyl-ation and intramolecular condensation, under mild basic conditions in relatively short time (Scheme 1).

Scheme 1.Synthetic route to benzo[b]furan derivatives 6.

 

Experimental

General. All of the reagents were obtained from com-mercial sources. Solvents were dried and purified with known conventional methods. Melting points (uncorrected) were determined on a Gallenkamp apparatus. 1H and 13C NMR spectra (at 500 MHz, 400 MHz or 300 MHz and 125 MHz, 100 MHz or 75 MHz, respectively) were recorded in CDCl3 with tetramethylsilane as internal reference. Chemical shifts were reported in parts per million. Mass spectra (MS) were measured by ESI. CDCl3 was used as delivered from Sigma-Aldrich. Silica gel (70–230 mesh) was used for flash column chromatography. All reactions were monitored by TLC using 0.25 mm silica gel plates with UV indicator (Shanghai Jiapeng Technology Co., Ltd., China). Unless other-wise noted, other reagents were obtained from commercial suppliers and used without further purification.

Representative Procedure for the Synthesis of N-Sub-stituted-2-chloroacetamide (3). To a magnetically stirred solution of substituted aniline 1 (10.0 mmol, 1.0 equiv) and K2CO3 (15.0 mmol, 1.5 equiv) in CH2Cl2 (100 mL), cooled in an ice bath, chloroacetyl chloride 2 (12.0 mmol, 1.2 equiv) was added slowly dropwise. The reaction mixture was stirred at room temperature and monitored by TLC. After the reaction was complete, solvent was removed under vacuum and ice water (200 mL) was added into the residue. The product 3 precipitated was filtered and washed with water, dried and used for the next step without further purification.

Representative Procedure for the Synthesis of Sub-stituted Acetamide (5). The solution of o-hydroxy aryl ketone 4 (5.0 mmol, 1.0 equiv), K2CO3 (6.0 mmol, 1.2 equiv), N-substituted-2-chloroacetamide 3 (5.0 mmol, 1.0 equiv) in CH3CN (10 mL) was refluxed and monitored by TLC. After completion of the reaction, solvent was removed under vacuum and water (20 mL) was added to the residue. The mixture was then extracted with ethyl acetate (4 × 30 mL). The organic layers were combined, dried over anhydr-ous MgSO4, and evaporated under vacuum to give the crude product. The residue obtained was purified by silica gel column chromatography to obtain corresponding compound 5.

Representative Procedure for the Synthesis of Sub-stituted Benzo[b]furans (6). Cyclization of substituted acetamide 5 (5.0 mmol, 1.0 equiv) by treating it with cesium carbonate (7.5 mmol, 1.2 equiv) in anhydrous DMF (10 mL) at 110 °C gave substituted benzo[b]furans 6. After the com-pletion of the reaction (monitored by TLC), the solvent was evaporated under reduced pressure and water (30 mL) was added into the residue. The mixture was then extracted with ethyl acetate (3 × 30 mL). The combined organic layers were washed with brine and dried over anhydrous MgSO4, filtered and evaporated under vacuum to give the crude product. The pure product 6 was obtained by column chromatography on silica gel (ethyl acetate: petroleum ether = 1:10).

N-(2-Pyridyl)-(benzo[b]furan-2-yl)carboxamide 6a: A white solid; mp 139.5–141 °C; 1H NMR (300 MHz, CDCl3) δ 9.08 (s, 1H), 8.39–8.37 (m, 2H), 7.78 (t, J = 7.6 Hz, 1H), 7.71 (d, J = 7.6 Hz, 1H), 7.63 (s, 1H), 7.55 (d, J = 8.4 Hz, 1H), 7.47 (t, J = 7.4 Hz, 1H), 7.33 (t, J = 7.4 Hz, 1H), 7.11 (t, J = 5.1 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 158.2, 156.3, 152.3, 149.5, 149.4, 139.9, 129.0, 128.9, 125.4, 124.3, 121.6, 115.7, 113.4, 113.3; HRMS (ESI): m/z 239.0843.

