First synthesis and anti-inflammatory effects of puerariafuran and its derivatives

Article abstract of DOI:10.1002/bkcs.10109

The total synthesis of puerariafuran and its derivatives was achieved for the first time by the direct reaction between substituted α-bromoacetophenones and resorcinol. The reaction was mediated by neutral alumina and was fully regio-controlled. Subsequen

Full text of DOI:10.1002/bkcs.10109

Article
DOI: 10.1002/bkcs.10109
BULLETIN OF THE
H.-H. Yoon et al.
KOREAN CHEMICAL SOCIETY
First Synthesis and Anti-Inflammatory Effects of Puerariafuran and its
Derivatives
Hyun-Ho Yoon,† Jin-Kyung Kim,‡ and Jong-Gab Jun†,
*
†DepartmentofChemistry andInstitute ofAppliedChemistry, HallymUniversity, Chuncheon 200-702, Korea.
*E-mail: jgjun@hallym.ac.kr
‡Department of Biomedical Science, College of Natural Science, Catholic University of Daegu,
Gyeungsan-Si 700-702, Korea
Received August 8, 2014, Accepted November 19, 2014
The total synthesis of puerariafuran and its derivatives was achieved for the first time by the direct reaction
between substituted α-bromoacetophenones and resorcinol. The reaction was mediated by neutral alumina
and was fully regio-controlled. Subsequently, the Sonogashira coupling method was applied for puerariafuran
preparation. Finally, the anti-inflammatory effects of these prepared compounds were evaluated in lipopoly-
saccharide (LPS) stimulated RAW 264.7 macrophages. The results revealed that puerariafuran and its deriva-
tives show weak inhibition activity on the production of inflammatory-mediated nitric oxide.
Keywords: Puerariafuran, 2-Arylbenzo[b]furans, α-Bromoacetophenones, Nitric oxide, Anti-Inflammatory
Introduction
and 8b with tert-butyldimethylsilyl (TBDMS) chloride fol-
lowed by Grignard reaction and then oxidation of the resulting
benzylic alcohols 10a and 10b yielded the acetophenones
7a and 7b in high yields. Other two acetophenones 7c and
7d were obtained by TBDMS protection of phenolic-OH
groups of acetophenones 11a and 11b (Scheme 3). Acetophe-
none 7e is commercially available.
Benzofuran scaffold is ubiquitous in the area of pharmacolog-
ically active agents and isolated natural products.1 Natural and
synthetic derivatives bearing the 2-arylbenzo[b]furan moiety
exhibit a broad range of biological and pharmacological activ-
ities, such as anti-inflammatory,2 pesticidal, and insecticidal,3
antimicrobial,4 antioxidant,5 antifungal,6 peroxisome prolifer-
ator-activated receptor delta (PPAR-δ) agonist,7 anti-HIV,
antitumor, and antiplatelet activities.8 Therefore, the synthetic
access to benzofurans is of considerable interest, and numer-
ous approaches to this scaffold have been disclosed in the
literature.9 Puerariafuran (1) (Figure 1) is a 2-arylbenzo[b]
furan isolated from the roots of Pueraria lobata Ohwi
(Leguminosae).10 The roots of P. lobata are being widely used
as antipyretic, antimigraine, and antispasmodic agents.11 Kim
and coworkers have investigated the inhibition activity of its
advanced glycation end products (AGEs).10
The substituted acetophenones 7a–e were then subjected
to α-bromination using CuBr2 (Scheme 4).13 The products
were obtained in good to high yields. The generated
α-bromoacetophenones 12a–e were subsequently reacted
with resorcinol in the presence of neutral alumina to yield
2-arylbenzo[b]furans 6a–e, and the reaction was fully regio-
controlled.14 Finally, the target products puerariafuran (1)
and its derivatives 2–5 were achieved from 6a–e by applying
the Vilsmeier–Haack method.15 In this reaction, formylation
at position 3 and desilylation were observed in one step.
We have also applied the Sonogashira coupling method for
puerariafuran (1) preparation (Scheme 5). The protected benz-
aldehyde 9a was subjected to Colvin rearrangement,16 and the
corresponding acetylene 15 was obtained in 63% yield. Sono-
gashira coupling17 of 15 with protected aryl bromide 14 pro-
duced diarylyne 16 in72% yield. Iodine-induced cyclization18
of 16 yielded 3-iodobenzofuran 17 in 41% yield, which sub-
sequently underwent formylation with n-BuLi/N-
formylpiperidine to give 3-formylbenzofuran 18 in 86% yield.
Finally, deprotection of 18 with TBAF produced pueraria-
furan (1) in 78% yield, and the spectroscopic data matched
well with those in the literature.10
In continuation of our work12 on the synthesis of bioactive
natural products, here we describe the synthesis and anti-
inflammatory activity evaluation of puerariafuran and its
derivatives.
Results and Discussion
Our retrosynthetic approach to puerariafuran (1) and its deri-
vatives is outlined in Scheme 1. The target compounds 1–5
would be envisioned to arise from benzofurans 6a–e, which
in turn can be obtained from the corresponding substituted
acetophenones 7a–e and resorcinol.
Our synthetic approach was initiated by the preparation of
substituted acetophenones 7a and 7bfrom their corresponding
aldehydes (Scheme2). Protection ofphenolic OHgroupsof8a
Inflammation is a part of the body's immune response. It is a
protective attempt of the host to remove the injurious stimuli,
including damaged cells, irritants, or pathogens, and leads to
the restoration of the normal tissue structure and function.19 In
Bull. Korean Chem. Soc. 2015
© 2015 Korean Chemical Society, Seoul & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Wiley Online Library
1

BULLETIN OF THE
Article
Synthesis and Anti-Inflammatory Effects of Puerariafuran
KOREAN CHEMICAL SOCIETY
Figure 1. Puerariafuran (1) and its synthetic analogs (2–5).
