Synthesis of New 2-Arylbenzo[b]furan Derivatives via ... - MDPI

Download PDF
0 downloads 0 Views 5MB Size Report
Comment
Sep 25, 2018 - architectural motif that is ubiquitous in medicinal chemistry. Keywords: heterobiaryl compounds; palladium(II) complex catalyst; Suzuki ...
molecules Communication

Synthesis of New 2-Arylbenzo[b]furan Derivatives via Palladium-Catalyzed Suzuki Cross-Coupling Reactions in Aqueous Media Qianqian Chen 1 , Panli Jiang 2 , Mengping Guo 2, * 1

2

*

and Jianxin Yang 1, *

Laboratory of Green Catalysis and Reaction Engineering of Haikou, Hainan Provincial Fine Chemical Engineering Research Center, College of Chemistry and Chemical Engineering, Hainan University, Haikou 570228, China; [email protected] Institute of Coordination Catalysis, College of Chemistry and Bio-Engineering, Yichun University, Yichun 336000, China; [email protected] Correspondence: [email protected] (M.G.); [email protected] (J.Y.); Tel.: +86-079-5320-0535 (M.G.)

Received: 16 August 2018; Accepted: 21 September 2018; Published: 25 September 2018

 

Abstract: 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 K2 CO3 , EtOH/H2 O 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. Keywords: heterobiaryl compounds; palladium(II) complex catalyst; Suzuki cross-coupling; aqueous phase

1. Introduction 2-Arylbenzo[b]furan moiety is a common structural subunit found in natural products [1–3] and synthetic compounds with important biological activities [4–7]. For example, a representative complex of the natural 3-deformylated 2-arylbenzo[b]furan is ailanthoidol in (Figure 1, 1), which was isolated from the chloroform-soluble fraction of the tree of Zanthoxylum ailanthoides, was found to have a broad range of biological activities such as anticancer [8], immunosuppressive [9–11], antivirus [12–15], antioxidant [10,11], antifungal [16], and antifeedant activities [17]. Meanwhile, 5-(3-hydroxypropyl-7-methoxy-2-(30 -methoxy-40 -hydroxyphenyl)benzo[b]furan-3-carbaldehyde (XH-14) (Figure 1, 2), which has been widely used in China for the treatment of coronary heart diseases such as myocardial infarction and angina pectoris [18], was isolated from the plant Salvia miltorrhiza Bunge (Chinese name “Danshen”). Jun [19] obtained three XH-14 analogues whose anti-inflammatory effects were examined in lipopolysaccharide(LPS)-stimulated RAW 264-7 macrophages. The results showed that three structurally modified derivatives (Figure 1, 3a–3c) inhibited significantly the production of inflammatory mediator nitric oxide without showing cytotoxicity. Moreover, Nishi and coworkers synthesized a series of 2-phenylbenzofuran derivatives with both carboxy and 5- or 6-diphenylmethylcarbamoyl groups (Figure 1, 4a–4c), which showed inhibitory activities against both enzymes and were more active against human type I enzyme than against type II enzyme [20].

Molecules 2018, 23, 2450; doi:10.3390/molecules23102450

www.mdpi.com/journal/molecules

Molecules 2018, 23, x FOR PEER REVIEW

2 of 7

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 [24–28]. This paper describes the Suzuki reaction applied to the synthesis of novel benzofuran derivatives Molecules 2018, 23, 2450 2 of 7 containing biaryl moiety.

Figure 1. Relevant molecules with a 2-arylbenzo[b]furan moiety. moiety.

Motivated by the above-mentioned 2-arylbenzo[b]furan derivatives as valuable building blocks 2. Results and Discussion with a wide range of biological activities, to discover new potentially active agents, in this research, The designed novel benzofuran derivatives containing biaryl moiety (9) were prepared in two a series of novel benzofuran derivatives containing biaryl moiety were designed and synthesized. steps (Scheme 1). First, 2-(4-bromophenyl)benzofuran (7) was obtained following the method, Biaryls are recurring functional groups in many natural products, pharmaceuticals and bioactive Pd(II)/CuI/PPh3-co-catalyzed coupling-cyclization reaction of the commercially available 2compounds [21–23]. Palladium-catalyzed cross-coupling of aryl halides with organoboronic acids, iodophenol (5) with 4-bromo-1-ethynylbenzene (6) in the presence of NEt3 in water at 80 °C, reported known as the Suzuki cross-coupling reaction, is a versatile and highly utilized reaction for the selective by the Guo group [29]. Second, the optimal reaction conditions were studied by employing the Suzuki formation of carbon-carbon bonds, in particular for the synthesis of biaryls [24–28]. This paper cross-coupling of 2-(4-bromophenyl)benzofuran (7) with 4-methoxyphenylboronic acid as model describes the Suzuki reaction applied to the synthesis of novel benzofuran derivatives containing reaction for the synthesis of the 2-arylbenzo[b]furan derivatives. As can be seen in Table 1, we first biaryl moiety. examined the catalytic activity using common palladium salts PdCl2 or Pd(OAc)2 as catalyst in the presence K2CO 3 in EtOH/H2O (1:1) at 80 °C, only moderate yields of 55% or 61% were achieved 2. Resultsofand Discussion (Table 1, entries 1–2), but the reaction proceeded well in 91% yield in the presence of our newly The designed novel benzofuran containing biaryl moiety (9) were prepared1 developed Pd(II) complex catalyst (10) derivatives [30] (Table 1, entry 3). Compared to loading of catalyst in two steps (Scheme 1). First, 2-(4-bromophenyl)benzofuran (7) was obtained following the mol%–4 mol%, the yield was obviously enhanced to 97% when 3 mol% Pd(II) complex catalyst was method, Pd(II)/CuI/PPh coupling-cyclization reaction of the commercially available 3 -co-catalyzed used (Table 1, entry 5). The effects of base on the reaction were next examined. 28%, 40%, 53%, 78% ◦ C, reported 2-iodophenol (5) with 4-bromo-1-ethynylbenzene (6) in the presence of NEt in water at 80 3 and 63% yield of the desired product was obtained when using NEt3, NaF, NaHCO3, NaOH and by the 3Guo group [29]. Second, the1,optimal reaction conditions were studied employing the Cs2CO as a base, respectively (Table entries 7–11). Replacing co-solvent EtOH/Hby 2O (1:1) with H2O, Suzuki cross-coupling 2-(4-bromophenyl)benzofuran (7) withrespectively, 4-methoxyphenylboronic acid as EtOH, DMF or DMSO of further optimized the reaction condition giving the product in model reaction for the synthesis of the 2-arylbenzo[b]furan derivatives. As can be seen in Table 1, only trace amounts (Table 1, entries 12–15). Further optimizations showed that increasing the reaction we first examined the catalytic activity using common palladium salts PdCl or Pd(OAc) as catalyst 2 2 time did not improve the reaction outcome (Table 1, entries 17–21) and decreasing reaction ◦ C, only moderate yields of 55% or 61% were in the presence of K CO in EtOH/H O (1:1) at 80 2 3 2 temperature obtained poor yields (Table 1, entries 16–17). 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

Molecules 2018, 23, 2450

3 of 7

Cs2 CO3 as a base, respectively (Table 1, entries 7–11). Replacing co-solvent EtOH/H2 O (1:1) with H2 O, EtOH, DMF or DMSO further optimized the reaction condition respectively, giving the product in only trace amounts (Table 1, entries 12–15). Further optimizations showed that increasing the reaction time did not improve the reaction outcome (Table 1, entries 17–21) and decreasing reaction temperature obtained2018, poor (Table 1, entries 16–17). Molecules 23,yields x FOR PEER REVIEW 3 of 7 1 mol% Cat. 2 mol%CuI/4 mol%PPh33

I + Br

3eq NEt33, 2 mL H22O, 80 ooC

OH

Pd(II) K22CO33

Br + (HO)22B

O 7

6

5

R22

R22

O

R11 8

R11 9

Scheme 1. Synthesis of benzofuran derivatives containing biaryl moiety 9. Table 1. Screening of reaction conditions aa. Table 1. Screening of reaction conditions .