N-(2-Pyridyl)-((3-methyl-benzo[b]furan)-2-yl)carbox-amide 6b: A light-yellow solid; mp 131.5–133 °C; 1H NMR (400 MHz, CDCl3) δ 9.12 (s, 1H), 8.39 (d, J = 8.4Hz, 1H), 8.36-8.33 (m, 1H), 7.79–7.74 (m, 1H), 7.65 (d, J = 7.4 Hz, 1H), 7.52–7.45 (m, 2H), 7.34–7.31 (m, 1H), 7.10-7.08 (m, 1H), 2.70 (s, 3H; CH3); 13C NMR (125 MHz, CDCl3) δ 158.3, 153.4, 151.1, 148.2, 142.0, 138.4, 129.7, 127.7, 124.6, 123.4, 121.1, 120.0, 114.1, 111.8, 9.1; HRMS (ESI): m/z 253.0976.

N-(2-Pyridyl)-((3-ethyl-benzo[b]furan)-2-yl)carboxamide 6c: A white solid; mp 99–100 °C; 1H NMR (500 MHz, CDCl3) δ 9.18 (s, 1H), 8.38 (d, J = 8.4 Hz, 1H), 8.34 (dd, J = 4.8, 0.9 Hz, 1H), 7.74–7.71 (m, 1H), 7.65 (d, J = 7.5 Hz, 1H), 7.46–7.41 (m, 2H), 7.29-7.26 (m, 1H), 7.06–7.04 (m, 1H), 3.21 (q, J = 7.6 Hz, 2H), 1.35 (t, J = 7.6 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 158.0, 153.5, 151.2, 148.1, 141.4, 138.4, 130.7, 128.8, 127.6, 123.3, 121.2, 119.9, 114.1, 111.9, 17.4, 14.3; HRMS (ESI): m/z 267.1129.

N-(2-Pyridyl)-((3-propyl-benzo[b]furan)-2-yl)carbox-amide 6d: A white solid; mp 107.5–109 °C; 1H NMR (300 MHz, CDCl3) δ 9.11 (s, 1H), 8.39–8.37 (m, 2H), 7.75 (t, J = 7.5 Hz, 1H), 7.68 (d, J = 7.8 Hz, 1H), 7.51–7.43 (m, 2H), 7.31 (t, J = 6.9 Hz, 1H), 7.08 (t, J = 5.7 Hz, 1H), 3.18 (t, J = 7.5 Hz, 2H), 1.86–1.77 (m, 2H), 1.04 (t, J = 7.3 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 159.5, 154.9, 152.5, 149.5, 143.2, 139.8, 130.7, 130.6, 129.0, 124.7, 122.8, 121.4, 115.5, 113.3, 27.2, 24.5, 15.6; HRMS (ESI): m/z 281.1285.

N-(2-Pyridyl)-((3-phenyl-5-methoxyl-benzo[b]furan)-2-yl)carboxamide 6e: A light-yellow solid; mp 167–168.5 °C; 1H NMR (300 MHz, CDCl3) δ 9.02 (s, 1H), 8.33–8.31 (m, 2H), 7.70–7.68 (m, 3H), 7.55–7.46 (m, 4H), 7.06 (t, J = 5.4 Hz, 2H), 6.97 (d, J = 8.7 Hz, 1H), 3.92 (s, 3H); 13C NMR (75 MHz, CDCl3) δ162.2, 158.6, 156.3, 152.6, 149.5, 142.5, 139.7, 131.8, 131.4, 130.0, 129.8, 129.7, 123.9, 123.5, 121.3, 115.7, 115.3, 96.8, 57.2; HRMS (ESI): m/z 345.1256.

