Total synthesis of ailanthoidol, egonol, and related analogues

Article abstract of DOI:10.1055/s-0029-1219224

Efficient and general synthetic protocols were developed for the total synthesis of ailanthoidol, egonol, and some related analogues. The key transformations describe here involve a two-step construction of the benzofuran and a Sonogashira coupling, and proved to be convenient and effective, starting from readily available reagents.

Full text of DOI:10.1055/s-0029-1219224

PAPER
1181
Total Synthesis of Ailanthoidol, Egonol, and Related Analogues
Synthesis of
A
ilan
i
thoidol
nand Egonol-Fang Duan,* Gang Shen, Zhan-Bin Zhang
Department of Chemistry, Beijing Normal University, Beijing, 100875, P. R. of China
Fax +86(10)58802075; E-mail: xinfangduan@vip.163.com
Received 26 November 2009; revised 8 December 2009
Various methodologies have been developed for the syn-
thesis of the benzofuran nucleus, including the following:
(a) metal-mediated Sonogashira coupling10 and C–C11 or
C–O12 arylation reactions, (b) oxidative cyclization of o-
Abstract: Efficient and general synthetic protocols were developed
for the total synthesis of ailanthoidol, egonol, and some related an-
alogues. The key transformations describe here involve a two-step
construction of the benzofuran and a Sonogashira coupling, and
proved to be convenient and effective, starting from readily avail- vinylphenols,13 (c) dehydration of a-phenoxy ketones,14
and (d) intramolecular McMurry coupling15 or Wittig re-
able reagents.
actions.16
Key words: benzofurans, cross-coupling, McMurry reaction,
Sonogashira coupling, natural products
To date, many methods have been developed for the prep-
aration of ailanthoidol (1), egonol (2a), and analogues 2b
and 2c (Figure 1). The number of reported preparation ap-
proaches includes six for ailanthoidol (1),3a,17 seven for
Benzofurans and their analogues constitute a major group
of naturally occurring compounds.1 They are of particular
interest for their broad range of biological activities and
significant pharmacological potential.2 Ailanthoidol (1)
and XH14 (1a) (Figure 1) were isolated from the Chinese
traditional herbal medicines Zanthoxylum ailanthoides3
and danshen,4 respectively, which demonstrated interest-
ing pharmacological activities.5 A few other 2-arylbenzo-
furans, egonol (2a), homoegonol (2b), and
demethoxyegonol (2c) (Figure 1) were isolated from
Styrax japonicum, Styrax officinalis L., and Styrax
obassia.6–8 These compounds have been reported to have
cytostatic activity against human leukemic HL-60 cells.9
egonol (2a),18 and three each for homoegonol (2b)18d,f,g
and demethoxyegonol (2c).18f,g,19 Most of these syntheses
are based on the construction of the benzofuran ring by a
Sonogashira coupling of o-bromo- or iodophenols with
copper–alkynes.
We report herein a general approach to the total synthesis
of ailanthoidol (1), egonol (2a), and analogues 2b and 2c
(Figure 1). It involves a stepwise reaction: the synthesis of
bromobenzofurans by selective cross McMurry coupling
is followed by sequential oxidative cyclization, Sono-
gashira coupling, reduction, and hydrolysis. This method
proved to be convenient and effective, as the starting ma-
terials are the readily available salicylaldehyde as well as
aromatic aldehydes, and the operations are simple.