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21

Loading of Loading of Catalyst Catalyst (mol%) (mol%) 2 22 22 12 1 3 3 4 4 3 3 3 3 33 33 33 33 33 33 33 33 33 33 33 33 33

Solvent (mL) Temperature (h) Yieldbbb (%) Temperature Time Time Yield (1:1)(mL) (1:1) (°C)◦ Solvent ( C) (h) (%) PdCl22 EtOH + H22O 80 4 55 1 PdCl222 EtOH +22H 55 61 Pd(OAc) EtOH +H O2O 80 80 44 2 Pd(OAc) EtOH +22H 61 91 Pd(II) (10) 2 EtOH +H O2O 80 80 44 3 Pd(II) (10) EtOH + H O 80 4 91 62 2 Pd(II) (10) EtOH + H22O 80 4 4 Pd(II) (10) EtOH + H O 80 4 62 97 2 Pd(II) (10) EtOH + H22O 80 4 5 Pd(II) (10) EtOH + H O 80 4 97 Pd(II) (10) EtOH + H22O 2 80 4 95 6 Pd(II) (10) EtOH + H2 O 80 4 95 Pd(II) (10) EtOH + H22O 80 4 28 7 Pd(II) (10) EtOH + H2 O 80 4 28 Pd(II) (10) EtOH + H22O 80 4 40 8 Pd(II) (10) EtOH + H2 O 80 4 40 Pd(II) (10)(10) EtOH +H O O 80 80 44 53 9 Pd(II) EtOH +22H 53 2 Pd(II) (10) EtOH + H 22O 80 4 10 Pd(II) (10) EtOH + H2 O 80 4 78 78 Pd(II) (10)(10) EtOH +H O O 80 80 44 11 Pd(II) EtOH +22H 63 63 2 Pd(II) (10)(10) EtOH 80 80 44 12 Pd(II) EtOH 32 32 Pd(II) (10)(10) H22H O2 O 80 80 44 13 Pd(II) 0 0 Pd(II) (10)(10) DMSO 80 80 4 14 Pd(II) DMSO 0 0 Pd(II) (10)(10) DMF 80 80 4 trace 15 Pd(II) DMF trace 16 Pd(II) EtOH +22H 13 13 Pd(II) (10)(10) EtOH +H O2O 40 40 4 17 Pd(II) EtOH +22H 47 47 Pd(II) (10)(10) EtOH +H O2O 60 60 4 18 Pd(II) EtOH +22H 71 71 Pd(II) (10)(10) EtOH +H O2O 80 80 11 19 Pd(II) EtOH +22H 93 93 Pd(II) (10)(10) EtOH +H O2O 80 80 22 20 Pd(II) EtOH +22H 95 95 Pd(II) (10)(10) EtOH +H O2O 80 80 33 21 Pd(II) EtOH +22H 98 98 Pd(II) (10)(10) EtOH +H O2O 80 80 55 a a Reaction Reaction conditions: 0.050.05 mmol 2-(4-bromophenyl)benzofuran, 0.08 mmol0.08 4-methoxyphenylboronic acid, 0.1 mmol conditions: mmol 2-(4-bromophenyl)benzofuran, mmol 4-methoxyphenylboronic base, 6 mL solvent, in air. b Isolated yield. b

Entry Entry

Catalyst Catalyst

Base Base (mmol) (mmol) K22CO33 K CO333 K222CO K CO333 K222CO K CO33 2 K22CO 3 K CO 2 K22CO333 K2 CO3 K22CO33 K2 CO3 NEt33 NEt3 NaF NaF KHCO KHCO333 NaOH NaOH Cs22CO 33 Cs 2 CO3 K222CO K CO333 K222CO K CO333 K222CO CO333 K222CO CO333 K22CO CO333 K CO333 K22CO K CO333 K22CO K CO333 K22CO K CO333 K222CO K CO333 K222CO

acid, 0.1 mmol base, 6 mL solvent, in air. Isolated yield.

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).

Molecules 2018, 23, 2450

4 of 7

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).

Molecules 2018, 23,23, x FOR PEER REVIEW Molecules 2018, 23, xxFOR FOR PEER REVIEW Molecules 2018, PEER REVIEW Molecules 2018, 23, FOR PEER REVIEW Molecules 2018, x FOR PEER REVIEW Molecules 2018, 23, x xFOR PEER REVIEW Molecules 2018, 23, xx23, FOR PEER REVIEW Molecules 2018, 23, x FOR PEER REVIEW Molecules 2018, 23, FOR PEER REVIEW Molecules 2018, 23, x FOR PEER REVIEW Molecules 2018, 23, x FOR PEER REVIEW Molecules 2018, 23, x FOR PEER REVIEW Molecules Molecules 2018,2018, 23, x23, FOR x FOR PEER PEER REVIEW REVIEW Table 2. Synthesis of new 2-arylbenzo[b]furan derivatives a .a

Entry Entry Entry Entry Entry Entry Entry Entry Entry Entry Entry Entry Entry Entry Entry 1 1111 11 1 11 11 111

2 222 22 2 22 22 222 3 333 33 3333 33 333 4 444 44 4444 4 44 44 5 555 55 5555 55 555 6 666 66 6 66 66 6666

7 777 77 7 77 77 7777

4 of 7of77 44of of of 4 4of 7 777 44 of 7474 of of 4 of 44 of 7 4 of 777 of 74 of

Table 2. 2. Synthesis ofof new 2-arylbenzo[b]furan derivatives . a.aaa.. Table 2. Synthesis of new 2-arylbenzo[b]furan derivatives Table Synthesis new 2-arylbenzo[b]furan derivatives Table 2. Synthesis of new 2-arylbenzo[b]furan derivatives Table 2. Synthesis of new 2-arylbenzo[b]furan derivatives Table 2.Synthesis Synthesis ofnew new 2-arylbenzo[b]furan derivatives a. a. a.. Table 2. of 2-arylbenzo[b]furan derivatives Table 2. Synthesis of new 2-arylbenzo[b]furan derivatives a a. Table 2. Synthesis Synthesis of new new 2-arylbenzo[b]furan derivatives Table 2. Synthesis of 2-arylbenzo[b]furan derivatives b (%) aa.. a Arylboronic Product (9) Table 2. of 2-arylbenzo[b]furan derivatives Table 2.Acid Synthesis of new new 2-arylbenzo[b]furan derivatives b (%) Table Table 2. Synthesis 2. Synthesis of new of new 2-arylbenzo[b]furan 2-arylbenzo[b]furan derivatives derivatives . a.. Yield Arylboronic Acid (8)(8) Product (9)(9) Yield Arylboronic Acid (8) Product (9) Yield (%) bbb(%) Arylboronic Acid (8) Product Yield b (%) Arylboronic Acid (8) Product (9) Yield (%) Arylboronic Acid Product Yield Arylboronic Acid (8)(8) Product (9)(9) Yield b b (%) b

Arylboronic Acid (8) Arylboronic Acid Arylboronic Acid (8) (8) Arylboronic Acid (8) Arylboronic Acid (8) Arylboronic Acid (8) Arylboronic Acid Acid (8)2 (8) H3Arylboronic CO B(OH) H CO B(OH) 2 H 3CO B(OH) H333CO CO H3H CO H H 3CO H33CO CO H 3CO H CO H CO H33CO H33CO

