Diversity oriented synthesis of natural 2-arylbenzofuran, moracin F

Article abstract of DOI:10.1002/bkcs.10847

Diversity oriented synthesis of natural 2-arylbenzofuran, moracin F (1) has been carried out from the commercially available starting materials using Sonogashira coupling, Suzuki coupling, neutral Al₂O₃ mediated cyclization, and intr

Full text of DOI:10.1002/bkcs.10847

Article
DOI: 10.1002/bkcs.10847
BULLETIN OF THE
S.-R. Yun and J.-G. Jun
KOREAN CHEMICAL SOCIETY
Diversity Oriented Synthesis of Natural 2-Arylbenzofuran, Moracin F
*
So-Ra Yun and Jong-Gab Jun
Department of Chemistry and Institute of Applied Chemistry, Hallym University, Chuncheon 24252,
Korea. *E-mail: jgjun@hallym.ac.kr
Received March 4, 2016, Accepted May 23, 2016, Published online July 21, 2016
Diversity oriented synthesis of natural 2-arylbenzofuran, moracin F (1) has been carried out from the com-
mercially available starting materials using Sonogashira coupling, Suzuki coupling, neutral Al2O3
mediated cyclization, and intramolecular Wittig reaction as key steps.
Keywords: Moracin F, Sonogashira coupling, Suzuki coupling, Neutral Al2O3 mediated cyclization,
Intramolecular Wittig reaction
Introduction
otherwise. All solvents used for reactions were freshly dis-
tilled from proper dehydrating agents under nitrogen gas.
All solvents used for chromatography were purchased and
Heterocyclic compounds share more than half of the exist-
ing organic compounds and can play a key role in medici-
nal chemistry and drug discovery. Benzofuran, a fused
heterocyclic compound, occurs in a large number of natural
products and occupies a prominent position among the
plant phenols in view of its medicinal and biological signif-
icance.1 In particular, several natural and non-natural 2-
substituted benzofurans display potent biological properties
including anti-inflammatory,2 antioxidant,3 anticancer,4
antifungal,5 antimicrobial,6 anti-platelet,7 and antiviral
activity.8 In addition, some derivatives are investigated as
enzyme inhibitors9 and diagnostic imaging agents targeting
amyloid plaques in Alzheimer’s disease (AD).10 Some ben-
zofuran compounds are explored in organic semiconduc-
tors.11 They also find applications as brightening agents12
and in agriculture as pesticides and insecticides.13
The genus Morus belongs to flowering plants family, Mor-
aceae. It contains around 16 species with worldwide distribu-
tion. It has gained considerable attention due to its medicinal
and economical value.14 In the recent review, Naik et al. high-
lighted the isolation of benzofurans (moracins A–Z) from the
genus Morus and outlined the different synthetic methods
used to construct the scaffold.15 Moracin F (1) (Figure 1) was
isolated16 from acetone extracts of the cortex and phloem tis-
sues of mulberry shoots infected with F. solani f. sp. mori and
to the best of our knowledge, its synthesis is not yet reported.
Continuing our interest on the synthesis and biological
evaluation of benzofurans as anti-inflammatory agents,17
herein, we describe the synthesis of natural 2-arylbenzo-
furan, moracin F using diverse methods which utilize Sono-
gashira coupling, Suzuki coupling, Al2O3 mediated
cyclization, and intramolecular Wittig reaction as key steps.