Scheme 1. Retrosynthesis of puerariafuran and its synthetic analogs.
Scheme 2. Reagentsand conditions: (a)TBDMSCl, imidazole, DMF, room temperature ~40 ꢀC, 2.5–5.5 h;(b) MeMgCl, THF, 0 ꢀC, 30–50 min;
and (c) PCC, CH2Cl2, room temperature, 3–4 h.
order to evaluate the anti-inflammatory effects of the prepared
puerariafuran (1) and its derivatives 2–5, we measured the
amount of nitric oxide (NO), which is one of the essential med-
iators of inflammation, in lipopolysaccharide (LPS)-
stimulated RAW 264.7 macrophages.20
All the compounds 1–5 tested proved to have little to weak
suppression of NO production at 10 μM level (Table 1) com-
pared to licochalcone A.21 The cell viability assay at 10 μM
concentration was not affected by puerariafuran (1) and its
derivatives 2–5, indicating no cytotoxicity, whereas
Bull. Korean Chem. Soc. 2015
© 2015 Korean Chemical Society, Seoul & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.bkcs.wiley-vch.de
2

BULLETIN OF THE
Article
Synthesis and Anti-Inflammatory Effects of Puerariafuran
KOREAN CHEMICAL SOCIETY
Scheme 3. Reagents and conditions: (a) TBDMSCl, imidazole, DMF, room temperature ~40 ꢀC, 4.5–5.5 h.
Scheme 4. Reagents and conditions: (a) CuBr2, EtOAc, reflux, 1.25–2.5 h; (b) resorcinol, Al2O3, xylene, reflux, 24 h; and (c) POCl3, DMF,
0–100 ꢀC, 16–24 h.
Scheme 5. Reagents and conditions: (a) TBDMSCl, imidazole, DMF, 40 ꢀC, 4.5 h, 96%; (b) TMSCHN2, n-BuLi, THF, −78 ꢀC, 2 h, 20 min,
63%;(c)14, PdCl2(PPh3)2, CuI, Et3N, DMF, roomtemperature, 9 h, 72%;(d)I2, CH2Cl2, roomtemperature, 3 h, 41%;(e)N-formylpiperidine, n-
BuLi, toluene, 0 ꢀC, 30 min, 86%; and (f ) TBAF, THF, room temperature, 10 min, 78%.
Bull. Korean Chem. Soc. 2015
© 2015 Korean Chemical Society, Seoul & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.bkcs.wiley-vch.de
3

BULLETIN OF THE
Article
Synthesis and Anti-Inflammatory Effects of Puerariafuran
KOREAN CHEMICAL SOCIETY
2
Table 1. Anti-inflammatory activities of puerariafurans 1–5.
NO production
1
1
5
0
Compound
1 μM
10 μM
Medium (MED)
1
2
3
4
5
9.6 2.1 (91.4)
98.0 3.9 (2.0)
97.1 2.6 (2.9)
101.8 2.5 (−1.8)
103.2 4.6 (−3.2)
100.4 5.4 (−0.4)
87.5 0.3 (12.5)
100.0 0.6 (0.0)
8.5 2.2 (91.5)
71.7 1.5 (28.3)
86.1 1.8 (13.9)
76.4 4.2 (23.6)
94.2 8.2 (5.8)
74.3 2.2 (25.7)
2.2 0.3 (97.8)
100.0 0.6 (0.0)
1
2
3
4
5
Licochalcone A
LPS
0.0
0.1
1
10
100
Concentration [log 10] μM
The results are reported as mean value SEM for n = 3. Percentage
IC50 values 1: 28.93 μM, 2: 81.97 μM, 3:38.64 μM, 4:119.4 μM, 5:33.21 μM
inhibition is based on LPS as shown in parentheses.
Figure 2. IC50 values for NO production of puerariafurans 1–5.
Table 2. Proliferation effect of puerariafurans 1–5.
Mass spectra were recorded using a JMS-700 (JEOL, Tokyo,
Japan) spectrometer. Melting points were measured on a
MEL-TEMP II apparatus and were uncorrected. Thin-layer
chromatography (TLC) was performed on DC-Plastikfolien
60, F254 (Merck, Whitehouse Station, N.J., USA, layer thick-
ness 0.2 mm) plastic-backed silica gel plates and visualized
by UV light (254 nm) or staining with p-anisaldehyde.
General Experimental Procedure for Substituted
Phenols—TBDMS Protection. To a prestirred solution
(30 min) of imidazole (1.3 mmol) and TBDMSCl (1.4 mmol)
in dimethylformamide (DMF) (3 mL) was added the phenol
(8a, 8b, 11a, and 11b) (1.0 mmol) in DMF (1 mL) at room
temperature, and the resulting mixture was stirred for
2.5–4.5 h at 40 ꢀC. After completion of the reaction, the reac-
tion mixture was partitioned between H2O (15 mL) and ether
(15 mL). Thewater layer wasextracted with ether(2 × 15 mL).
The combined ether layer was washed sequentially with water
(2 × 25 mL) and brine (2 × 25 mL), dried over anhydrous
Na2SO4, and concentrated in vacuo. The crude product was
purified by column chromatography (EtOAC/Hexane =
1:15–1:9) to afford the corresponding pure products 9a, 9b,
7c, 7d, and 14. (Note: for two phenolic-OH protection, imid-
azole (2.6 mmol) and TBDMSCl (2.8 mmol) were used.)