B(OH)222 B(OH) B(OH) B(OH) B(OH) 2 2 2 B(OH) B(OH) 2 2 B(OH) B(OH) 2 2 B(OH) 8a8a 8aB(OH) 2 2

8a 8a8a 8a 8a 8a 8a 8a 8a 8a 8a COC H COC

H3H 3COC H3 3COC COC H3H COC 3COC H H 3COC 3 H H 3COC H H33COC COC H3COC COC H COC 3

3

B(OH) B(OH) 2 2 B(OH) B(OH) 22 B(OH) B(OH) 2 B(OH) B(OH) 2 2 2 B(OH) B(OH) 2 2 B(OH) 2 2 8b8bB(OH) B(OH) B(OH)

8b 8b 8b 8b 8b 8b 8b 8b 8b 8b 8b 8b 8b

2

2 2 B(OH) B(OH) 22 B(OH) B(OH) 2 B(OH) B(OH) 2 2 2 B(OH) B(OH) 2 2 B(OH) B(OH) 2 2 B(OH) B(OH) 2 2

8d8d 8d 8d 8d8d 8d 8d 8d 8d 8d 8dB(OH) 8d B(OH) 8d

2 2 B(OH) B(OH) 22 B(OH) B(OH) 2 B(OH) B(OH) 2 2 2 B(OH) B(OH) 2 2 B(OH) B(OH) 2 2 B(OH) B(OH) 2

O OO O OO O O O O O O O O

2

B(OH) B(OH) 2 2 B(OH) B(OH) 22 B(OH) B(OH) 2 B(OH) B(OH) 2 2 2 B(OH) B(OH) 2 2 B(OH) 2 2 B(OH) B(OH) 8c 8cB(OH)

2 8c 8c 8c8c 8c 8c 8c 8c 8c 8c 8c B(OH) 8cB(OH)

Product (9) Product O OO Product (9) (9) (9) O Product Product (9) Product (9) OCH OO Product Product (9) (9) O OCH O 3 3 OCH O O OCH 33 OCH OCH O O 3 OCH OCH O O 3 3 3 OCH OCH 3 3 OCH OCH 3 3 OCHOCH 3 3 9a 9a9a

O OO O OO O O O O O O O O

9a 9a 9a9a 9a 9a 9a 9a 9a 9a 9a 9a

9b9b 9b 9b 9b 9b9b 9b 9b 9b 9b 9b 9b 9b 9b

COCH COCH 3 3 COCH COCH 33 COCH COCH 3 COCH COCH 3 3 3 COCH COCH 3 3 COCH COCH 3 3 COCH COCH 3 3

9c 9c9c9c 9c 9c

92 92

O OO 9c 9c O 9c OO 9c O O O O O O O O

9595 95

95 9595 95 95 95 95 95 95 95

9d9d 9d 9d 9d9d 9d 9d 9d 9d

95 95

O OO9d 9d O9d OO 9d O O O O O O O O

F FF F B(OH)222 B(OH) F F B(OH) F B(OH) F B(OH) 2 2 2 F B(OH) F B(OH) 2 2 F B(OH) F B(OH) 2 2 F F FF B(OH) B(OH) 2 2 F F F F F 8f F 8f F F F 8f8f 8f 8f F F 8f 8f 8f 8f F FF 8f 8f 8f F 8f 8f F F F F F F F F B(OH) F F B(OH) 2 2 B(OH) B(OH) 22 B(OH) B(OH) 2 B(OH) B(OH) 2 2 2 B(OH) B(OH) 2 2 B(OH) B(OH) 2 2 F FF B(OH) B(OH) 2 2 F F F F F 8g8g F F 8g F 8g F 8g F F 8g 8g 8g

9e9e 9e 9e 9e9e 9e 9e 9e 9e

O OO 9e 9e O 9e OO O O 9e O O O O O O

9f9f 9f 9f 9f9f 9f 9f 9f 9f 9f 9f 9f 9f

O OO O OO O O O O O O O O

97 97 97 97 97 97 9292

8585 85 85 85 85

8585 85 85 85 85 85 85 85

2

8e8e 8e 8e 8e8e 8e 8e 8e 8e 8e 8e 8e 8e B(OH) B(OH) 2 2 B(OH)

97 97 97 97 97 979797 97

92 92 92 9292 92 92 92 92 92 92

9c 9c 9c 9c 9c

2

Yield Yield b (%) b (%) Yield (%) Yield b b (%) Yield b (%) b Yield (%) Yield Yield (%) (%) 97 9797 97 97 9797 97 97 97 97 97 97 97 97

F FF F F F F F F F F F FF F FF F F F F F F F F F F F F FF F F F F F F F F F F F F FF F F F F F F F F F F F

7878 78 78 7878 78 78 78 78 78 78 78 78 78

9696 96 96 9696 96 96 96 96 96 96 96 96 96

9g9g 9g 9g 9g9g 9g 9g 8g 8g 9g 9g Reaction conditions: 0.05 mmol 2-(4-bromophenyl)benzofuran, mmol arylboronic acid, 0.10.1 Reaction conditions: 0.05 mmol 2-(4-bromophenyl)benzofuran, 0.08 mmol arylboronic acid, 0.1 8g 8g 9g 9g 0.08 Reaction conditions: 0.05 mmol 2-(4-bromophenyl)benzofuran, 0.08 mmol arylboronic acid, 8g 8g 8gmmol Reaction conditions: 0.05 mmol 2-(4-bromophenyl)benzofuran, 0.08 mmol arylboronic acid, 0.1 9g 9g Reaction conditions: 0.05 mmol 2-(4-bromophenyl)benzofuran, 0.08 mmol arylboronic acid, Reaction conditions: 0.05 2-(4-bromophenyl)benzofuran, 0.08 mmol arylboronic acid, 0.10.1