1
directly used without further purification. H-NMR spectra
were recorded on Varian Mercury-300 MHz FT-NMR
(Palo alto, CA, USA) and 75 MHz for 13C, with the chemi-
cal shift (δ) reported in parts per million (ppm) downfield
relative to TMS and the coupling constants (J) quoted in
Hz. CDCl3/CD3OD was used as a solvent and an internal
standard. Mass spectra were recorded on a JMS-700
(JEOL, Tokyo, Japan) spectrometer. Melting points were
measured on a MEL-TEMP II apparatus (Triad Scientific,
Manasquan, NJ, USA) and were uncorrected. Thin-layer
chromatography (TLC) was performed on DC-Plastikfolien
60, F254 (layer thickness 0.2 mm; Merck, Darmstadt, Ger-
many) plastic-backed silica gel plates and visualized by UV
light (254 nm) or staining with p-anisaldehyde and phos-
phomolybdic acid (PMA) stain. Chromatographic purifica-
tion was carried out using Kieselgel 60 (60–120 mesh,
Merck).
tert-Butyl(3,4-dimethoxyphenoxy)dimethylsilane
(3).
TBSCl (0.29 g, 1.95 mmol) in anhyd. DMF (1.5 mL) was
added to a stirred solution of 3,4-dimethoxyphenol (2)
(0.20 g, 1.30 mmol) and imidazole (0.22 g, 3.25 mmol) in
anhyd. DMF (6.0 mL). The reaction mixture was stirred at
40ꢀC for 4 h. After completion of the reaction, diluted with
ether (20 mL), washed water (3 × 25 mL), brine
(3 × 25 mL), dried over anhyd. Na2SO4, and concentrated
in vacuo. The crude product was purified by column chro-
matography (EtOAc/hexane = 1/15) to afford the pure
product 3 (0.33 g, 94%) as colorless liquid. Rf = 0.48
(EtOAc/hexane = 1/15); 1H NMR (300 MHz, CDCl3) δ
6.70 (1H, d, J = 8.1 Hz), 6.41 (1H, d, J = 2.4 Hz), 6.35
(1H, dd, J = 8.1, 2.4 Hz), 3.83 (3H, s), 3.82 (3H, s), 0.98
(9H, s), 0.18 (6H, s); 13C NMR (75 MHz, CDCl3) δ 149.6,
149.3, 143.5, 111.6, 110.5, 104.8, 56.3, 55.8, 25.8,
18.3, −4.3.
Experimental
All chemicals were obtained from commercial suppliers
and were used without further purification unless stated
2-Iodo-4,5-dimethoxyphenol (4). To a stirred solution of
compound 3 (0.20 g, 0.76 mmol) in ethyl alcohol (6 mL)
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to afford the pure product (0.10 g, 79%) as colorless liquid.
1H NMR (300 MHz, CDCl3) δ 6.85 (2H, d, J = 2.4 Hz),
6.75 (1H, t, J = 2.4 Hz), 5.20 (4H, s), 3.73 (4H, q,
J = 6.9 Hz), 3.06 (1H, s), 1.25 (6H, t, J = 6.9 Hz); 13C
NMR (75 MHz, CDCl3) δ 158.0, 123.3, 113.2, 106.2, 93.1,
83.3, 64.4, 15.2.
2-(3,5-Bis(ethoxymethoxy)phenyl)-5,6-dimethoxybenzo-
furan (8). Compound 4 (0.07 g, 0.26 mmol), compound
7 (0.08 g, 0.32 mmol), and trimethylamine (0.11 mL,
0.78 mmol) were placed in sealed tube and anhydrous
DMF was added to it. PdCl2(PPh3)2 (0.01 g, 0.02 mmol)
and CuI (0.01 g, 0.02 mmol) were added to the mixture
and degassed for 2 min. The reaction was stirred at 80ꢀC
for 15 h. After completion of the reaction, cooled to room
temperature and the solvent was removed under reduced
pressure. The crude was purified by column chromatogra-
phy (EtOAc/hexane = 1/8) to afford the pure product
8 (0.03 g, 20 %) as brown liquid. Rf = 0.28 (EtOAc/hex-
ane = 1/3); 1H NMR (300 MHz, CDCl3) δ 7.13 (2H, d,
J = 1.8 Hz), 7.11, (1H, s), 7.01 (1H, s), 6.93 (1H, s), 6.72
(1H, t, J = 2.1 Hz), 5.26 (4H, s), 3.94 (3H, s), 3.92 (3H, s),
3.76 (4H, q, J = 6.9 Hz), 1.25 (6H, t, J = 6.9 Hz); 13C
NMR (75 MHz, CDCl3) δ 158.5, 154.4, 149.5, 148.0,
146.4, 132.4, 120.8, 105.6, 104.5, 102.0, 95.2, 93.2, 93.1,
64.4, 56.3, 56.2, 15.2 [Note: compound 8 was also obtained
from 21 and 23 using PdCl2(dppf ).CH2Cl2/anhyd.K3PO4
system by Suzuki coupling reaction17b].