4-((tert-Butyldimethylsilyl)oxy)-2-methoxybenzaldehyde
(9a): Reaction time: 2.5 h; yield: 96%; Rf = 0.53 (EtOAc/Hex-
ane = 1/15); 1H NMR (300 MHz, CDCl3) δ 10.25 (1H, s), 7.72
(1H, d, J = 8.7 Hz), 6.45 (1H, dd, J = 8.7, 2.1 Hz), 6.38 (1H, d,
J = 2.1 Hz), 3.87 (3H.s), 0.98 (9H, s), 0.23 (6H, s); 13C NMR
(75 MHz, CDCl3) δ 188.2, 159.9, 159.4, 131.3, 118.3, 114.6,
102.4, 55.5, 23.4, 20.4, −4.92.
Proliferation
Compound
1 μM
10 μM
Medium (MED)
1
2
3
4
5
101.1 3.54
119.0 5.05
103.3 8.89
107.0 3.99
113.0 2.22
103.6 6.83
103.3 7.44
101.1 3.54
119.4 5.36
107.9 7.63
118.6 4.49
112.4 7.75
107.3 2.23
84.8 4.99
Licochalcone A
licochalcone A showed cytotoxicity, as shown in Table 2. The
IC50 values of these compounds 1–5 were evaluated by using
GraphPad Prism 4.0 software (San Diego, California, USA)
and showed 28.93, 81.97, 38.64, 119.4, and 33.21 μM, respec-
tively (Figure 2).
In summary, we have described the first total synthesis of
puerariafuran (1) and its derivatives 2–5 by neutral-alumina-
mediated
condensation
between
substituted
α-bromoacetophenones and resorcinol and the reaction was
fully regio-controlled. Alternatively, the Sonogashira cou-
pling method was also applied for puerariafuran preparation.
Finally, the anti-inflammatory effects of these prepared com-
pounds were evaluated in LPS-stimulated RAW 264.7 macro-
phages. The results revealed that puerariafuran and its
derivatives show weak inhibition activity on the production
of inflammatory-mediated nitric oxide.
Experimental
3,4-Bis((tert-butyldimethylsilyl)oxy)benzaldehyde (9b):
Reaction time: 4.5 h; yield: 92%; Rf = 0.53 (EtOAc/Hexane
= 1/15); 1H NMR (300 MHz, CDCl3) δ 9.79 (1H, s),
7.35–7.37 (2H, m), 6.93 (1H, d, J = 8.7 Hz), 1.00 (18H, s),
0.25 (6H, s), 0.23 (6H, s); 13C NMR (75 MHz, CDCl3) δ
190.6, 153.4, 147.7, 130.8, 125.4, 120.9, 120.6, 26.1, 26.0,
18.8, 18.7, −3.8, −3.7.
All chemicals were purchased from Sigma-Aldrich (St. Louis,
Mo 63103, USA) and used without further purification unless
noted otherwise. H NMR spectra were recorded at Varian
Mercury 300-MHz Fourier transform NMR spectrometer (Palo
Alto, California, USA) and 13C spectra with 75 MHz. The
chemical shift (δ) is reported in parts per million (ppm) relative
to TMS and the coupling constants (J) are quoted in hertz.
CDCl3/CD3OD was used as a solvent and an internal standard.
1
1-(2,4-Bis((tert-butyldimethylsilyl)oxy)phenyl)ethanone
(7c): Reaction time: 5.5 h; yield: 78%; Rf = 0.39 (EtOAc/
Bull. Korean Chem. Soc. 2015
© 2015 Korean Chemical Society, Seoul & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.bkcs.wiley-vch.de
4

BULLETIN OF THE
Article
Synthesis and Anti-Inflammatory Effects of Puerariafuran
KOREAN CHEMICAL SOCIETY
Hexane = 1/15); 1H NMR (300 MHz, CDCl3) δ 7.61 (1H, d, J
= 8.7 Hz), 6.45 (1H, dd, J = 8.7, 2.4 Hz), 6.30 (1H, d, J = 2.4
Hz), 2.56 (3H, s), 1.00 (9H, s), 0.97 (9H, s), 0.29 (6H, s), 0.21
(6H, s); 13C NMR (75 MHz, CDCl3) δ 198.6, 160.1, 156.7,
131.8, 124.4, 113.5, 111.4, 31.4, 26.0, 25.7, 18.6, 18.3,
−3.7, −4.2.
1-(3,5-Bis((tert-butyldimethylsilyl)oxy)phenyl)ethanone
(7d): Reaction time: 4.5 h; yield: 98%; Rf = 0.64 (EtOAc/Hex-
ane = 1/15); 1HNMR(300 MHz, CDCl3)δ 7.01(2H,d, J = 2.1
Hz), 6.51 (1H, t, J = 2.1 Hz), 2.53 (3H, s), 0.98 (18H, s), 0.21
(12H, s); 13C NMR (75 MHz, CDCl3) δ 197.7, 156.8, 139.2,
117.0, 113.5, 27.1, 26.0, 18.6, −4.0.