a a aa a a a a a a aaa aa

Reaction conditions: 0.05 mmol 2-(4-bromophenyl)benzofuran, mmol arylboronic acid, 0.1 Reaction conditions: 0.05 mmol 0.08 mmol arylboronic b Isolated b Isolated mmol K2KCO 3, 3% mmol Pd(II) (10), 6 mL EtOH +H 2H O 8080 °C, 40.08 h, in air. yield. Reaction conditions: 0.05 mmol 2-(4-bromophenyl)benzofuran, 0.08 mmol arylboronic acid,acid, 0.1 0.1 Reaction conditions: 0.05 mmol 2-(4-bromophenyl)benzofuran, 0.08 mmol arylboronic acid, 0.1 mmol K 2CO 3% mmol Pd(II) (10), 662-(4-bromophenyl)benzofuran, mL EtOH ++H 2(1:1), O (1:1), 80 °C, 44h, h, in air. yield. b mmol 2conditions: CO 3conditions: ,333,,,3% mmol Pd(II) (10), 6mL mL EtOH +H 2O (1:1), °C, 4h, in air. Isolated yield. Reaction 0.05 mmol 2-(4-bromophenyl)benzofuran, 0.08 mmol arylboronic acid, 0.1 Reaction 0.05 mmol 2-(4-bromophenyl)benzofuran, 0.08 mmol arylboronic acid, 0.1 bbacid, mmol K CO 3% mmol Pd(II) (10), mL EtOH H O (1:1), 80 °C, h, in air. Isolated yield. b Isolated Reaction conditions: 0.05 mmol 2-(4-bromophenyl)benzofuran, 0.08 mmol arylboronic 0.1 mmol K CO Reaction Reaction conditions: conditions: 0.05 0.05 mmol mmol 2-(4-bromophenyl)benzofuran, 2-(4-bromophenyl)benzofuran, 0.08 0.08 mmol mmol arylboronic arylboronic acid, acid, 0.13 , 0.1 mmol K 22CO 3% mmol Pd(II) (10), 6 mL EtOH + H 22O (1:1), 80 °C, 4 h, in air. Isolated yield. mmol K 2 CO 3 , 3% mmol Pd(II) (10), 6 EtOH + 2 O (1:1), 80 °C, 4 in air. yield. b b 2 mmol K 2CO ,, 3% Pd(II) (10), 66 mL EtOH + H 2+ O (1:1), 80 °C, 4 h, in air. yield. mmol K2233CO CO 3, mmol 3% mmol mmol Pd(II) (10), 6 mL mL EtOH H 2O (1:1), 80 °C, 4 h, in air. Isolated yield. b Isolated b Isolated mmol K 2CO 3% Pd(II) (10), mL EtOH + H 2 O (1:1), 80 °C, 4 h, in air. Isolated yield. mmol K 3, mmol 3% Pd(II) (10), 6 EtOH + H 2 O (1:1), 80 °C, 4 h, in air. yield. ◦ C, 4+h, b Isolated yield. b b Isolated 3% mmol Pd(II) (10), 6 mL EtOH + H O (1:1), 80 in air. mmol K 2 CO 3 , 3% mmol Pd(II) (10), 6 mL EtOH H 2 O (1:1), 80 °C, 4 h, in air. Isolated yield. b b mmol K 2 CO 3 , 3% mmol Pd(II) (10), 6 mL EtOH + H 2 O (1:1), 80 °C, 4 h, in air. yield. 2 (10), mmol mmol K2CO K23CO , 3%3, mmol 3% mmol Pd(II) Pd(II) (10), 6 mL 6 mL EtOH EtOH + H2+OH(1:1), 2O (1:1), 80 °C, 80 4°C, h, 4inh,air. in air. Isolated Isolated yield. yield.