Figure 1. Structure of moracin F (1).
were added molecular iodine (0.21 g, 0.84 mmol) and sil-
ver sulfate (0.24 g, 0.84 mmol). The reaction was stirred
for 48 h at room temperature. After completion of the reac-
tion, it was diluted with saturated sodium thiosulphate solu-
tion and ethanol solvent was removed in vacuo. The
compound was then extracted with EtOAc (2 × 25 mL),
washed with brine (2 × 30 mL), dried over anhyd. Na2SO4
and concentrated in vacuo. The crude product was purified
by column chromatography (EtOAc/hexane = 1/6) to afford
the pure product 4 (0.14 g, 67%) as brown liquid. Rf = 0.28
(EtOAc/hexane = 1/2); 1H NMR (300 MHz, CDCl3) δ
7.02 (1H, s), 6.59 (1H, s), 5.25 (1H, s), 3.84 (3H, s), 3.80
(3H, s); 13C NMR (75 MHz, CDCl3) δ 151.0, 149.8, 144.1,
119.9, 99.6, 71.8, 56.9, 56.3.
3,5-Bis(ethoxymethoxy)benzaldehyde (6). To a stirred
solution of 3,5-dihydroxybenzaldehyde (0.14 g, 1.0 mmol)
in anhydrous DMF (7 mL) was added K2CO3 (0.55 g,
4.0 mmol) under nitrogen atmosphere at room temperature.
After stirring for 15 min, chloromethyl ethyl ether
(0.28 mL, 3.0 mmol) was added dropwise and stirred for
overnight at room temperature. After completion of the
reaction, reaction mixture was diluted with ether (40 mL)
and washed with water (3 × 15 mL). The organic layer
was washed successively with water (3 × 30 mL), brine
(3 × 30 mL), dried over anhyd. Na2SO4 and concentrated
in vacuo. The crude was purified by column chromatogra-
phy (EtOAc/hexane = 1/6) to afford the pure compound
(0.19 g, 76%) as colorless liquid. Rf = 0.54 (EtOAc/hex-
5-(5,6-Dimethoxybenzofuran-2-yl)benzene-1,3-diol
(Moracin F) (1). To a stirred solution of 8 (0.03 g,
0.06 mmol) in anhydrous MeOH (2 mL) was added Dow-
ex® 50X2-100 (Sigma-Aldrich, St.Louis, Missouri, USA)
resin (0.03 g) under nitrogen atmosphere. The mixture was
stirred at room temperature for 12 h. After completion of
the reaction, resin was filtered and washed with EtOAc
(15 mL). The filtrate was concentrated in vacuo. Crude res-
idue was purified by column chromatography (EtOAc/hex-
ane = 1/1) to yield the pure compound 1 (0.01 g, 75%) as
white solid. Rf = 0.32 (EtOAc/hexane = 1/1); mp
1
ane = 1/5); H NMR (300 MHz, CDCl3) δ 9.89 (1H, s),
7.19 (2H, d, J = 2.4 Hz), 6.98 (1H, t, J = 2.4 Hz), 5.24
(4H, s), 3.73 (4H, q, J = 6.9 Hz), 1.23 (6H, t, J = 6.9 Hz);
13C NMR (75 MHz, CDCl3) δ 191.8, 159.0, 138.6, 111.4,
110.6, 93.5, 64.8, 15.5.