1-(4-((tert-Butyldimethylsilyl)oxy)-2-methoxyphenyl)
ethanone (7a): Reaction time: 4.0 h; yield: 86%; Rf = 0.25
(EtOAc/Hexane = 1/15); 1H NMR (300 MHz, CDCl3) δ
7.72 (1H, d, J = 8.7 Hz), 6.43 (1H, dd, J = 8.7, 2.1 Hz), 6.38
(1H, d, J = 2.1 Hz), 3.86 (3H, s), 2.56 (3H, s), 0.98 (9H, s),
0.24 (6H, s); 13C NMR (75 MHz, CDCl3) δ 181.9, 160.9,
160.8, 132.2, 121.5, 112.0, 103.5, 55.4, 31.8, 25.7,
18.3, −4.18.
1-(3,4-Bis((tert-butyldimethylsilyl)oxy)phenyl)ethanone
(7b): Reaction time: 3.0 h; yield: 75%; Rf = 0.5 (EtOAc/Hex-
1
ane = 1/15); H NMR (300 MHz, CDCl3) δ 7.43–7.45 (2H,
m) 6.84 (1H, d, J = 9.0 Hz), 2.51 (3H, s), 1.00 (9H, s), 0.99
(9H, s), 0.23 (6H, s), 0.22 (6H, s); 13C NMR (75 MHz, CDCl3)
δ 196.8, 152.1, 147.0, 131.3, 123.0, 121.0, 120.6, 26.6, 26.3,
26.2, 18.9, 18.8, −3.7, −3.6.
(4-Bromo-3-methoxyphenoxy)(tert-butyl)dimethylsilane
(14): Reaction time: 4.5 h; yield: 96%; Rf = 0.5 (EtOAc/Hex-
1
ane = 1/9); H NMR (300 MHz, CDCl3) δ 7.30 (1H, d, J =
8.7 Hz), 6.38 (1H, d, J = 2.4 Hz), 6.31 (1H, dd, J = 8.7, 2.4
Hz), 3.82 (3H, s), 0.96 (9H, s), 0.19 (6H, s).
General Experimental Procedure for Bromination of Sub-
stituted Acetophenones. To a stirred solution of substituted
acetophenone 7a–e (0.5 mmol) in EtOAc (5 mL) was added
copper(II) bromide (1.25 mmol) at room temperature, and
the mixture was refluxed for 1.25–2.5 h. After cooling to room
temperature, the mixture was filtered through a Celite pad and
washed with EtOAc (10 mL). The filtrate was concentrated in
vacuo. The crude product was purified on a short column
(EtOAc/hexane = 1/15) to yield the corresponding pure com-
pound 12a–e.
2-Bromo-1-(4-((tert-butyldimethylsilyl)oxy)-2-methox-
yphenyl)ethanone (12a): Reaction time: 1.25 h; yield: 81%;
Rf = 0.41 (EtOAc/Hexane = 1/15); 1H NMR (300 MHz,
CDCl3) δ 7.81 (1H, d, J = 8.7 Hz), 6.47 (1H, dd, J = 8.7,
2.1 Hz), 6.39 (1H, d, J = 2.1 Hz), 4.58 (2H, s), 3.89 (3H, s),
0.99 (9H, s), 0.25 (6H, s); 13C NMR (75 MHz, CDCl3) δ
190.3, 161.0, 160.7 133.6 ,113.4, 112.9, 103.7, 55.9, 38.2,
25.9, 18.6, −3.88.
1-(3,4-Bis((tert-butyldimethylsilyl)oxy)phenyl)-
2-bromoethanone (12b): Reaction time: 2.5 h; yield: 82%;
Rf = 0.32 (EtOAc/Hexane = 1/15); 1H NMR (300 MHz,
CDCl3) δ 7.46–7.48 (2H, m), 6.84 (1H, d, J = 9.0 Hz), 4.34
(2H, s), 0.97 (18H, s), 0.20 (12H, s); 13C NMR (75 MHz,
CDCl3) δ 190.0, 149.3, 148.9, 126.8, 123.3, 120.9, 113.3,
31.7, 28.1, 20.1, −4.10.
1-(2,4-Bis((tert-butyldimethylsilyl)oxy)phenyl)-2-
bromoethanone (12c): Reaction time: 2.25 h; yield: 82%; Rf
= 0.5 (EtOAc/Hexane = 1/10); 1H NMR (300 MHz, CDCl3) δ
7.61 (1H, d, J = 9.3 Hz), 6.38–6.41 (2H, m), 4.36 (2H, s),
0.98 (18H, s), 0.26 (12H, s); 13C NMR (75 MHz, CDCl3) δ
188.2, 161.9, 154.6, 128.8, 122.0, 117.1, 115.0, 34.1, 21.4,
20.6, −3.82.
General Experimental Procedure for Grignard Reaction.
To a stirred solution of substituted benzaldehyde 9a (9b) (1.5
mmol) in THF (6 mL) at 0 ꢀC was slowly added methylmag-
nesium chloride solution (3.0 M in THF, 1 mL), and the reac-
tion mixture was stirred for 30–50 min at room temperature.
After completion of the reaction, excess methylmagnesium
chloride was quenched with a saturated aqueous solution of
NH4Cl (1.5 mL). The mixture was then filtered on a Celite
pad and washed with EtOAc (15 mL). The filtrate was
extracted with EtOAc (2 × 15 mL). The combined organic
layer was washed with brine (2 × 20 mL), dried over anhy-
drous Na2SO4, and concentrated in vacuo. The crude was pur-
ified by column chromatography (EtOAc/hexane = 1:15–1:2)
to afford the corresponding pure product 10a (10b).