3.3.Experimental 3. Experimental Experimental 3. Experimental 3. Experimental 3.Experimental Experimental 3. 3. Experimental 3. Experimental 3. 3. 3. Experimental Experimental 3. Experimental Experimental 3. Experimental 3. Experimental 3.1. General Information 3.1. General Information 3.1. General Information 3.1. General Information 3.1. General Information 3.1. General Information 3.1. General Information 3.1. General Information 3.1. General Information 3.1. General Information 3.1. General Information 3.1. General Information 3.1. General Information 3.1.3.1. General General Information Information Commercial reagents employed inin the synthesis were analytical grade, obtained from Alfa Aesar Commercial reagents employed in the synthesis were analytical grade, obtained from Alfa Aesar Commercial reagents employed the synthesis were analytical grade, obtained from Alfa Aesar Commercial reagents employed in the synthesis were analytical grade, obtained from Alfa Aesar Commercial reagents employed in the synthesis were analytical grade, obtained from Alfa Aesar Commercial reagents employed inthe the synthesis were analytical grade, obtained from Alfa Aesar Commercial reagents employed in synthesis were analytical grade, obtained from Alfa Aesar Commercial reagents employed in the synthesis were analytical grade, obtained from Alfa Aesar Commercial reagents employed in the synthesis were analytical grade, obtained from Alfa Aesar 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 (Ward Hill, MA, USA) and used as received without any prior purification. Silica gel GF254 (Qingdao Commercial reagents the synthesis were analytical grade, obtained from Alfa Aesar 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 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 Commercial Commercial reagents reagents employed employed inreceived the in the synthesis synthesis were were analytical analytical grade, grade, obtained obtained from from Alfa Alfa Aesar Aesar (Ward Hill, MA, USA) and used as without any prior purification. Silica GF254 (Qingdao (Ward Hill, MA, USA) and used asreceived received without any prior purification. Silica gelgel GF254 (Qingdao (Ward Hill, MA, USA) and used as without any prior purification. Silica gel GF254 (Qingdao (Ward Hill, MA, USA) and used as received without any prior purification. Silica gel GF254 (Qingdao (Ward Hill, MA, USA) and used as received without any prior purification. Silica gel GF254 (Qingdao (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 Haiyang Chemical Co., Ltd., Qingdao, China) was used for analytical thin-layer chromatography (Ward as received without any prior purification. Silica gel GF254 (Qingdao (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 (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 (Ward (Ward Hill, Hill, MA, MA, USA) USA) and and used used asQingdao, received as received without without any any prior prior purification. Silica Silica gelchromatography gel GF254 GF254 (Qingdao (Qingdao Haiyang Chemical Co., Ltd., China) was used for analytical thin-layer chromatography Haiyang Chemical Co., Ltd., Qingdao, China) was used forpurification. analytical thin-layer chromatography Haiyang Chemical Co., Ltd., Qingdao, China) was used for analytical thin-layer Haiyang Chemical Co., Ltd., Qingdao, China) was used for analytical thin-layer chromatography 1H-NMR, 13C13CHaiyang Chemical Co., Ltd., Qingdao, China) was used for analytical thin-layer chromatography Haiyang Chemical Co., Ltd., Qingdao, China) was used for analytical thin-layer chromatography (TLC) (glass coating 0.25 mm thick) using hexane and dichloromethane asas the eluent. (TLC) (glass coating 0.25 mm thick) using hexane and dichloromethane as the eluent. H-NMR, 11H-NMR, 13 13 Haiyang Chemical Co., Ltd., Qingdao, China) was used for analytical thin-layer chromatography Haiyang Chemical Co., Ltd., Qingdao, China) was used for analytical thin-layer chromatography (TLC) (glass coating 0.25 mm thick) using hexane and dichloromethane the eluent. CHaiyang Chemical Co., Ltd., Qingdao, China) was used for analytical thin-layer chromatography 11H-NMR, 13 (TLC) (glass coating 0.25 mm thick) using hexane and dichloromethane as the eluent. H-NMR, C1 13CHaiyang Haiyang Chemical Chemical Co., Co., Ltd., Ltd., Qingdao, Qingdao, China) China) was was used used for for analytical analytical thin-layer thin-layer chromatography chromatography (TLC) (glass coating 0.25 mm thick) using hexane and dichloromethane as the eluent. (TLC) (glass coating 0.25 mm thick) using hexane and dichloromethane asthe the eluent. H-NMR, 1H-NMR, 13C1H-NMR, 13C(TLC) (glass coating 0.25 mm thick) using hexane and dichloromethane as eluent. (TLC) (glass coating 0.25 mm thick) using hexane and dichloromethane as the eluent. 1 13 1 13C1 (TLC) (glass coating 0.25 mm thick) using hexane and dichloromethane as the eluent. H-NMR, C(TLC) (glass coating 0.25 mm thick) using hexane and dichloromethane as the eluent. H-NMR, NMR spectra were recorded on a BRUKER DRX (400 MHz) spectrometer (Billerica, MA, USA) using 1 13 NMR spectra were recorded on a BRUKER DRX (400 MHz) spectrometer (Billerica, MA, USA) using 1 13C(TLC) (glass coating 0.25 mm thick) using hexane and dichloromethane as the H-NMR, (TLC) (glass coating 0.25 mm thick) using hexane and dichloromethane as the eluent. H-NMR, CNMR spectra were recorded on a BRUKER DRX (400 MHz) spectrometer (Billerica, MA, USA) using 1 1 13 13 (TLC) (glass coating 0.25 mm thick) using hexane and dichloromethane as eluent. H-NMR, CNMR spectra were recorded on a BRUKER DRX (400 MHz) spectrometer (Billerica, MA, USA) using (TLC) (TLC) (glass (glass coating coating 0.25 0.25 mmon mm thick) using hexane hexane and and dichloromethane dichloromethane as(Billerica, the as(Billerica, the eluent. eluent. H-NMR, H-NMR, CCNMR spectra were recorded aausing BRUKER DRX (400 MHz) spectrometer MA, USA) using NMR spectra were recorded onaon athick) BRUKER DRX (400 MHz) spectrometer (Billerica, MA, USA) using NMR spectra were recorded BRUKER DRX (400 MHz) spectrometer MA, USA) using NMR spectra were recorded on BRUKER DRX (400 MHz) spectrometer (Billerica, MA, USA) using 13 NMR spectra were recorded on a BRUKER DRX (400 spectrometer (Billerica, MA, USA) using NMR spectra were recorded on a BRUKER DRX (400 MHz) (Billerica, MA, USA) using tetramethylsilane as the internal standard and CDCl 3MHz) or CD 2Cl2spectrometer 2Cl as the solvent. Low-resolution masstetramethylsilane as the internal standard and CDCl 3or or CD 2spectrometer as the solvent. Low-resolution massC-NMR spectra were recorded on a BRUKER DRX (400 MHz) (Billerica, MA, USA) NMR spectra were recorded on a BRUKER DRX (400 MHz) spectrometer (Billerica, MA, USA) using tetramethylsilane as the internal standard and CDCl 3 CD 2 Cl 2 as the solvent. Low-resolution massNMR spectra were recorded on a BRUKER DRX (400 MHz) spectrometer (Billerica, MA, USA) using tetramethylsilane as the internal standard and CDCl or CD Cl as the solvent. Low-resolution massNMR NMR spectra spectra were were recorded recorded on aon BRUKER astandard BRUKER DRX DRX (400 (400 MHz) MHz) spectrometer (Billerica, (Billerica, MA,MA, USA) USA) using using tetramethylsilane as the internal and CDCl 33 or CD 22spectrometer Cl 22 as the solvent. Low-resolution masstetramethylsilane asthe the internal standard and CDCl 3 or CD 2Cl 2 as the solvent. Low-resolution masstetramethylsilane as internal standard and CDCl 3 or 2CD Cl as solvent. Low-resolution masstetramethylsilane as the internal standard and CDCl 3CD or 2Cl 2the as the solvent. Low-resolution masstetramethylsilane as the internal standard and CDCl 3 or 3CD 2CD Cl2CD 22Cl as solvent. Low-resolution masstetramethylsilane as the internal standard and CDCl or 2the as the solvent. Low-resolution massspectra were recorded on anan Agilent gas chromatography mass spectrometry 7890A-5795C spectra were recorded on an Agilent gas chromatography mass spectrometry 7890A-5795C using tetramethylsilane as the internal standard and or Cl as the solvent. Low-resolution tetramethylsilane as the internal standard and CDCl 33CDCl or 22CD Cl 2222as solvent. Low-resolution massspectra were recorded on Agilent gas chromatography mass spectrometry 7890A-5795C tetramethylsilane as the internal standard and CDCl 3CD or CD Cl 2the as the solvent. Low-resolution mass3 2 2 spectra were recorded on an Agilent gas chromatography mass spectrometry 7890A-5795C tetramethylsilane tetramethylsilane as the as the internal internal standard standard and and CDCl CDCl or 3 CD or Cl Cl as 2 the as the solvent. solvent. Low-resolution Low-resolution massmassspectra were recorded Agilent gas chromatography mass spectrometry 7890A-5795C spectra were recorded onon anan Agilent gas chromatography mass spectrometry 7890A-5795C spectra were recorded on an Agilent gas chromatography mass spectrometry 7890A-5795C spectra were recorded an Agilent gas chromatography mass spectrometry 7890A-5795C spectra were recorded on on an Agilent gas chromatography mass spectrometry 7890A-5795C 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 instrument. High-resolution mass spectra (HRMS) were obtained using Agilent 6210 ESI/TOF mass mass-spectra were recorded on Agilent gas chromatography mass spectrometry 7890A-5795C 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 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 spectra spectra were were recorded recorded on on an an Agilent Agilent gas gas chromatography chromatography mass mass spectrometry spectrometry 7890A-5795C 7890A-5795C instrument. High-resolution mass spectra (HRMS) were obtained using Agilent 6210 ESI/TOF mass instrument. High-resolution mass spectra (HRMS) were obtained using Agilent 6210 ESI/TOF mass instrument. High-resolution mass spectra (HRMS) were obtained using Agilent 6210 ESI/TOF mass instrument. High-resolution mass spectra (HRMS) were obtained using Agilent 6210 ESI/TOF mass instrument. High-resolution mass spectra (HRMS) were obtained using Agilent 6210 ESI/TOF mass 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 spectrometer (Santa Clara, CA, USA). Melting points were determined using a Mettler FP5 melting instrument. High-resolution mass spectra (HRMS) using Agilent 6210 ESI/TOF mass instrument. High-resolution mass spectra (HRMS) were obtained ESI/TOF mass spectrometer (Santa Clara, CA, USA). Melting points were determined using a Mettler FP5 melting instrument. High-resolution mass spectra (HRMS) were obtained using Agilent 6210 ESI/TOF mass spectrometer (Santa Clara, CA, USA). Melting points were determined using Mettler FP5 melting instrument. instrument. High-resolution High-resolution mass mass spectra spectra (HRMS) (HRMS) were were obtained obtained using using Agilent Agilent 6210 6210 ESI/TOF ESI/TOF mass mass spectrometer (Santa Clara, CA, USA). Melting points were determined using aaa Mettler FP5 melting spectrometer (Santa Clara, CA, USA). Melting points were determined using Mettler FP5 melting spectrometer (Santa Clara, CA, USA). Melting points were determined using aa aMettler FP5 melting spectrometer (Santa Clara, CA, USA). Melting points were determined using melting 1H-NMR, 13C1FP5 spectrometer (Santa Clara, CA, USA). Melting points were determined using Mettler FP5 melting spectrometer (Santa Clara, CA, USA). Melting points were determined using aa Mettler Mettler melting point apparatus (Columbus, OH, USA) in open capillaries and were uncorrected. The point apparatus (Columbus, OH, USA) in open capillaries and were uncorrected. The H-NMR, C1H-NMR, 1313 1FP5 13 spectrometer (Santa Clara, CA, USA). Melting points were determined using a Mettler FP5 melting 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 Cspectrometer (Santa Clara, CA, USA). Melting points were determined using Mettler FP5 melting 1 13 point apparatus (Columbus, OH, USA) in open capillaries and were uncorrected. The H-NMR, C1 13 spectrometer spectrometer (Santa (Santa Clara, Clara, CA, CA, USA). USA). Melting Melting points points were were determined determined using using a Mettler a Mettler melting melting point apparatus (Columbus, OH, USA) in open capillaries and were uncorrected. The H-NMR, point apparatus (Columbus, OH, USA) in open capillaries and were uncorrected. The H-NMR, 1FP5 13C-C1FP5 13Cpoint apparatus (Columbus, OH, USA) in open capillaries and were uncorrected. The point apparatus (Columbus, OH, USA) in open capillaries and were uncorrected. The H-NMR, C1H-NMR, 13C- 13C1H-NMR, point apparatus (Columbus, OH, USA) in open capillaries and were uncorrected. The H-NMR, point apparatus (Columbus, OH, USA) in open capillaries and were uncorrected. The NMR and HRMS for all the synthesized compounds are available in the supplementary materials. NMR and HRMS for all the synthesized compounds are available in the supplementary materials. 11H-NMR, 13 1H-NMR, 13CNMR and HRMS for all the synthesized compounds are available in the supplementary materials. point apparatus (Columbus, OH, USA) in open capillaries and were uncorrected. The C1 13 13 point apparatus (Columbus, OH, USA) in open capillaries and were uncorrected. The NMR and HRMS for all the synthesized compounds are available in the supplementary materials. point point apparatus apparatus (Columbus, (Columbus, OH,OH, USA) USA) in open in open capillaries capillaries and and were were uncorrected. uncorrected. TheThe H-NMR, H-NMR, C- CNMR and HRMS synthesized compounds are available the supplementary materials. NMR and HRMS forfor allall thethe synthesized compounds are available in in the supplementary materials. NMR and HRMS for the synthesized compounds are in supplementary materials. NMR HRMS for all the synthesized compounds are available in the supplementary materials. NMR andand HRMS for all all the synthesized compounds are available available in the the supplementary materials. NMR and HRMS for all the compounds are in the materials. NMR and HRMS for compounds are in materials. NMR and HRMS forthe all synthesized the synthesized synthesized compounds are available available in supplementary the supplementary supplementary materials. NMR NMR andand HRMS HRMS for all all for the all synthesized the synthesized compounds compounds are available available are available in the the in supplementary the supplementary materials. materials.