1
186–188ꢀC; H NMR (300 MHz, CD3OD) δ 7.15 (1H, s),
7.08 (1H, s), 6.92 (1H, s), 6.74 (2H, d, J = 1.2 Hz), 6.21
(1H, t, J = 1.2 Hz), 3.88 (3H, s), 3.86 (3H, s); 13C NMR
(75 MHz, CD3OD) δ 158.7, 155.4, 149.7, 148.4, 146.9,
132.5, 121.5, 103.0, 102.7, 102.3, 101.3, 95.4, 55.9, 55.7;
EI-MS m/z 286 (M+, base), 271, 257; HRMS calcd for
C16H14O5 (M+) 286.0841, found 286.0835.
1,3-Bis(ethoxymethoxy)-5-ethynylbenzene (7). To a stir-
red solution of (trimethylsilyl)diazomethane (2.0 M solu-
tion in diethyl ether, 0.75 mL, 1.5 mmol) in anhyd. THF
ꢀ
(3 mL) at −78 C was added n-BuLi (2.0 M solution in
1-(3,5-Bis((tert-butyldimethylsilyl)oxy)phenyl)ethanone
cyclohexane, 1.5 mL, 1.5 mmol) dropwise and stirred for
30 min. To this, compound 6 (0.13 g, 0.5 mmol) in anhyd.
THF (3 mL) was added dropwise and stirred for 1 h. After
completion of the reaction, aqueous saturated NH4Cl solu-
tion (1 mL) was added slowly and the reaction mixture
warmed to room temperature. The reaction mixture was
extracted with EtOAc (2 × 20 mL). Combined organic
layer was washed with brine (2 × 15 mL), dried over
anhyd. Na2SO4 and concentrated in vacuo. The crude was
purified by column chromatography (EtOAc/hexane = 1/8)
(10).
3,5-Dihydroxyacetophenone (0.08 g, 0.5 mmol),
TBSCl (0.23 g, 1.5 mmol), and imidazole (0.17 g,
2.5 mmol) in anhyd. DMF (6 mL) reacted for 4.5 h, fol-
lowing the procedure described for compound 3 preparation
to afford the compound 10 (0.18 g, 98%) as colorless liq-
uid. Rf = 048 (EtOAc/hexane = 1/15); 1H NMR (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.
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Synthesis of Moracin F
KOREAN CHEMICAL SOCIETY
1-(3,5-Bis((tert-butyldimethylsilyl)oxy)phenyl)-2-
1.5 Hz), 4.54 (4H, dt, J = 4.8, 1.5 Hz); 13C NMR
(75 MHz, CDCl3) δ 166.0, 159.7, 133.0, 132.3, 132.1,
118.4, 118.1 108.5, 107.3, 69.4, 66.0. To a stirred solution
of the above ester (0.18 g, 0.64 mmol) in MeOH (5 mL)
was added 1.0 N NaOH (1.91 mL) and refluxed for 2 h.
After cooling to room temperature, solvent was removed
under reduced pressure. The crude pH was adjusted to
2 with 1 N HCl and extracted with EtOAc (2 × 25 mL).
The combined organic layer was washed with brine
(2 × 30 mL), dried over anhyd. Na2SO4 and concentrated
in vacuo. The crude acid 14 (0.13 g, 85%) obtained as
white solid was utilized in the next step without further
bromoethanone (11). To a stirred solution of substituted
acetophenone 10 (0.19 g, 0.5 mmol) in EtOAc (5 mL) was
added copper(II) bromide (0.28 g, 1.25 mmol) at room
temperature, and the mixture was refluxed for 2.5 h. After
cooling to room temperature, the mixture was filtered
through a Celite® pad (Samchun Chemical, pyeongtaek,
South Korea) 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 cor-
responding pure compound 11 (0.2 g, 87%) as pale yellow
liquid. 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.