HO
OH
O
Recently we reported various selective cross McMurry
couplings of structurally similar diaryl or aryl ketones and
aromatic aldehydes.20 A two-step synthetic strategy for
benzofurans based on selective cross McMurry coupling
has been developed as well.20b During our synthesis of
benzofurans,20b the cross McMurry couplings were medi-
ated by TiCl4 and Zn in THF. Most recently, our laborato-
ry has made good progress in further improving the yield
of this cross-coupling reaction when TiCl4/Mn/THF was
used in the place of TiCl4/Zn/THF (Table 1). Other types
of low-valent-titanium reagents were also tested, but
TiCl4/Mn/THF gave the best results (Table 1). Although
[TiCp2Cl2]/Mn has previously been reported to promote
pinacol-type coupling of aldehydes,21 this is the first time
that alkenes were generated by the use of TiCl4 and Mn in
THF. This can serve as an improved and alternative pro-
tocol for our previously reported selective cross-
McMurry couplings and two-step construction of benzo-
furans.20b
OMe
OMe
1
CHO
HO
OH
O
OMe
OMe
1a
HO
R2
O
R3
R1
2a R1 = OMe, R2–R3 = OCH2O
2b R1 = R2 = R3 = OMe
2c R1 = H, R2–R3 = OCH2O
Figure 1 Structures of ailanthoidol (1), XH14 (1a), egonol (2a), and
analogues 2b and 2c
The oxidative cyclization of o-vinylphenols to form ben-
zofurans is usually achieved by the use of one of the fol-
lowing three reagents: (a) 2,3-dichloro-5,6-dicyano-1,4-
benzoquinone (DDQ),13b,c (b) m-chloroperoxybenzoic
SYNTHESIS 2010, No. 7, pp 1181–1187
Advanced online publication: 12.01.2010
DOI: 10.1055/s-0029-1219224; Art ID: Z25609SS
x
x
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x
x
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0
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© Georg Thieme Verlag Stuttgart · New York

1182
X.-F. Duan et al.
PAPER
Br
CHO
OH
Table 1 Selective Cross-McMurry Coupling of 3a and 4a Promoted
OHC
OMe
OBn
TiCl4, Mn, THF
75%
by Various Low-Valent Titanium Systemsa
+
OMe
4b
OMe
3b
CHO
OMe
CHO
LVT
OMe
OMe
OBn
+
OBn
Br
OH
OMe
OH
Br
OMe
OMe
OMe
K2CO3, I2, THF
94%
O
3a
4a
5aa
OH
OMe
6bb
Entry Titanium promoter (LVT)b Reaction time (h) Yieldc (%)
5bb
OMe
OAc
1
2
3
4
5
TiCl4/Mn (1:2)
6.0
6.0
6.0
8.0
6.0
78
70
48
64
45
OMe
OBn
TiCl4/Zn (1:2)
OAc
TiCl4
88%
PdCl2(PhCN)2
[(t-Bu)3PH]BF4
TiCl4/Zn/CuCl (1:2:0.1)
TiCl4/Sm (1:2)
O
7bb
71%
OMe
OAc
TiCl4/LAH (1:2)
OMe
OH
a Reaction conditions: 3a (1 equiv), 4a (1.2 equiv), LVT (2.5 equiv).
For the investigation of other types of low-valent-titanium promoters,
see ref. 16.
NaOH, MeOH
93%
O
O
b Molar ratio given in parentheses.
8
9
OMe
OMe
c Isolated yield.
OH
OMe
OH
acid/p-toluenesulfonic acid,13d and (c) iodine/potassium
carbonate.13a Here, we demonstrate that o-vinylphenols
were cyclized by using iodine/potassium carbonate to fur-
nish benzofurans in high yields (>90%).
The standard procedures3a,22 used for Sonogashira cou-
pling of propargyl acetate with bromobenzofurans cata-
lyzed by tetrakis(triphenylphosphine)palladium led to
only low yields (<35%) in our hands. The yields of the
couplings were, finally, significantly improved (all
>70%) when [PdCl2(NCPh)2] with [t-Bu3PH]BF4 was
used as the palladium catalyst.
LiAlH4
82%
OMe
OH
ailanthoidol (1)
HO
total yield: 34%
O
OMe
OMe
OH
H2, Pd/C
92%
AcO
7bb
O
As illustrated in Scheme 1, the synthesis of ailanthoidol
(1) started with the two readily available compounds 3b
and 4b. Bromobenzofuran 6bb was obtained in an overall
yield of 71% via a selective cross McMurry coupling, fol-
lowed by oxidative cyclization. The bromobenzofuran
was coupled with propargyl acetate by a palladium-cata-
lyzed Sonogashira reaction to generate 7bb. By debenzy-
lation and hydrolysis, 7bb was converted into compound
9. Reduction of propargyl alcohol 9 to give the corre-
sponding trans-allyl alcohol by the use lithium aluminum
hydride23 finally gave ailanthoidol (1), after a six-step
synthesis with a total yield of 34%.