3.2. General Procedure forfor Suzuki Coupling 3.2. General Procedure for Suzuki Coupling 3.2. General Procedure Suzuki Coupling 3.2. General Procedure for Suzuki Coupling 3.2. General Procedure for Suzuki Coupling 3.2. General Procedure forSuzuki Suzuki Coupling 3.2. General Procedure for Coupling 3.2. General Procedure for Suzuki Coupling 3.2. General Procedure for Suzuki Coupling 3.2. General Procedure for Suzuki Coupling 3.2. General Procedure for Suzuki Coupling 3.2. General Procedure for Suzuki Coupling 3.2.3.2. General General Procedure Procedure for Suzuki for Suzuki Coupling Coupling 2-(4-Bromophenyl)benzofuran (0.05 mmol, 0.0137 g),g), palladium(II) (10) (0.0015 mmol, 0.0012 g),g), 2-(4-Bromophenyl)benzofuran (0.05 mmol, 0.0137 g), palladium(II) (10) (0.0015 mmol, 0.0012 g), 2-(4-Bromophenyl)benzofuran (0.05 mmol, 0.0137 palladium(II) (10) (0.0015 mmol, 0.0012 2-(4-Bromophenyl)benzofuran (0.05 mmol, 0.0137 g), palladium(II) (10) (0.0015 mmol, 0.0012 g), 2-(4-Bromophenyl)benzofuran (0.05 mmol, 0.0137 g), palladium(II) (10) (0.0015 mmol, 0.0012 2-(4-Bromophenyl)benzofuran (0.05 mmol, 0.0137 g),palladium(II) palladium(II) (10) (0.0015 mmol, 0.0012 g),g), 2-(4-Bromophenyl)benzofuran (0.05 mmol, 0.0137 g), (10) (0.0015 mmol, 0.0012 g), 2-(4-Bromophenyl)benzofuran (0.05 mmol, 0.0137 g), palladium(II) (10) (0.0015 mmol, 0.0012 g), 2-(4-Bromophenyl)benzofuran (0.05 mmol, 0.0137 g), palladium(II) (10) (0.0015 mmol, 0.0012 g), 2-(4-Bromophenyl)benzofuran (0.05 mmol, 0.0137 g), palladium(II) (10) (0.0015 mmol, 0.0012 KK 2K CO 3 (0.1 mmol, 0.0138 g) and relevant arylboronic acid (0.08 mmol) were dissolved in EtOH + H 2 O 2 CO 3 (0.1 mmol, 0.0138 g) and relevant arylboronic acid (0.08 mmol) were dissolved in EtOH + H 2O O (0.05 mmol, 0.0137 g), palladium(II) (0.0015 mmol, 0.0012 (0.05 mmol, 0.0137 g), palladium(II) (10) (0.0015 mmol, 0.0012 g), 22-(4-Bromophenyl)benzofuran CO2-(4-Bromophenyl)benzofuran 3 (0.1 mmol, 0.0138 g) and relevant arylboronic acid (0.08 mmol) (10) were dissolved in EtOH +g), H2g),

Molecules 2018, 23, 2450

5 of 7

point apparatus (Columbus, OH, USA) in open capillaries and were uncorrected. The 1 H-NMR, and HRMS for all the synthesized compounds are available in the supplementary materials.