((5-(5,6-Dimethoxybenzofuran-2-yl)-1,3-phenylene)bis
(oxy))bis(tert-butyldimethylsilane) (12). A mixture of
2 (0.07 g, 0.44 mmol), phenacyl bromide 11 (0.20 g,
0.44 mmol), and neutral aluminum oxide (0.16 g,
1.53 mmol) was refluxed in xylene (3 mL) for 48 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 (0.02 g, 8%) as
brown liquid. Rf = 0.22 (EtOAc/hexane = 1/3); 1H NMR
(300 MHz, CDCl3) δ 7.09 (1H, s), 6.98 (1H, s), 6.89 (2H,
d, J = 1.8 Hz), 6.85 (1H, s), 6.28 (1H, t, J = 1.8 Hz), 3.94
(3H, s), 3.92 (3H, s), 1.00 (18H, s), 0.23 (12H, s); 13C
NMR (75 MHz, CDCl3) δ 157.0, 154.9, 149.8, 148.2,
146.7, 132.5, 121.2, 112.1, 109.8, 102.3, 102.0, 95.5, 56.6,
56.5, 26.1, 18.6, −3.9.
1
purification. mp 64–66ꢀC; H NMR (300 MHz, CDCl3) δ
7.28 (2H, d, J = 2.4 Hz), 6.70 (1H, t, J = 2.4 Hz), 6.06
(2H, m), 5.44 (2H, dd, J = 17.1, 1.5 Hz), 5.32 (2H, dd,
J = 10.5, 1.5 Hz), 4.58 (4H, dt, J = 5.5, 1.5 Hz); 13C NMR
(75 MHz, CDCl3) δ 172.0, 159.6, 132.7, 131.0, 118.1,
108.6, 108.0, 69.1
2-(Hydroxymethyl)-4,5-dimethoxyphenol (17). To a stir-
red solution of 2-hydroxy-4,5-dimethoxybenzaldehyde (16)
(0.10 g, 0.54 mmol) in EtOH (3 mL) was added sodium
borohydride (0.02 g, 0.55 mmol) at 0ꢀC. The reaction mix-
ture was stirred at room temperature for 1 h. After the sol-
vent was removed, aq. 1 N HCl solution (4 mL) was added
to the residue and extracted with CH2Cl2 (2 × 20 mL). The
organic phase was dried over anhyd. Na2SO4 and filtered.
The filtrate was concentrated to give the alcohol 17 (0.09 g,
1
90%) as clear liquid. Rf = 0.20 (EtOAc/hexane = 1/2); H
NMR (300 MHz, CDCl3) δ 6.74 (1H, s), 5.93 (1H, s), 5.82
(1H, br s), 4.58 (2H, br d, J = 4.5 Hz), 4.15 (1H, br s),
3.86 (3H, s), 3.83 (3H, s); 13C NMR (75 MHz, CDCl3) δ
159.8, 159.0, 147.9, 129.4, 108.2, 107.3, 60.0, 59.0, 56.8.
2-((Bromotriphenylphosphoranyl)methyl)-4,5-
5-(5,6-Dimethoxybenzofuran-2-yl)benzene-1,3-diol
(Moracin F) (1). To a stirred solution of TBS-protected
benzofuran 12 (0.02 g, 0.03 mmol) in anhyd. THF was
added 1.0 M TBAF (0.07 mL, 0.07 mmol) and stirred for
4 h at room temperature. After completion of the reaction,
solvent was removed in vacuo. The crude was purified by
column chromatography (EtOAc/hexane = 1/1) to afford
the pure compound 1 (0.01 g, 90%) as white solid.
dimethoxyphenol (18). To a stirred solution of compound
17 (0.08 g, 0.41 mmol) in acetonitrile (3 mL) was added
triphenylphosphine hydrobromide (0.14 g, 0.41 mmol) and
the mixture was refluxed for 2 h. After completion of the
reaction, cooled to room temperature, filtered and washed
with acetonitrile (8 mL) and dried to give the solid 18
1
(0.20 g, 95%). H NMR (300 MHz, CDCl3) δ 7.78–7.39
3,5-Bis(allyloxy)benzoic acid (14). To a stirred suspen-
sion of 3,5-dihydroxybenzoic acid (13) (0.2 g, 1.30 mmol)
and K2CO3 (0.90 g, 6.49 mmol) in anhydrous DMF
(8 mL) was added allyl bromide (0.34 mL, 3.80 mmol)
slowly under nitrogen atmosphere at room temperature.