10
OMe
Scheme 1 Total synthesis of ailanthoidol (1) and precursor 10 of
XH14 (1a)
tively. The bromobenzofurans 6ba, 6bc, and 6ca were
also each prepared in two steps by means of selective
cross McMurry coupling in overall yields of 57–68%. The
3-hydroxypropyl side chain was introduced on the benzo-
furan rings by Sonogashira coupling, followed by hydro-
genation and hydrolysis.
To sum up, ailanthoidol (1) was synthesized from readily
available 5-bromo-3-methoxysalicylaldehyde (3b) and 4-
(benzyloxy)-3-methoxybenzaldehyde (4b) in six steps in
34% overall yield. In addition, egonol (2a), homoegonol
(2b), and demethoxyegonol (2c) were prepared in five
steps in 40, 40, and 34% overall yield, respectively. This
method uses a modified reaction with a new low-valent-
titanium reagent (TiCl4 and Mn in THF) in the selective
cross McMurry coupling. It represents an improvement to
our previously reported protocol for the two-step con-
struction of the benzofuran ring. The tethered three-car-
bon side chain at the 5-position of these benzofurans is
It should be noted that our synthetic strategy can be con-
veniently employed in the formal synthesis of XH14 (1a).
Compound 7bb (Scheme 1) was smoothly hydrogenated
and debenzylated under the catalysis of palladium on car-
bon under one atmosphere of hydrogen to generate 10 in
92% yield. Obviously, this key precursor 10 can be
regioselectively formylated according to a reported
procedure24 to afford XH14 (1a).
As illustrated in Scheme 2, egonol (2a), homoegonol
(2b), and demethoxyegonol (2c) were each synthesized in
five steps with overall yields of 40, 40, and 34%, respec-
Synthesis 2010, No. 7, 1181–1187 © Thieme Stuttgart · New York

PAPER
Synthesis of Ailanthoidol and Egonol
1183
R2
R2
R2
R2
Br
CHO
OH
Br
OHC
TiCl4, Mn, THF
K2CO3, I2, THF
+
OH
R1
R1
5ba: 71%
5bc: 74%
5ca: 63%
3b: R1 = OMe
3c: R1 = H
4a: R2–R3 = OCH2O
4c: R2 = R2 = OMe
OAc
R2
R2
Br
OAc
H2, Pd/C
R2
R2
PdCl2(PhCN)2
[(t-Bu)3PH]BF4
O
O
R1
R1
6ba: 96%
6bc: 91%
6ca: 91%
7ba: 71%
7bc: 73%
7ca: 70%
R2
R2
NaOH
MeOH
AcO
HO
R2
R2
O
O
R1
R1
11ba: 89%
11bc: 90%
11ca: 90%
2a: 92%; 40% overall
2b: 90%; 40% overall
2c: 94%; 34% overall
Scheme 2 Total synthesis of egonol (2a), homoegonol (2b), and demethoxyegonol (2c)
tion mixture was heated at reflux until the carbonyl compounds
were consumed (as monitored by TLC). The reaction mixture was
quenched with 10% aq NaHCO3 (90 mL) and extracted with CH2Cl2
(3 × 40 mL). The organic layers were combined and dried
(Na2SO4). The solvent was removed and the residue was purified by
flash column chromatography (silica gel, PE–EtOAc, 3:1); this
gave 5aa.
completed by a palladium-catalyzed Sonogashira cou-
pling.
In conclusion, we have developed an effective and general
synthetic strategy for the preparation of ailanthoidol,
egonol, and analogues. On the whole, this can be accom-
plished with readily available reagents.