1-(4-((tert-Butyldimethylsilyl)oxy)-2-methoxyphenyl)
ethanol (10a): Reaction time: 30 min; yield: 86%; Rf = 0.23
1
(EtOAc/Hexane = 1/2); H NMR (300 MHz, CDCl3) δ 7.12
(1H, d, J = 7.8 Hz), 6.39 (1H, dd, J = 7.8, 2.4 Hz), 6.36 (1H,
d, J = 2.4 Hz), 5.00–5.03 (1H, m), 3.80 (3H, s), 1.48 (3H, d,
J = 6.9 Hz), 0.98 (9H, s), 0.20 (6H, s); 13C NMR (75 MHz,
CDCl3) δ 157.6, 156.1, 126.7, 126.5, 111.7, 103.7, 66.3,
55.5, 26.0, 23.0, 18.5, −3.96.
1-(3,4-Bis((tert-butyldimethylsilyl)oxy)phenyl)ethanol
(10b): Reaction time: 50 min; yield: 92%; Rf = 0.5 (EtOAc/
Hexane = 1/15); 1H NMR (300 MHz, CDCl3) δ 6.84 (1H, s)
6.79 (1H, d, J = 8.4 Hz), 6.76 (1H, d, J = 8.4 Hz), 4,76 (1H,
q, J = 6.3 Hz), 1.44 (3H, d, J = 6.3 Hz), 0.99 (9H, s), 0.98
(9H, s), 0.20 (6H, s), 0.19 (6H, s); 13C NMR (75 MHz, CDCl3)
δ 146.9, 146.3, 139.3, 121.0, 118.6, 70.3, 26.3, 25.3, 21.4,
18.8, 14.6, −3.7.
General Experimental Procedure for PCC Oxidation of
Benzyl Alcohols. To a stirred solution of benzylalcohol
10a (10b) (1 mmol) in CH2Cl2 (15 mL) was added PCC
(2.5 mmol) at 0 ꢀC. The reaction mixture was stirred at room
temperature for 3–4 h. After completion of the reaction, the
mixture was filtered through a Celite pad and washed with
ether (15 mL). The filtrate was concentrated in vacuo. The
crude product was purified on a short column (EtOAc/hexane
= 1:15) to yield the pure compound 7a (7b).
1-(3,5-Bis((tert-butyldimethylsilyl)oxy)phenyl)-2-
bromoethanone (12d): Reaction time: 2.5 h; yield: 87%; Rf
= 0.64 (EtOAc/Hexane = 1/10); 1H NMR (300 MHz, CDCl3)
δ 7.12 (2H, s), 6.56 (1H, s), 4.37 (2H, s), 0.98 (18H, s), 0.22
(12H, s); 13C NMR (75 MHz, CDCl3) δ 189.1, 160.8, 133.8,
114.2, 110.9, 34.7, 25.3, 14.3, −4.20.
2-Bromo-1-(3,5-dimethoxyphenyl)ethanone (12e): Reac-
tion time: 2.5 h; yield: 76%; Rf = 0.55 (EtOAc/Hexane = 1/3);
1H NMR (300 MHz, CDCl3) δ 7.08 (2H, d, J = 1.8 Hz),
Bull. Korean Chem. Soc. 2015
© 2015 Korean Chemical Society, Seoul & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.bkcs.wiley-vch.de
5

BULLETIN OF THE
Article
Synthesis and Anti-Inflammatory Effects of Puerariafuran
KOREAN CHEMICAL SOCIETY
6.67 (1H, t, J = 2.4 Hz), 4.22 (2H, s), 3.83 (6H, s); 13C NMR
(75 MHz, CDCl3) δ 189.1, 160.1, 138.5, 107.5, 107.4,
55.4, 31.7.
General Experimental Procedure for Formylation of 2-
Arylbenzo[b]furans. The Vilsmeier reagent was prepared
by the dropwise addition of POCl3 (1.5 mmol) to cooled
DMF (0.2 mL) with constant stirring. After stirring for
30 min, the benzofuran 6a–e (0.25 mmol) dissolved in DMF
(0.5 mL) was added dropwise to the Vilsmeier reagent. The
reaction mixture was gradually brought to room temperature
and then stirred at 100 ꢀC for 16–24 h. After the completion
of the reaction, the reaction mixture was cooled to room tem-
perature and neutralized with saturated aqueous NaOAc solu-
tion. The crude product was filtered and purified by column
chromatography (EtOAc/hexane = 1:3–1:1) to yield the corre-
sponding benzofuran 1–5 (Note: In the reaction of 6b and 6d
along with 2 and 4, desilylated compounds without formyla-
tion were also observed in 20 and 18% respectively).
Puerariafuran (1): Reaction time: 24 h; Yield: 72%; Rf =
0.47 (EtOAc/hexane = 1/1); yellow solid; mp 293–294 ꢀC; 1H
NMR (300 MHz, CD3OD) δ 9.89 (1H, s), 7.86 (1H, d, J = 9.0
Hz), 7.41 (1H, d, J = 9.0 Hz), 6.90 (1H, d, J = 2.1 Hz), 6.82
(1H, dd, J = 8.4, 1.8 Hz), 6.58 (1H, d, J = 1.8 Hz), 6.54 (1H,
dd, J = 8.4, 2.1 Hz), 3.81 (3H, s); 13C NMR (75 MHz,
CD3OD) δ 189.4, 165, 163.1, 160.3, 157.6, 156.9, 133.7,
123.1, 118.5, 118.4, 114.4, 110.2, 109.1, 100.6, 98.6, 56.3;
MS: 284 (M+, base), 253, 213, 128.