The reaction mixture was stirred for 3 h. After completion
of the reaction, filtered through Celite® pad and washed
with ether (30 mL). The filtrate was washed with water
(3 × 15 mL), brine (3 × 15 mL), dried over anhyd.
Na2SO4 and concentrated in vacuo. The crude was purified
by column chromatography (EtOAc/hexane = 1/2) to yield
allyl 3,5-bis(allyloxy)benzoate (0.33 g, 92%) as colorless
liquid. Rf = 0.80 (EtOAc/hexane = 1/2); 1H NMR
(300 MHz, CDCl3) δ 7.20 (2H, d, J = 2.4 Hz), 6.68 (1H, t,
J = 2.4 Hz), 6.02 (3H, m), 5.40 (3H, dd, J = 17.1, 1.5 Hz),
5.28 (3H, dd, J = 10.2, 1.5 Hz), 4.80 (2H, dt, J = 5.4,
(15H, m), 6.89 (1H, s), 6.37 (1H, s), 5.39 (1H, s), 4.49
(2H, d, J = 12.0 Hz), 3.71 (3H, s), 3.68 (3H, s).
2-(3,5-Bis(allyloxy)phenyl)-5,6-dimethoxybenzofuran
(19). Thionyl chloride (0.07 mL, 0.96 mmol) was added to
the acid 14 (0.15 g, 0.64 mmol) and refluxed for 2 h. After
cool to room temperature, the excess thionyl chloride was
removed under reduced pressure to give acid chloride 15
(0.15 g, 93%) as brown liquid. 1H NMR (300 MHz,
CDCl3)
δ 7.24 (2H, d, J = 2.1 Hz), 6.77 (1H, t,
J = 2.1 Hz), 6.03 (2H, m), 5.42 (2H, dd, J = 17.1, 0.9 Hz),
5.31 (2H, dd, J = 10.8, 0.9 Hz), 4.56 (4H, d, J = 5.4 Hz)
13C NMR (75 MHz, CDCl3) δ 167.9, 159.5, 134.7, 132.2,
118.2, 109.8, 109.1, 69.2. To the above acid chloride was
added the Wittig salt 18 (0.30 g, 0.44 mmol), triethylamine
(0.20 mL), and toluene (10 mL) and refluxed for 3 h. After
cool to room temperature, the precipitate was filtered and
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Synthesis of Moracin F
KOREAN CHEMICAL SOCIETY
washed with EtOAc (10 mL). The filtrate was concentrated
in vacuo. The crude was purified by column chromatogra-
phy (EtOAc/hexane = 1/7) to afford the pure benzofuran
19 (0.03 g, 15%) as clear liquid. Rf = 0.28 (EtOAc/hex-
2-(3,5-Bis(ethoxymethoxy)phenyl)-4,4,5,5-tetramethyl-
1,3,2-dioxaborolane (23). Compound 23 was prepared
from compound 22 following the literature procedure.17b
Yield: 91%; clear liquid; Rf = 0.65 (EtOAc/hexane = 1/2);
1H NMR (300 MHz, CDCl3) δ 7.08 (2H, d, J = 2.4 Hz),
6.82 (1H, t, J = 2.4 Hz), 5.21 (4H, s), 3.72 (4H, q,
J = 6.9 Hz), 1.32 (12H, s) 1.22 (6H, t, J = 6.9 Hz); 13C
NMR (75 MHz, CDCl3) δ 157.8, 115.3, 108.2, 93.1, 83.8,
64.3, 24.9, 15.2.