N-(3-Pyridyl)-((3-methyl-benzo[b]furan)-2-yl)carbox-amide 6f: A white solid; mp 180–182 °C; 1H NMR (500 MHz, CDCl3) δ 8.76 (d, J = 2.5 Hz, 1H), 8.50 (s, 1H), 8.39 (dd, J = 5.0, 1.5 Hz, 1H), 8.36–8.33 (m, 1H), 7.64 (d, J = 8.0 Hz, 1H), 7.49–7.44 (m, 2H), 7.34–7.30 (m, 2H), 2.67 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 158.4, 153.4, 145.5, 141.9, 141.4, 134.4, 129.7, 127.8, 127.2, 124.6, 123.8, 123.5, 121.2, 111.7, 9.1; HRMS (ESI): m/z 253.0972.

N-(3-Pyridyl)-((3-ethyl-benzo[b]furan)-2-yl)carboxamide 6g: A white solid; mp 132.5–134 °C; 1H NMR (400 MHz, CDCl3) δ 8.77 (s, 1H), 8.46 (s, 1H), 8.41 (d, J = 4.4 Hz, 1H), 8.36 (d, J = 8.4 Hz, 1H), 7.70 (d, J = 8.0 Hz, 1H), 7.54–7.45 (m, 2H), 7.33 (t, J = 7.4 Hz, 2H), 3.22 (q, J = 7.5 Hz, 2H), 1.36 (t, J = 7.5 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 158.2, 153.5, 145.5, 141.3, 134.4, 130.8, 128.8, 127.7, 127.2, 123.7, 123.5, 121.4, 111.8, 17.3, 14.2; HRMS (ESI): m/z 267.1125.

N-(3-Pyridyl)-((3-propyl-benzo[b]furan)-2-yl)carbox-amide 6h: A white solid; mp 163.5–164.5 °C; 1H NMR (300 MHz, CDCl3) δ 8.76–8.75 (m, 1H), 8.46 (s, 1H), 8.41–8.36 (m, 2H), 7.70 (d, J = 7.8 Hz, 1H), 7.53–7.45 (m, 2H), 7.34 (t, J = 7.2 Hz, 2H), 3.18 (t, J=b> = 7.6 Hz, 2H), 1.82 -1.78 (m, 2H), 1.03 (t, J = 7.3 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 157.2, 152.5, 144.4, 140.7, 140.2, 133.4, 128.3, 128.2, 126.6, 126.2, 122.7, 122.4, 120.5, 110.7, 24.7, 22.0, 13.1; HRMS (ESI): m/z 280.1349.

N-Phenyl-((3-methyl-benzo[b]furan)-2-yl)carboxamide 6i: A yellow solid; mp 126–128 °C; 1H NMR (500 MHz, CDCl3) δ 8.34 (s, 1H), 7.70 (d, J = 7.5 Hz, 2H), 7.61 (d, J = 7.5 Hz, 1H), 7.48 (d, J = 8.0 Hz, 1H), 7.45–7.42 (m, 1H), 7.37 (t, J = 7.8 Hz, 2H), 7.30 (t, J = 7.5 Hz, 1H), 7.14 (t, J = 7.5 Hz, 1H), 2.66 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 158.1, 153.3, 142.4, 137.5, 129.9, 129.1, 127.4, 124.5, 123.8,123.3, 121.1, 120.0, 111.6, 9.1; HRMS (ESI): m/z 252.1017.

N-Phenyl-((3-ethyl-benzo[b]furan)-2-yl)carboxamide 6j: A yellow solid; mp 95–97 °C; 1H NMR (500 MHz, CDCl3) δ 8.37 (s, 1H), 7.71 (d, J = 8.0 Hz, 2H), 7.67 (d, J = 8.0 Hz, 1H), 7.51 (d, J = 8.0 Hz, 1H), 7.44 (t, J = 7.5 Hz, 1H), 7.37 (t, J = 8.0 Hz, 2H), 7.31 (t, J = 7.5 Hz, 1H), 7.15 (t, J = 7.5 Hz, 1H), 3.22 (q, J = 7.5 Hz, 2H), 1.35 (t, J = 7.5 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 157.9, 153.4, 141.9, 137.5, 129.9, 129.1, 129.0, 127.3, 124.5, 123.3, 121.2, 120.0, 111.7, 17.3, 14.3; HRMS (ESI): m/z 266.1166.