General Experimental Procedure for Synthesis of 2-Aryl-
benzo[b]furans from α-Bromoacetophenone and Resor-
cinol. A mixture of the resorcinol (0.75 mmol), the
α-bromoacetophenone 12a–e (0.5 mmol), and neutral alumi-
num oxide (7.5 mmol) was refluxed in xylene (12 mL) for
24 h. The resulting mixture was filtered through a Celite pad
and evaporated. The residue was purified by column chroma-
tography on silica gel using ethyl acetate/hexane as eluent to
yield the corresponding benzofuran 6a–e.
2-(4-((tert-Butyldimethylsilyl)oxy)-2-methoxyphenyl)
benzofuran-6-ol (6a): Yield: 21%; Rf = 0.43 (EtOAc/Hex-
ane = 1/10); 1H NMR (300 MHz, CDCl3) δ 7.82 (1H, d, J =
8.4 Hz), 7.36 (1H, d, J = 8.1 Hz) 7.10 (1H, s), 6.96 (1H, d, J
= 1.2 Hz), 6.71 (1H, dd, J = 8.4, 1.8 Hz), 6.53 (1H, dd, J =
8.1, 2.4 Hz), 6.47 (1H, d, J = 2.4 Hz), 4.86 (1H, br s), 3.92
(3H, s), 1.01 (9H, s), 0.25 (6H, s); 13C NMR (75 MHz,
CDCl3) δ 157.4, 156.8, 154.7, 153.2, 152.0, 127.5, 123.8,
121.0, 113.5, 112.3, 111.7, 104.3, 104.0, 98.1, 55.7, 26.0,
18.6, −3.88.
2-(3,4-Bis((tert-butyldimethylsilyl)oxy)phenyl)benzo-
furan-6-ol (6b): Yield: 28%; Rf = 0.17 (EtOAc/Hexane = 1/
1
15); H NMR (300 MHz, CDCl3) δ 7.34 (1H, d, J = 8.4
2-(3,4-Dihydroxyphenyl)-6-hydroxybenzofuran-3-
carbaldehyde (2): Reaction time: 24 h; Yield: 57%; pale yel-
Hz), 7.24–7.28 (2H, m), 6.98 (1H, d, J = 1.8 Hz), 6.86 (1H,
dd, J = 6.9, 2.4 Hz), 6.72–6.75 (2H, m), 4.81 (1H, br s),
1.02 (9H, s), 0.99 (9H, s), 0.25 (6H, s), 0.22 (6H, s); 13C
NMR (75 MHz, CDCl3) δ 155.4, 155.1, 153.1, 147.2,
146.9, 124.2, 122.9, 121.2, 120.6, 117.9, 117.4, 111.7,
99.6, 98.2, 26.1, 26 0, 14.2, −3.92.
1
low liquid; Rf = 0.62 (EtOAc/Hexane = 1/1); H NMR (300
MHz, CD3OD) δ 10.0 (1H, s), 7.89 (1H, d, J = 7.2 Hz),
7.87 (1H, s), 7.56 (1H, d, J = 8.7 Hz), 7.47 (1H, s), 7.43
(1H, d, J = 7.2 Hz), 6.60 (1H, d, J = 8.7 Hz); 13C NMR (75
MHz, CD3OD) δ 188.4, 180.1, 167.1, 165.4, 156.0, 147.1,
131.0, 129.6, 128.0, 123.3, 122.7, 116.9, 116.6, 114.6,
98.6; MS: 252, 207, 179.
2-(2,4-Bis((tert-butyldimethylsilyl)oxy)phenyl)benzo-
furan-6-ol (6c): Yield: 24%; Rf = 0.38 (EtOAc/Hexane = 1/
1
6); H NMR (300 MHz, CDCl3) δ 7.34 (1H, d, J = 8.4 Hz),
2-(2,4-Dihydroxyphenyl)-6-hydroxybenzofuran-3-
carbaldehyde (3): Reaction time: 16 h; Yield: 43%; pale yel-
low liquid; Rf = 0.62 (EtOAc/Hexane = 1/1); 1H NMR
(300 MHz, CDCl3) δ 9.67 (1H, s), 7.08 (1H, s), 7.04 (2H, d,
J = 8.1 Hz), 6.38 (2H, dd, J = 8.1, 2.1 Hz), 6.37 (2H, d, J =
2.1 Hz), 5.24 (1H, s); 13C NMR (75 MHz, CDCl3) δ 188.4,
174.8, 157.3, 155.5, 150.4, 143.1, 138.9, 128.6, 128.0,
123.7, 123.3, 113.7, 109.7, 104.8, 98.6; MS: 228, 183, 152.
2-(3,5-Dihydroxyphenyl)-6-hydroxybenzofuran-3-
carbaldehyde (4): Reaction time: 24 h; Yield: 44%; pale yel-
low liquid; Rf = 0.43 (EtOAc/Hexane = 1/1); 1H NMR
(300 MHz, CD3OD) δ 10.0 (1H, s), 7.43 (1H, d, J = 8.1
Hz), 6.97 (1H, s), 6.93 (2H, d, J = 2.4 Hz), 6.78 (1H, dd, J
= 8.1, 2.4 Hz), 6.70 (1H, d, J = 2.4 Hz); 13C NMR (75
MHz, CD3OD) δ 182.7, 175.5, 173.5, 168.6, 162.7, 160.9,
154.9, 154.5, 137.7, 131.1, 121.4, 110.2, 97.2; MS: 207,
183, 152.