1
ane = 1/4); H NMR (300 MHz, CDCl3) δ 7.07 (1H, s),
6.99 (1H, s), 6.96 (2H, d, J = 2.1 Hz), 6.88 (1H, s), 6.46
(1H, t, J = 2.4 Hz), 6.07 (2H, m), 5.44 (2H, dd, J = 17.1,
1.2 Hz), 5.31 (2H, dd, J = 10.2, 1.2 Hz), 4.58 (4H, dt,
J = 5.4 Hz), 3.94 (3H, s), 3.93 (3H, s); 13C NMR
(75 MHz, CDCl3) δ 159.7, 154.5, 149.3, 147.3, 146.3,
132.8, 132.2, 120.7, 117.6, 103.2, 101.9, 101.7, 101.5,
95.0, 68.8, 56.2, 56.1.
Results and Discussion
Synthesis of 1 using Sonogashira coupling as a key reac-
tion17a was commenced with protection of 3,4-
dimethoxyphenol (2) using tert-butyldimethylsilyl chloride
(TBDMS-Cl) (Scheme 1). Regioselective iodination of
3 using I2/AgSO4 system offered the tert-butyldimethylsilyl
(TBS)-free iodo compound 4. 3,5-Dihydroxybenzaldehyde
(5) was treated with chloromethyl ethyl ether (EOM-Cl) in
presence of K2CO3 and the resulting ethoxymethyl (EOM)-
protected aldehyde 6 was then converted as its homologous
alkyne by Colvin rearrangement.18 Next, Sonogashira cou-
pling between 4 and 7 gave the EOM-protected benzofuran
8 which upon treatment with Dowex® resin led to the target
compound, moracin F (1).
5-(5,6-Dimethoxybenzofuran-2-yl)benzene-1,3-diol
(Moracin F) (1). Pd(PPh3)4 (0.002 g, 2 mmol%) was
added to a stirred suspension of 19 (0.03 g, 0.07 mmol)
and K2CO3 (0.06 g 0.41 mmol) in anhydrous MeOH
(3 mL) under nitrogen atmosphere. The mixture was stirred
at 60ꢀC for 3 h. After cooling to room temperature, solvent
was removed under reduced pressure. The crude was neu-
tralized with 1 N HCl and extracted with CH2Cl2
(2 × 15 mL). The combined organic layer was washed with
brine (2 × 10 mL), dried over anhyd. Na2SO4 and concen-
trated in vacuo. The crude was purified by column chroma-
tography (EtOAc/hexane = 1/2) to afford the pure
benzofuran 1 (0.02 g, 86%) as white solid.
Next, the synthesis of 1 using neutral Al2O3 mediated
cyclization as a key step in which the yields are generally
low to moderate19 was began with TBS-protection of 3,5-
dihydroxyacetophenone9 (Scheme 2). The resulting com-
pound 10 was transformed as its phenacyl bromide 11
using copper bromide (CuBr2). Regioselective cyclization
of 2 with 11 was facilitated with neutral Al2O3 to afford
the TBS-protected benzofuran 12 which was subsequently
treated with 1.0 M tetrabutylammonium fluoride (TBAF)
(in THF) to yield the desired compound 1 in high yield.
Synthesis of the natural benzofuran, 1 was also carried
out by another approach which is outlined in Scheme 3.
The key step for the formation of the benzofuran backbone
was achieved by an intramolecular Wittig reaction20
between triphenylphosphonium salt 18 and 3,5-bis
2-(2,2-Dibromovinyl)-4,5-dimethoxyphenol
(20).
Compound 20 was prepared from compound 16 following
the literature procedure.17b Yield: 49%; brown liquid; Rf =
1
0.23 (EtOAc/hexane = 1/1); H NMR (300 MHz, CDCl3)
δ 7.51 (1H, s), 7.10 (1H, s), 6.43 (1H, s), 4.80 (1H, s), 3.87
(3H, s), 3.86 (3H, s); 13C NMR (75 MHz, CDCl3) δ 150.4,
147.3, 143.0, 132.0, 113.8, 111.5, 100.6, 90.7, 56.7.