White solid; yield: 1.00 g (78%); mp 162.3–164.0 °C.
IR (KBr): 3041, 1598, 1478, 1269, 1141, 1061 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.28 (d, J = 16.4 Hz, 1 H), 7.17
(dd, J = 8.0, 1.0 Hz, 1 H), 7.16 (s, 1 H), 7.12 (m, 1 H), 7.07 (dd,
J = 8.3, 1.8 Hz, 1 H ), 6.83–6.87 (m, 2 H), 6.76 (dd, J = 8.0, 1.2 Hz,
1 H), 5.96 (s, 1 H), 3.96 (s, 3 H), 3.92 (s, 3 H), 3.91 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 149.2, 148.9, 146.7, 143.3, 131.1,
129.3, 124.0, 121.1, 119.9, 119.5, 118.7, 111.3, 109.2, 109.0, 56.1,
56.0, 55.9.
All glassware was oven-dried (120 °C) and cooled under a stream
of argon gas. The reagents and solvents used for the pinacol-type
couplings were freshly distilled or dehydrated before use. All other
starting materials were obtained from commercial suppliers and
used without further purification. Analytical TLC was conducted by
using QDHY GF254 plates. Column chromatography was per-
formed on QDYD silica gel (200–300 mesh). Melting points were
recorded on a TECH X-4 microscopic instrument and are uncorrect-
ed. IR spectra were obtained on a Vaatar 360 FT-IR spectrophotom-
eter. 1H and 13C NMR spectra were recorded at 400 MHz and 100
MHz, respectively, on a Bruker Avance 400 spectrometer; TMS
was used as internal standard. Mass spectra were recorded on a
Traces MS spectrometer. Elemental analyses were obtained by us-
ing an Elementar Vario EL instrument.
MS (EI): m/z (%) = 286 (100) [M+], 284 (50), 271 (40), 211 (10).
Anal. Calcd for C17H18O4: C, 71.31; H, 6.34. Found: C, 70.98; H,
6.36.
2-[4-(Benzyloxy)-3-methoxystyryl]-4-bromo-6-methoxyphenol
(5bb)
2-(3,4-Dimethoxystyryl)-6-methoxyphenol (5aa); Typical Pro-
cedure for the Synthesis of o-Vinylphenols 5 by McMurry Cou-
pling
White solid; mp 138.2–139.0 °C.
IR (KBr): 3419, 1595, 1513, 1462, 1266 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.44 (m, 2 H), 7.35–7.39 (m, 2 H),
7.30–7.32 (m, 2 H), 7.17–7.21 (m, 1 H), 7.04–7.10 (m, 2 H), 6.99–
7.01 (m, 1 H), 6.85–6.87 (m, 2 H), 5.85 (s, 1 H), 5.18 (s, 2 H), 3.95
(s, 3 H), 3.90 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 149.8, 148.2, 147.3, 142.3, 137.1,
131.0, 130.2, 128.6, 127.8, 127.2, 125.4, 121.1, 120.0, 119.8, 114.0,
112.3, 111.7, 109.5, 71.0, 56.4, 56.0.
Under an argon atmosphere, a four-necked flask equipped with a
magnetic stirrer was charged with Mn powder (1.4 g, 24 mmol) and
THF (80 mL). The mixture was cooled to –5 to 0 °C, and TiCl4 (1.3
mL, 12 mmol) was slowly added by syringe, while the temperature
was kept at <0 °C. The suspension was warmed to r.t. and stirred for
0.5 h, then heated at reflux for 2.5 h. The mixture was again cooled
to –5 to 0 °C, and a soln of 2-hydroxy-3-methoxybenzaldehyde (3a;
0.73 g, 4.8 mmol) and 3,4-dimethoxybenzaldehyde (4a; 0.96 g, 5.8
mmol) in THF (30 mL) was added slowly. After addition, the reac-
MS (EI): m/z (%) = 440 (20) [M+], 349 (100), 241 (25), 96 (100).