7.28 (1H, d, J = 2.4 Hz), 7.25 (1H, d, J = 3.0 Hz), 6.98 (1H,
d, J = 1.8 Hz), 6.86 (1H, dd, J = 6.9, 2.4 Hz), 6.72–6.75
(2H, m), 4.71 (1H, br s), 1.02 (9H, s), 1.01 (9H, s), 0.24
(6H, s), 0.22 (6H, s); 13C NMR (75 MHz, CDCl3) δ 155.4,
155.2, 153.0, 147.2, 146.9, 124.1, 123.0, 121.2, 120.6,
118.0, 117.4, 111.7, 99.5, 98.2, 26.1, 26.0, 18.6, −3.92.
2-(3,5-Bis((tert-butyldimethylsilyl)oxy)phenyl)benzo-
furan-6-ol (6d): Yield: 31%; Rf = 0.29 (EtOAc/Hexane = 1/
1
10); H NMR (300 MHz, CD3OD) δ 7.36 ( 1H, d, J = 8.1
Hz), 6.99 (1H, d, J = 1.8 Hz), 6.89 (2H, d, J = 2.1 Hz), 6.85
(1H, d, J = 2.4 Hz), 6.75 (1H, dd, J = 8.1, 2.4 Hz), 6.29 (1H,
t, J = 2.1 Hz), 5.17 (1H, br s), 0.98 (18H, s), 0.22 (12H, s);
13C NMR (75 MHz, CDCl3) δ 156.7, 155.6, 154.9, 153.6,
132.1, 122.7, 121.0, 112.0, 109.8, 101.4, 98.3, 25.8,
14.3, −4.2.
2-(3,5-Dimethoxyphenyl)benzofuran-6-ol (6e): Yield:
1
20%; Rf = 0.15 (EtOAc/Hexane = 1/3); H NMR (300 MHz,
2-(3,5-Dimethoxyphenyl)-6-hydroxybenzofuran-3-
carbaldehyde (5): Reaction time: 16 h; Yield: 82%; pale yel-
lowsolid;decomposedwhilempcheckingabove300 ꢀC;Rf =
0.43 (EtOAc/Hexane = 1/1); 1H NMR (300 MHz, CD3OD) δ
10.1 (1H, s), 7.40 (1H, d, J = 8.4 Hz), 6.93(1H, s), 6.88 (2H, d,
J = 2.1 Hz), 6.76 (1H, dd, J = 8.4, 1.8 Hz), 6.68 (1H, d, J =
CDCl3) δ 7.38 (1H, d, J = 8.1 Hz), 7.00 (1H, s), 6.95 (2H,
d, J = 2.4 Hz), 6.92 (1H,s), 6.76 (1H, dd, J = 8.1, 2.0 Hz),
6.43 (1H, t, J = 2.4 Hz), 5.06 (1H, br s), 3.84 (6H, s); 13C
NMR (75 MHz, CDCl3) δ 160.8, 155.5, 154.8, 153.5,
132.2, 122.6, 121.1, 112.0, 102.7, 101.6, 100.5, 98.2, 55.5.
Bull. Korean Chem. Soc. 2015
© 2015 Korean Chemical Society, Seoul & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.bkcs.wiley-vch.de
6

BULLETIN OF THE
Article
Synthesis and Anti-Inflammatory Effects of Puerariafuran
KOREAN CHEMICAL SOCIETY
2.1 Hz), 3.93 (6H, s); 13C NMR (75 MHz, CD3OD) δ 191.1,
166.2, 164.4, 153.2, 122.7, 114.2, 113.8, 109.2, 108.2,
100.7, 99.5, 98.5, 56.6; MS : 298 (M+, base), 254, 211, 184.
tert-Butyl(4-ethynyl-3-methoxyphenoxy)dimethylsi-
3. F. A. John, B. Sentsetsa, L. Guoqiang, S. Michelle, J. Nat. Prod.
1997, 60, 1214.
4. R. Basawaraj, G. Parameshwarappa, S. S. Sangapure, Indian
Drugs 2007, 44, 8.
5. D. H. S. Silva, F. C. Pereira, M. V. B. Zanoni, M. Yoshida, Phy-
tochemistry 2001, 57, 437.
6. S. Zacchino, G. Rodriguez, G. Pezzenati, G. Orellana, R. Enriz,
S. M. Gonzalez, J. Nat. Prod. 1997, 60, 659.
7. G. F. Filzen, L. Bratton, X. M. Cheng, N. Erasga, A. Geyer,
C. Lee, G. Lu, J. Pulaski, R. J. Sorenson, P. C. Unangst, B. K.
Trivedi, X. Xu, Bioorg. Med. Chem. Lett. 2007, 13, 3630.
8. W. J. Song, X. D. Yang, X. H. Zeng, X. L. Xu, G. L. Zhang, H. B.
Zhang, RSC Adv. 2012, 2, 4612.
9. X.-L. Hou, Z. Yang, H. N. C. Wong, Prog. Heterocycl. Chem.
2002, 14, 139.
10. D. S. Jang, J. M. Kim, Y. M. Lee, Y. S. Kim, J.-H. Kim, J. S. Kim,
Chem. Pharm. Bull. 2006, 54, 1315.
11. (a) J.-E. Kinjo, J.-I. Furusawa, J. Baba, T. Takeshita, M. Yama-
saki, T. Nohara, Chem. Pharm. Bull. 1987, 35, 4846; (b) Y.
Ohshima, T. Okuyama, K. Takahashi, T. Takizawa, S. Shibata,
Planta Med. 1988, 54, 250; (c) S. J. Lee, H. J. Baek, C. H. Lee, H.
P. Kim, Arch. Pharm. Res. 1994, 17, 31; (d) T. Yasuda, M. Endo,
T. Kon-no, T. Kato, M. Mitsuzuka, K. Ohsawa, Biol. Pharm.
Bull. 2005, 28, 1224.