2-Bromo-5,6-dimethoxybenzofuran (21). Compound 21
was prepared from compound 20 following the literature
procedure.17b Yield: 81%; brown liquid; Rf = 0.64 (EtOAc/
hexane = 1/1); 1H NMR (300 MHz, CDCl3) δ 6.99 (1H, s),
6.92 (1H, s), 6.60 (1H, s), 3.90 (6H, s); 13C NMR
(75 MHz, CDCl3) δ 150.3, 150.3, 146.7, 125.2, 120.5,
108.0, 101.2, 95.0, 56.4, 56.2.
Scheme 1. Synthesis of moracin F (1) using Sonogashira reaction as a key step.
Bull. Korean Chem. Soc. 2016, Vol. 37, 1253–1258
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Synthesis of Moracin F
KOREAN CHEMICAL SOCIETY
Scheme 2. Synthesis of moracin F (1) using neutral Al2O3 mediated cyclization as a key step.
Scheme 3. Synthesis of moracin F (1) using intramolecular Wittig reaction as a key step.
Scheme 4. Synthesis of moracin F (1) using Suzuki coupling as a key step.
(allyloxy)benzoyl chloride 15 (Scheme 3). The desired Wit-
tig reagent 18 was readily prepared from triphenylpho-
sphine hydrobromide (PPh3.HBr) and the benzyl alcohol
17, which in turn was obtained from the corresponding
aldehyde by reduction. The acid chloride 15 was generated
from its 3, 5-dihydroxybenzoic acid 13 by allyl protection,
ester hydrolysis followed by chlorination synthetic
sequence. Wittig reaction afforded the allyl-protected ben-
zofuran 19, which upon treatment with K2CO3 and catalytic
Pd(PPh3)4 gave the target compound 1 in 86% yield.
Finally, we verified the Suzuki coupling approach17d for
the synthesis of 1. This method was initiated with the
Bull. Korean Chem. Soc. 2016, Vol. 37, 1253–1258
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BULLETIN OF THE
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Synthesis of Moracin F
KOREAN CHEMICAL SOCIETY
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(Scheme 4). The resulting gem-dibromoolefin 20 underwent
intramolecular cross-coupling using anhydrous K3PO4/CuI
system to yield 2-bromobenzofuran 21. The corresponding
boronic ester coupling agent 23 was obtained from the
commercial 5-bromoresorcinol (22).17b Suzuki coupling
between 21 and 23 using Pd(PPh3)4 (10 mmol%) and
aq. 2.0 M K2CO3 as base in sealed tube and THF as a sol-
vent medium at 100ꢀC gave the benzofuran 8 only in 10%
yield. Next, we tried with PdCl2(dppf ).CH2Cl2 (5 mmol%)
and anhydrous K3PO4 as base in N,N-dimethylformamide
(DMF) solvent at 110ꢀC in sealed tube and the benzofuran
8 was obtained in 35% yield, from which 1 was obtained
as shown in Scheme 1.
Conclusion
We have described a diversity oriented synthesis of natural
2-arylbenzofuran, moracin
F
using four different
approaches in which Sonogashira coupling, Suzuki cou-
pling, neutral Al2O3 mediated cyclization, and intramolecu-
lar Wittig reaction employed as key steps. All the
approaches were proceeded from the commercially availa-
ble starting materials and we feel the Suzuki coupling
approach is the viable method among the other approaches.
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Acknowledgments. This research was financially sup-
ported by Priority Research Centers Program through the
National Research Foundation of Korea (NRF) funded by
the Ministry of Education, Science and Technology (NRF-
2009-0094071) and by Hallym University Research Fund,
2016 (HRF-201603-011).
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Bull. Korean Chem. Soc. 2016, Vol. 37, 1253–1258
© 2016 Korean Chemical Society, Seoul & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.bkcs.wiley-vch.de 1258