Synthesis 2010, No. 7, 1181–1187 © Thieme Stuttgart · New York

1184
X.-F. Duan et al.
PAPER
Anal. Calcd for C23H21BrO4: C, 62.60; H, 4.80. Found: C, 62.38; H,
4.52.
13C NMR (100 MHz, CDCl3): d = 157.2, 149.8, 149.0, 145.4, 142.8,
136.8, 132.3, 128.6, 128.0, 127.3, 123.3, 118.2, 115.9, 115.7, 113.9,
109.8, 108.7, 99.8, 71.0, 56.3, 56.2.
2-(3,4-Methylenedioxystyryl)-4-bromo-6-methoxyphenol (5ba)
White solid; mp 173.5–175.1 °C.
IR (KBr): 3485, 1604, 1502, 1445, 1251 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.30 (d, J = 13.4 Hz, 1 H), 7.19 (d,
J = 16.4 Hz, 1 H), 6.81–7.12 (m, 5 H), 6.00 (s, 2 H), 5.88 (s, 1 H),
3.92 (s, 3 H).
MS (EI): m/z (%) = 438 (15) [M+], 346 (60), 240 (45), 91 (100).
Anal. Calcd for C23H19BrO2: C, 62.88; H, 4.36. Found: C, 63.10; H,
4.59.
2-(3,4-Methylenedioxyphenyl)-5-bromo-7-methoxybenzofuran
(6ba)
White solid; mp 167.4–168.4 °C.
IR (KBr): 1621, 1501, 1474, 1260 cm–1.
13C NMR (100 MHz, CDCl3): d = 148.2, 147.3, 142.3, 131.9, 130.1,
125.3, 121.8, 121.0, 119.8, 112.4, 111.7, 108.4, 105.7, 101.2, 56.4.
MS (EI): m/z (%) = 348 (85) [M+], 254 (45), 152 (60), 139 (60).
1H NMR (400 MHz, CDCl3): d = 7.40 (dd, J = 1.7, 8.2 Hz, 1 H),
7.30 (dd, J = 1.7, 9.4 Hz, 2 H), 6.89 (m, 2 H), 6.79 (s, 1 H), 6.02 (s,
2 H), 4.03 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 156.9, 148.4, 148.1, 145.5, 142.8,
132.2, 124.1, 119.5, 115.9, 115.7, 110.0, 108.7, 105.6, 101.4, 99.8,
56.4.
Anal. Calcd for C16H13BrO4: C, 55.04; H, 3.75. Found: C, 55.21; H,
3.49.
2-(3,4-Dimethoxystyryl)-4-bromo-6-methoxyphenol (5bc)
White solid; mp 157.0–158.5 °C.
IR (KBr): 3407, 1597, 1513, 1427, 1264 cm–1.
MS (EI): m/z (%) = 346 (40) [M+], 268 (100), 152 (75), 84 (35).
1H NMR (400 MHz, CDCl3): d = 7.24 (s, 1 H), 7.13 (d, J = 16.4 Hz,
1 H), 6.99–7.03 (m, 3 H), 6.79 (d, J = 6.2 Hz, 2 H), 5.78 (s, 1 H),
3.87 (s, 3 H), 3.83 (s, 6 H).
Anal. Calcd for C16H11BrO4: C, 55.36; H, 3.19. Found: C, 55.59; H,
3.38.
2-(3,4-Dimethoxyphenyl)-5-bromo-7-methoxybenzofuran (6bc)
White solid; mp 204.5–205.8 °C.
IR (KBr): 3007, 1614, 1510, 1470.0, 1254 cm–1.
13C NMR (100 MHz, CDCl3): d = 149.1, 147.3, 142.3, 130.5, 130.3,
125.5, 121.1, 120.2, 119.6, 112.3, 111.7, 111.3, 109.0, 56.4, 55.94,
55.91.
MS (EI): m/z (%) = 364 (20) [M+], 366 (21), 225 (20), 138 (100), 63
(95).