13 C-NMR

3.2. General Procedure for Suzuki Coupling 2-(4-Bromophenyl)benzofuran (0.05 mmol, 0.0137 g), palladium(II) (10) (0.0015 mmol, 0.0012 g), K2 CO3 (0.1 mmol, 0.0138 g) and relevant arylboronic acid (0.08 mmol) were dissolved in EtOH + H2 O (v/v = 1:1, 6 mL) and the resulting suspension stirred at 80 ◦ C for 4 h. After cooling to ambient temperature brine (10 mL) was added to the mixture, the aqueous layer was extracted with dichloromethane (3 × 10 mL). The combined organic layers were dried (Na2 SO4 ) and concentrated, and the residue was purified by thin layer chromatography to give the 2-arylbenzo[b]furan derivatives 9a–9g. 2-(40 -Methoxybiphenyl-4-yl)benzofuran (9a). White powder m.p. 270–271 ◦ C; 1 H-NMR (400 MHz, CDCl3 ): δ 7.92 (d, J = 8.0 Hz, 2H), 7.65 (d, J = 8.0 Hz, 2H), 7.60–7.51 (m, 4H), 7.27–7.25 (m, 2H), 7.04 (s, 1H), 7.01 (d, J = 8.0 Hz, 2H), 3.86 (s, 3H). 13 C-NMR (100 MHz, CDCl3 ): δ 159.4, 155.8, 154.9, 140.8, 132.9, 129.3, 128.7, 128.0, 126.9, 125.3, 124.2, 122.9, 120.8, 114.3, 111.1, 101.1, 55.3. GC-MS (EI): 300.1 ([M]+ ). HRMS (ESI) m/z: calcd for C21 H16 O2 [M + H]+ 301.1223; found 301.1227. 1-(40 -Benzofuran-2-ylbiphenyl-4-yl)ethanone (9b). White powder m.p. 273–275 ◦ C; 1 H-NMR (400 MHz, CD2 Cl2 ): δ 7.97 (d, J = 8.0 Hz, 2H), 7.91 (d, J = 8.0 Hz, 2H), 7.69 (d, J = 8.0 Hz, 4H), 7.55 (d, J = 8.0 Hz, 1H), 7.47 (d, J = 8.0 Hz, 1H), 7.25–7.15 (m, 2H), 7.05 (s, 1H), 2.53 (s, 3H). 13 C-NMR (100 MHz, CD2 Cl2 ): δ 197.2, 155.3, 155.0, 144.6, 139.7, 136.1, 130.2, 129.1, 128.9, 127.5, 126.9, 125.3, 124.5, 123.0, 120.9, 111.0, 101.9, 26.4. GC-MS (EI): 312.2 ([M]+ ). HRMS (ESI) m/z: calcd for C22 H16 O2 [M + H]+ 313.1223; found 313.1219. 2-(40 -Propylbiphenyl-4-yl)benzofuran (9c). Pale yellow solid m.p. 244–246 ◦ C; 1 H NMR (400 MHz, CDCl3 ): δ 7.91 (d, J = 8.4 Hz, 2H), 7.66 (d, J = 8.5 Hz, 2H), 7.57 (d, J = 10.0 Hz, 2H), 7.53 (dd, J = 9.3, 1.3 Hz, 2H), 7.32–7.19 (m, 4H), 7.03 (d, J = 0.5 Hz, 1H), 2.70–2.56 (m, 2H), 1.77–1.59 (m, 2H), 0.98 (t, J = 7.3 Hz, 3H). 13 C NMR (100 MHz, CDCl3 ): δ 155.80, 154.93, 142.25, 141.21, 137.75, 129.30, 129.08, 128.99, 127.23, 126.78, 125.31, 124.22, 122.94, 120.85, 111.15, 101.26, 37.72, 24.54, 13.88. GC-MS (EI): 312.1 ([M]+ ). HRMS (ESI) m/z: calcd for C23 H20 O [M + H]+ 313.1587; found 313.1593. 2-(30 -Methylbiphenyl-4-yl)benzofuran (9d). Pale yellow solid mp 168–169 ◦ C (lit. 162–164 ◦ C [7]); 1 H-NMR (400 MHz, CDCl3 ): δ 7.93 (d, J = 8.0 Hz, 2H), 7.68 (d, J = 8.0 Hz, 2H), 7.59 (d, J = 8.0 Hz, 1H), 7.54 (d, J = 8.0 Hz, 1H), 7.45 (d, J = 8.0 Hz, 2H), 7.35 (t, J = 12.0 Hz, 1H), 7.30–7.17 (m, 3H), 7.05 (s, 1H), 2.43 (s, 3H). 13 C-NMR (100 MHz, CDCl3 ): δ 155.7, 154.9, 141.4, 140.4, 138.4, 131.9, 129.3, 128.7, 128.3, 127.7, 127.4, 125.3, 124.2, 124.1, 122.9, 120.8, 111.1, 101.3, 21.5. GC-MS (EI): 284.1 ([M]+ ). 2-(20 -Methylbiphenyl-4-yl)benzofuran (9e). Pale yellow solid m.p. 80–81 ◦ C; 1 H-NMR (400 MHz, CDCl3 ): δ 7.84 (d, J = 8.0 Hz, 2H), 7.53 (d, J = 8.0 Hz, 1H), 7.47 (d, J = 8.0 Hz, 1H), 7.35 (d, J = 8.0 Hz, 2H), 7.23–7.14 (m, 6H), 6.97 (s, 1H), 2.24 (s, 3H). 13 C-NMR (100 MHz, CDCl3 ): δ 154.8, 153.9, 141.2, 140.2, 134.3, 130.9, 129.4, 128.6, 128.2, 127.9, 126.4, 124.8, 123.6, 123.2, 121.9, 119.8, 110.1, 100.2, 19.4. GC-MS (EI): 284.1 ([M]+ ). HRMS (ESI) m/z: calcd for C21 H16 O [M + H]+ 285.1274; found 285.1279. 2-(30 ,40 -Difluorobiphenyl-4-yl)benzofuran (9f). White powder m.p. 195–197 ◦ C; 1 H-NMR (400 MHz, CDCl3 ): δ 7.93 (d, J = 8.5 Hz, 2H), 7.61 (d, J = 8.4 Hz, 2H), 7.60 (d, J = 8.3 Hz, 1H), 7.54 (d, J = 8.0 Hz, 1H), 7.43 (ddd, J = 11.5, 7.5, 2.2 Hz, 1H), 7.38–7.33 (m, 1H), 7.33–7.28 (m, 1H), 7.28–7.19 (m, 2H), 7.07 (s, 1H). 13 C-NMR (100 MHz, CDCl ): δ 155.27 (s), 154.96 (s), 150.58 (dd, J = 248.0, 12.8 Hz), 150.07 (dd, J = 248.8, 3 12.8 Hz), 139.01 (s), 137.54 (dd, J = 5.9, 3.9 Hz), 129.94 (s), 129.15 (s), 127.27 (s), 125.44 (s), 124.49 (s), 123.05 (s), 122.87 (dd, J = 6.2, 3.5 Hz), 120.97 (s), 117.64 (d, J = 17.2 Hz), 115.84 (d, J = 17.7 Hz), 111.20 (s), 101.78 (s). GC-MS (EI): 306.1 ([M]+ ). HRMS (ESI) m/z: calcd for C20 H12 F2 O [M + Na]+ 329.0748; found 329.0751. 2-(30 ,50 -Difluorobiphenyl-4-yl)benzofuran (9g). White powder m.p. 163–165 ◦ C; 1 H-NMR (400 MHz, CDCl3 ): δ 7.93 (d, J = 8.5 Hz, 2H), 7.62 (d, J = 8.6 Hz, 2H), 7.59 (dd, J = 8.0, 0.7 Hz, 1H), 7.53 (br d,

Molecules 2018, 23, 2450

6 of 7

J = 8.0 Hz, 1H), 7.35–7.27 (m, 1H), 7.27–7.21 (m, 1H), 7.19–7.09 (m, 2H), 7.07 (s, 1H), 6.80 (tt, J = 8.8, 2.3 Hz, 1H). 13 C-NMR (100 MHz, CDCl3 ): δ 163.38 (dd, J = 248.2, 13.1 Hz), 155.15 (s), 155.01 (s), 143.72 (t, J = 9.5 Hz), 138.69 (t, J = 2.5 Hz), 130.55 (s), 129.13 (s), 127.33 (s), 125.45 (s), 124.58 (s), 123.08 (s), 121.02 (s), 111.23 (s), 109.96–109.52 (m), 102.75 (t, J = 25.4 Hz), 102.02 (s). GC-MS (EI): 306.1 ([M]+ ). HRMS (ESI) m/z: calcd for C20 H12 F2 O [M + H]+ 307.0929; found 307.0934. 4. Conclusions In summary, a series of novel benzofuran derivatives containing biaryl moiety were designed and synthesized. This work establishes that 2-(4-bromophenyl)benzofuran are suitable substrates for Suzuki cross-coupling reactions with relevant arylboronic acids. We found that in the presence of Pd(II) (10) as palladium catalyst, the Suzuki reactions proceed in relatively good yields in aqueous medium. This could provide a promising access to new heterobiaryl compounds, valuable building blocks for use in medicinal chemistry. Supplementary Materials: The 1 H-NMR, available online.

13 C-NMR

and HRMS for all the synthesized compounds are

Author Contributions: Data Curation, Q.C. and P.J.; Writing—Original Draft Preparation, Q.C.; Writing—Review & Editing, M.G. and P.J.; Project Administration, M.G. and J.Y.; Funding Acquisition, M.G. and J.Y. Funding: This research was funded by the National Natural Science Foundation of China (Grant No. 51663009, 21063015) and Hainan Provincial Natural Science Foundation of China (Grant No. 20162017). Conflicts of Interest: The authors declare no conflict of interest.

References 1. 2.

3. 4.

5.

6. 7. 8. 9.

10.

11.