N-Phenyl-((3-propyl-benzo[b]furan)-2-yl)carboxamide 6k: A yellow solid; 1H NMR (300 MHz, CDCl3) δ 8.39 (s, 1H), 7.68 (d, J = 7.8 Hz, 2H), 7.59 (d, J = 7.8 Hz, 1H), 7.44– 7.21 (m, 5H), 7.09 (t, J = 7.4 Hz, 1H), 3.13 (t, J = 7.4 Hz, 2H), 1.76 (s, J = 7.4, 7.4 Hz, 2H), 1.00 (t, J = 7.4 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 157.9, 153.4, 142.3, 137.5, 129.4, 129.1, 128.4, 127.3, 124.5, 123.3, 121.4, 120.0, 111.7, 25.8, 23.1, 14.2; HRMS (ESI): m/z 280.1329.

N-(2-Nitrophenyl)-((3-methyl-benzo[b]furan)-2-yl)carbox-amide 6l: A yellow solid; mp 177–179 °C; 1H NMR (400 MHz, CDCl3) δ 11.64 (s, 1H), 9.00 (dd, J = 8.4, 1.2 Hz, 1H), 8.30 (dd, J = 8.4, 1.6 Hz, 1H), 7.73–7.68 (m, 1H), 7.66 (d, J = 8.0 Hz, 1H), 7.60 (d, J = 8.0 Hz, 1H), 7.52–7.48 (m, 1H), 7.36–7.32 (m, 1H), 7.25–7.21(m, 1H), 2.70 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 158.6, 153.6, 142.1, 136.6, 135.9, 134.8, 129.6, 128.0, 126.0, 125.4, 123.5, 123.3, 122.1, 121.1, 112.1, 9.2; HRMS (ESI): m/z 297.0859.

N-(2-Nitrophenyl)-((3-ethyl-benzo[b]furan)-2-yl)carbox-amide 6m: A yellow solid; mp 131–133 °C; 1H NMR (400 MHz, CDCl3) δ 11.64 (s, 1H), 8.99 (d, J = 8.5 Hz, 1H), 8.28 (d, J = 8.5 Hz, 1H), 7.71–7.67 (m, 2H), 7.59 (d, J = 8.4 Hz, 1H), 7.50–7.47 (m, 1H), 7.35–7.31 (m, 1H), 7.24–7.19 (m, 1H), 3.22 (q, J = 7.6 Hz, 2H), 1.36 (t, J = 7.6 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 158.4, 153.8, 141.5, 136.5, 135.9, 134.8, 131.5, 128.8, 127.9, 125.9, 123.4, 123.3, 122.1, 121.2, 112.2, 17.4, 14.2; HRMS (ESI): m/z 311.1019.

N-(2-Nitrophenyl)-((3-propyl-benzo[b]furan)-2-yl)carbox-amide 6n: A yellow solid; mp 134–136 °C; 1H NMR (400 MHz, CDCl3) δ 11.64 (s, 1H), 8.99 (d, J = 8.4 Hz, 1H), 8.29 (dd, J = 8.4, 0.9 Hz, 1H), 7.71–7.67 (m, 2H), 7.60 (d, J = 8.4 Hz, 1H), 7.48 (t, J = 7.6 Hz, 1H), 7.33 (t, J = 7.4 Hz, 1H), 7.22 (t, J = 7.8 Hz, 1H), 3.18 (t, J = 7.6 Hz, 2H), 1.81 (s, J = 7.6, 7.4 Hz, 2H), 1.04 (t, J = 7.4 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 158.4, 153.7, 141.9, 136.6, 135.9, 134.8, 130.0, 129.2, 127.9, 125.9, 123.4, 123.3, 122.1, 121.4, 112.2, 25.8, 23.0, 14.1; HRMS (ESI): m/z 325.1165.