12. (a)S.-J. Kim, C. G. Kim, S.-R. Yun, J.-K. Kim, J.-G. Jun, Bioorg.
Med. Chem. Lett. 2014, 24, 181; (b) N. L. Lee, J. J. Lee, J.-K.
Kim, J.-G. Jun, Bull. Korean Chem. Soc. 2012, 33, 1907; (c)
J.-H. Jeon, M. R. Kim, J.-G. Jun, Synthesis 2011, 370.
13. (a) L. C. King, G. K. Ostrum, J. Org. Chem. 1964, 29, 345; (b) B.
A. Bakke, M. C. McIntosh, K. D. Turnbull, J. Org. Chem. 2005,
70, 4338.
14. L. Arias, Y. Vara, F. P. Cossío, J. Org. Chem. 2012, 77, 266.
15. Z. Yang, H. B. Liu, C. M. Lee, H. M. Chang, H. N. C. Wong,
J. Org. Chem. 1992, 57, 7248.
16. E. W. Colvin, B. J. Hamill, J. Chem. Soc. Perkin Trans. 1
1977, 869.
17. K. Sonogashira, J. Organomet. Chem. 2002, 653, 46.
18. H. B. Bang, S. Y. Han, D. H. Choi, D. M. Yang, J. W. Hwang,
H. S. Lee, J.-G. Jun, Synth. Commun. 2009, 39, 506.
19. J. H. Vernooy, M. A. Dentener, R. J. van Suylen, W. A. Buurman,
E. F. Wouters, Am. J. Respir. Cell Mol. Biol. 2002, 26, 152.
20. K. H. Kwon, A. Murakami, R. Hayashi, H. Ohigashi, Biochem.
Biophys. Res. Commun. 2005, 337, 647.
21. (a) J.-H. Jeon, S.-J. Kim, C. G. Kim, J.-K. Kim, J.-G. Jun, Bull.
Korean Chem. Soc. 2012, 33, 953; (b) S. Tanifuji, E. Aizu-
Yokota, M. Funakoshi-Tago, Y. Sonoda, H. Inoue, T. Kasahara,
Int. Immunopharmacol. 2010, 10, 769.
1
lane (15): Rf = 0.7 (EtOAc/Hexane = 1/10); H NMR (300
MHz, CDCl3) δ 7.30 (1H, d, J = 7.8 Hz), 6.39 (1H, d, J =
2.1 Hz), 6.35 (1H, dd, J = 7.8, 2.1 Hz), 3.85 (3H, s), 3.24
(1H, s), 0.98 (9H s), 0.22 (6H, s).
1,2-Bis(4-((tert-butyldimethylsilyl)oxy)-2-methoxyphe-
1
nyl)ethyne (16): Rf = 0.43 (EtOAc/Hexane = 1/9); H NMR
(300 MHz, CDCl3) δ 7.02 (2H, d, J = 8.4 Hz), 6.46 (2H, dd,
J = 8.4, 2.4 Hz), 6.39 (2H, d, J = 2.4 Hz), 3.84 (6H, s), 0.99
(18H, s), 0.24 (12H).
tert-Butyl((2-(4-((tert-butyldimethylsilyl)oxy)-2-meth-
oxyphenyl)-3-iodobenzofuran-6-yl)oxy)dimethylsilane (17):
Rf = 0.43 (EtOAc/Hexane = 1/10); 1H NMR (300 MHz, CDCl3)
δ 7.30 (1H, d, J = 1.8 Hz), 7.20 (1H, s), 6.98 (1H, d, J = 8.4 Hz),
6.34–6.43 (3H, m), 3.84 (3H, s), 0.98 (18H, s), 0.23 (12H, s).
6-((tert-Butyldimethylsilyl)oxy)-2-(4-((tert-butyldimethylsi-
lyl)oxy)-2-methoxyphenyl)benzofuran-3-carbaldehyde (18):
1
Rf = 0.5 (EtOAc/Hexane = 1/10); H NMR (300 MHz, CDCl3)
δ 9.44 (1H, s), 7.28 (1H, d, J = 8.4 Hz), 6.56 (1H, s), 6.41 (2H,
d, J = 8.4 Hz), 6.37 (2H, s), 3.85 (3H, s), 0.97 (18H, s), 0.23
(12H, s).
Acknowledgments. This research was financially supported
by Priority Research Centers Program through the National
Research Foundation of Korea (NRF) funded by the Ministry
ofEducation, Science andTechnology (NRF-2009-0094071);
by the Ministry of Education, Science Technology (MEST);
by the Korea Institute for Advancement of Technology
(KIAT) through the Human Resource Training Project for
Regional Innovation (2012H1B8A2026036): and by the Hal-
lym University Research Fund, 2014 (HRF-201408-011).
References
1. (a) D. M. X. Donelly, M. J. Meegan, In Comprehensive Hetero-
cyclic Chemistry, Vol. 4, A. R. Katritzky Ed., Pergamon, New
York, 1984, p. 657; (b) L. D. Luca, G. Nieddu, A. Porcheddu,
G. Giacomelli, Curr. Med. Chem. 2009, 16, 1; (c) T. Ohtsuka,
Y. Aoka, Drugs Future 2003, 28, 143.
2. S. H. Day, N. Y. Chiu, L. T. Tsao, J. P. Wang, C. N. Lin, J. Nat.
Prod. 2000, 63, 1560.
Bull. Korean Chem. Soc. 2015
© 2015 Korean Chemical Society, Seoul & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.bkcs.wiley-vch.de
7