Donnelly, D.M.X.; Meegan, M.J.I. Comprehensive Heterocyclic Chemistry; Pergamon: New York, NY, USA, 1984. Maddali, L.N.R.; Dheeraj, K.; Awasthi, J.B.T. Palladium-catalyzed cross-couplings of functionalized 2-bromobenzofurans for atom-economic synthesis of 2-arylbenzofurans using triarylbismuth reagents. Tetrahedron Lett. 2012, 53, 2662–2666. Ruan, L.-B.; Shi, M.; Mao, S.-W.; Yu, L.-F.; Yang, F.; Tang, J. An efficient approach to construct 2-arylbenzo[b]furans from 2-methoxychalcone epoxides. Tetrahedron 2014, 70, 1065–1070. [CrossRef] Pieters, L.; Van, D.S.; Gao, M.; Bai, R.; Hamel, E.; Vlietinck, A.; Lemière, G. Synthesis and biological evaluation of dihydrobenzofuran lignans and related compounds as potential antitumor agents that inhibit tubulin polymerization. J. Med. Chem. 1999, 42, 5475–5481. [CrossRef] [PubMed] Apers, S.; Paper, D.; Bùrgermeister, J.; Baronikova, S.; Dyck, S.V.; Lemière, G.; Vlietinck, A.; Pieters, L. Antiangiogenic activitity of synthetic dihydrobenzofuran lignans. J. Nat. Prod. 2002, 65, 718–720. [CrossRef] [PubMed] Che, J.-X.; Li, J.-J.; Su, W.-K. Palladium-catalyzed tandem reaction of 2-hydroxyarylacetonitriles with sodium sulfinates: One-pot synthesis of 2-arylbenzofurans. Org. Biomol. Chem. 2014, 12, 4078–4083. Mandali, P.K.; Chand, D.K. Palladium nanoparticles catalyzed synthesis of benzofurans by a domino approach. Synthesis 2015, 47, 1661–1668. Sheen, W.-S.; Tsai, I.-L.; Teng, C.-M.; Chen, I.-S. Nor-neolignan and phenyl propanoid from Zanthoxylum ailanthoides. Phytochemistry 1994, 36, 213–235. Iwasaki, T.; Kondo, K.; Kuroda, T.; Moritani, Y.; Yamagata, S.; Sugiura, M.; Kikkawa, H.; Kaminuma, O.; Ikezawa, K. New selective PDE IV inhibitors as antiasthmatic agents. Synthesis and biological activities of a series of 1-aryl-2,3-bis(hydroxymethyl)naphthalene lignans. J. Med. Chem. 1996, 39, 2696–2704. [CrossRef] [PubMed] Gordaliza, M.; Castro, M.A.; Miguel del Corral, J.M.; López-Vázquez, M.L.; Feliciano, A.S.; Faircloth, G.T. In vivo immunosuppressive activity of some cyclolignans. Bioorg. Med. Chem. Lett. 1997, 7, 2781–2786. [CrossRef] Gordaliza, M.; Faircloth, G.T.; Castro, M.A.; Miguel del Corral, J.M.; López-Vázquez, M.L.; Feliciano, A.S. Immunosuppressive cyclolignans. J. Med. Chem. 1996, 39, 2865–2868. [CrossRef] [PubMed]

Molecules 2018, 23, 2450

12. 13. 14.

15. 16. 17. 18. 19. 20.

21.

22.

23. 24. 25.

26. 27.

28. 29.

30.

7 of 7

Tsai, I.-L.; Hsien, C.-F.; Duh, C.-Y. Additional cytotoxic neolignans from persea obovatifolia. Phytochemistry 1998, 48, 1371–1375. [CrossRef] Jenab, M.; Thompson, L.U. The influence of flaxseed and lignans on colon carcinogenesis and beta-glucuronidase activity. Carcinogenesis 1996, 17, 1343–1348. [CrossRef] [PubMed] Thompson, L.U.; Richard, S.E.; Orcheson, L.J.; Seidl, M.M. Flaxseed and its lignan and oil components reduce mammary tumor growth at a late stage of carcinogenesis. Carcinogenesis 1996, 17, 1373–1376. [CrossRef] [PubMed] Thompson, L.U.; Seidl, M.M.; Ríchard, S.E.; Orcheson, L.J.; Fong, H.H.S. Antitumorigenic effect of a mammalian lignan precursor from flaxseed. Nutr. Cancer 1996, 26, 159–165. [CrossRef] [PubMed] Lu, H.; Liu, G.-T. Antioxidant activity of dibenzocyclooctene lignans isolated from Schisandraceae. Planta Med. 1992, 58, 311–313. [CrossRef] [PubMed] Zacchino, S.; Rodriguez, G.; Pezzenati, G.; Orellana, G. In Vitro evaluation of antifungal properties of 8.O.40 -neolignans. J. Nat. Prod. 1997, 60, 659–662. [CrossRef] [PubMed] Sally, A.H.; Henning, L.; Peter, J.S. A new synthesis of the benzofuran adenosine antagonist XH-14. Bioorg. Med. Chem. Lett. 1997, 7, 3081–3084. Hwang, J.W.; Choi, D.H.; Jeon, J.-H.; Kim, J.-K.; Jun, J.-G. Facile preparation of 2-arylbenzo[b]furan molecules and their anti-inflammatory effects. Bull. Korean Chem. Soc. 2010, 31, 965–970. [CrossRef] Ishibashi, K.; Nakajima, K.; Sugoika, N.; Sugiyama, M.; Hamada, T.; Horikoshi, H.; Nishi, T. Synthesis and 5α-reductase inhibitory activities of benzofuran derivatives with a carbamoyl group. Bioorg. Med. Chem. Lett. 1998, 8, 561–566. [CrossRef] Liu, S.-W.; Lv, M.-Y.; Xiao, D.-A.; Li, X.-G.; Zhou, X.-L.; Guo, M.-P. A highly efficient catalyst of a nitrogen-based ligand for the Suzuki coupling reaction at room temperature under air in neat water. Org. Biomol. Chem. 2014, 12, 4511–4516. [CrossRef] [PubMed] Guo, M.-P.; Jian, F.-F.; He, R. The air-stable and highly efficient P, N-chelated palladium(II) complexes as catalysts for the Suzuki cross-coupling reaction at room temperature. Tetrahedron Lett. 2006, 47, 2033–2036. [CrossRef] Guo, M.-P.; Jian, F.-F.; He, R. Cross-coupling reactions catalyzed by P, O chelate palladium complexes at room temperature. Tetrahedron Lett. 2005, 46, 9017–9020. [CrossRef] Li, J.-X.; Yang, S.-R.; Wu, W.-Q.; Jiang, H.-F. Recent advances in Pd-catalyzed cross-coupling reaction in ionic liquids. Eur. J. Org. Chem. 2018, 11, 1284–1306. [CrossRef] Veisi, H.; Mirshokraie, S.A.; Ahmadian, H. Synthesis of biaryls using palladium nanoparticles immobilized on metformine-functionalized polystyrene resin as a reusable and efficient nanocatalyst. Int. J. Biol. Macromol. 2018, 108, 419–425. [CrossRef] [PubMed] Irene, M.; Oscar, N. Recent developments in the Suzuki-Miyaura reaction: 2010–2014. Molecules 2015, 20, 7528–7557. Hu, H.-N.; Ge, C.-H.; Zhang, A.-J.; Ding, L.-S. Synthesis of novel 3,5-dichloro-2-arylpyridines by palladium acetate-catalyzed ligand-free Suzuki reactions in aqueous media. Molecules 2009, 14, 3153–3160. [CrossRef] [PubMed] Malose, J.M.; Mamasegare, M.M. One-pot synthesis of 2,3,4-triarylquinolines via Suzuki-Miyaura cross-coupling of 2-aryl-4-chloro-3-iodoquinolines with arylboronic acids. Molecules 2010, 15, 7423–7437. Jiang, P.L.; Guo, M.P.; Fu, L.Q.; Wen, Y.J.; Shen, X.L.; Zhou, L.J. [(PhCH2 O)2 P(CH3 )2 CHNCH(CH3 )2 ]2 PdCI2 /CuI as cocatalyst for coupling-cyclization of 2-iodophenol with terminal alkynes in water. Catalysts 2018, 8, 136. [CrossRef] Guo, M.P.; Jian, F.F.; He, R. Efficient synthesis of fluorinated biphenyl derivatives via Pd-catalyzed Suzuki coupling reactions in aqueous solvents at room temperature. J. Fluor. Chem. 2006, 127, 177–181. [CrossRef]

Sample Availability: Samples of the compounds are not available from the authors. © 2018 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).