N-(2-Naphthyl)((3-methyl-benzo[b]furan)-2-yl)carbox-amide 6o: A White floc solid; mp 171–177 °C; 1H NMR (400 MHz, CDCl3) δ 8.82 (s, 1H), 8.19 (d, J = 7.6 Hz, 1H), 8.03 (d, J = 8.0 Hz, 1H), 7.91 (d, J = 7.6 Hz, 1H), 7.74 (d, J = 8.4 Hz, 1H), 7.68 (d, J = 8.0 Hz, 1H), 7.62–7.47 (m, 5H), 7.35 (t, J=7.6 Hz, 1H), 2.72 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 158.6, 153.4, 142.7, 134.2, 131.7, 129.9, 128.9, 127.5, 127.0, 126.5, 126.1, 125.8, 125.8, 124.0, 123.4, 121.1, 120.5, 120.4, 111.7, 9.1; HRMS (ESI): m/z 302.1189.

 

Results and Discussion

Our work began with the unexpected reaction of 3a and 1-(2-hydroxyphenyl)ethanone (4b). At the beginning of the reaction, pyridin-2-amine (1a) (1.0 equiv) was reacted with chloroacetyl chloride (2) (1.5 equiv) in K2CO3/CH2Cl2 at room temperature, giving 2-chloro-N-(pyridine-2-yl)acetamide (3a) as the product. The crude amide 3a was then reacted with 1-(2-hydroxyphenyl)ethanone (4b) (1.2 equiv) in refluxing K2CO3/CH3CN, afforded O-alkylated compound 5b. However, under the basic condition, O-alkylated compound 5b was quickly transformed into a kind of unknown white crystals in excellent yield, instead of undergoing Smiles rearrangement to give 1-(2-(pyridin-2-ylamino)phenyl)-ethanone. Through complete analysis by 1H NMR, 13C NMR and HRMS, the unknown compound turned out to be 3-methyl-N-(pyridin-2-yl)benzo[b]furan-2-carboxamide (6b), as a new compound.

Table 1.aReaction conditions: O-alkylated compound (5b) (1.0 mmol), base (1.5 mmol), solvent (10 mL). bIsolated yield after column purification in the condensation step.

Inspired by above result, we then optimized the reaction condition. Since the best conditions of first two steps had been investigated before, we herein focused on the condi-tions of intramolecular condensation reaction and results were summarized in Table 1. Firstly, the effect of base on the reaction was explored. Cs2CO3 catalyzed reaction led to a very good yield of the desired benzofuran product 6b (Table 1, entry 2), while using a range of other conventional bases as catalysts resulted in far less effectiveness (Table 1, entries 1, 3 and 4). Especially, only a trace amount of target mole-cule was obtained when the reaction underwent in K2CO3/DMF system, even with longer reaction time. The reactions with NaOH or NaH as the base in DMF generated the desired product in 51% and 47% yield, respectively, and the former reaction required very long reaction time. Then the Cs2CO3/DMF system assisted the reactions in higher yield and shorter reaction time, compared with the reactions in Cs2CO3/CH3CN system (Table 1, entries 1, 5). Furthermore, DMF proved to be more efficient than the tested solvents such as dichloromethane and acetonitrile. Finally, the following investigation on the reaction condition suggested that Cs2CO3/DMF system at 110 °C is the best condition for this reaction (Table 1, entries 2, 6, 7 and 8).

Table 2.aReaction conditions: O-alkylated compounds (5) (1.0 mmol), Cs2CO3 (1.5 mmol), DMF (10 mL). bIsolated yield after column purification in the condensation step.

Under the optimized reaction conditions, we investigated the molecular diversity of novel substituted benzofurans. As depicted in Table 2, the yields of the condensation reaction of the new target compounds are between 79 and 95%. All the structures of newly synthesized compounds were clearly confirmed by 1H NMR, 13C NMR and HRMS spectral data, as well as by melting point. Using the above feasible reac-tion conditions, we are interested in investigating the effect of substituent introduced at various positions of the sub-strates of the reactions. As it can be seen from Table 2, a variety of o-hydroxy aryl ketones 4a-e reacted smoothly with aniline, 2-nitroaniline, pyridin-2-amine or pyridin-3-amine to generate the corresponding target products in good yields with excellent selectivity. According to the experi-mental results, the o-hydroxy aryl ketone containing an ethyl or n-propyl group gave higher yields of the desired benzo-furan products than that of the o-hydroxy aryl ketone with a methyl group (Table 2, entries 2–4, 6–8, 9–11, 12-14). Such a comparison of the data indicated that the larger steric hindrance in alkyl substitution group of o-hydroxy aryl ketone unit contributed to significantly higher substrate conversion rate. Notably, we were pleased to observe that the reaction of (2-hydroxy-4-methoxyphenyl)(phenyl)-methanone (4e) and 3a proceeded well and generated corresponding products (6e) in marvelous yield (95%).

To assess the generality of this procedure, we then intro-duced a set of amines including pyridyl, aryl and naphthyl amines to the reaction. When pyridin-3-amine reacted with o-hydroxy acetophenonev (4b), we found that the desired product (6) was generated, yielding 83% (Table 2, entry 6). The other substituted amines showed properties similar to pyridin-3-amine, which is in accordance with the data given in Table 2. It was worth pointing out that the reaction of other amines with 1-(2-hydroxyphenyl)ethanone (4b) gene-rated the benzofuran derivatives, but in a lower yield than compound (6b) (Table 2, entries 6, 9, 12 and 15).

According to our previous studies,40 a plausible mech-anism, which accounted for the formation of benzofuran has been shown in Scheme 2 (exemplified by 6b) to illustrate the experimental consequences. The O-alkylated product 5b was easily formed by the nucleophilic attack of compound 4b on the amide 3a

The compound 5b could proceed in two paths (path 1 and path 2). In path 1, which was the main approach, the next step involved the conversion of product 5b to the inter-mediate 8b by intramolecular condensation, followed by the dehydration of compound 9b led to the formation of benzo-furan product (6b) under Cs2CO3/DMF system condition. However, in path 2, the O-alkylated product 5b underwent Smiles rearrangement, affording N-azaaryl anilines (11b) as the by-product of the reaction. In support of the proposed mechanism, the substrate with larger steric hindrance had difficulty in undergoing Smiles rearrangement, leading to the lower yield of the by-products and higher yield of the desired products. Furthermore, the O-alkylated products containing the pyridin-2-amine moiety could not undergo Smiles rearrangement well, while they afforded benzofurans in excellent yields. Therefore, the process involved two competitive reactions, and the direct condensation (path 1) was proven to be dominant.

Scheme 2.Proposed mechanism for the formation of 6b.

 

Conclusions

In conclusion, a direct access to a range of benzofurans via N-acylation, O-alkylation and intramolecular condensation was developed. This method afforded a convenient and efficient route for preparing a variety of benzofurans by the reaction of chloroacetamides from substituted arylamines or pyridinamine and o-hydroxy aryl ketone, with only a trace amount of N-azaaryl anilines as a by-product. The use of simple inexpensive starting materials, moderate to excellent yields, metal-free procedure, short reaction time, mild reac-tion conditions and easy purification procedure present the notable advantages of this method. Studies on the biological activities of these products and the further application of the reactions are currently undergoing in our laboratory.

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