1H NMR (400 MHz, CDCl3): d = 7.38 (dd, J = 8.3, 2.0 Hz, 1 H),
7.35 (d, J = 2.0 Hz, 1 H), 7.22 (d, J = 1.7 Hz, 1 H), 7.02 (m, 1 H),
6.95 (d, J = 8.3 Hz, 1 H), 6.89 (d, J = 1.7 Hz, 1 H), 3.93 (s, 3 H),
3.80 (s, 3 H), 3.76 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 156.6, 149.8, 149.0, 145.2, 142.0,
132.0, 121.9, 117.7, 115.5, 115.2, 112.0, 109.8, 108.3, 100.3, 56.2,
55.6, 55.5.
Anal. Calcd for C17H17BrO4: C, 55.91; H, 4.69. Found: C, 56.03; H,
4.47.
2-(3,4-Methylenedioxystyryl)-4-bromophenol (5ca)
White solid; mp 173.0–174.0 °C.
IR (KBr): 1603, 1501, 1485, 1444, 1257, 1039 cm–1.
MS (EI): m/z = 364 (50) [M+], 362 (50), 149 (53), 81 (69), 69 (100).
1H NMR (400 MHz, CDCl3): d = 7.62 (d, J = 2.2 Hz, 1 H), 7.00–
7.23 (m, 4 H), 6.96 (d, J = 7.99 Hz, 1 H), 6.83 (d, J = 8.0 Hz, 1 H),
6.71 (d, J = 8.5 Hz, 1 H), 5.95 (s, 2 H), 5.32 (s, 1 H).
Anal. Calcd for C17H15BrO4: C, 56.22; H, 4.16. Found: C, 56.32; H,
4.42.
2-(3,4-Methylenedioxyphenyl)-5-bromobenzofuran (6ca)
White solid; mp 156.6–158.0 °C.
IR (KBr): 1605, 1572, 1483, 1172, 1110 cm–1.
1H NMR (500 MHz, CDCl3): d = 7.68 (s, 1 H), 7.35–7.40 (m, 3 H),
7.31 (s, 1 H), 6.92 (d, J = 8.1 Hz, 1 H), 6.82 (s, 1 H), 6.05 (s, 2 H).
13C NMR (100 MHz, CDCl3): d = 153.1, 135.3, 133.7, 128.8, 128.6,
128.0, 127.6, 126.1, 125.8, 125.7, 123.8, 123.6, 121.5, 116.0, 41.8.
MS (EI): m/z (%) = 316 (100) [M+], 179 (35), 150 (51), 75 (24).
13C NMR (100 MHz, CDCl3): d = 151.9, 147.6, 130.8, 130.7, 129.3,
121.8, 119.8, 117.5, 108.4, 105.6, 101.2, 44.9.
MS (EI): m/z (%) = 318 (86) [M+], 181 (56), 152 (69).
Anal. Calcd for C15H11BrO3: C, 56.45; H, 3.47. Found: C, 56.21; H,
3.20.
2-[4-(Benzyloxy)-3-methoxyphenyl]-5-bromo-7-methoxybenzo-
furan (6bb); Typical Procedure for the Synthesis of 5-Bromo-
benzofurans 6 by Oxidative Cyclization
Anal. Calcd for C15H9BrO3: C, 56.81; H, 2.86. Found: C, 57.06; H,
2.58.
Anhyd K2CO3 (1.53 g, 11.1 mmol) was added to a soln of 5bb (0.88
g, 2 mmol) in THF (20 mL), and subsequently the mixture was
stirred for 10 min. I2 (2.82 g, 11.1 mmol) was added, and the mix-
ture was stirred at r.t. until o-vinylphenol 5bb was consumed. The
mixture was poured into sat. aq NaHCO3 (30 mL) and treated with
sat. aq NaHSO3 (25 mL) to remove the nonreacted I2. The mixture
was extracted with EtOAc (3 × 50 mL) and the organic layer was
dried (Na2SO4) and then concentrated. The crude material was pu-
rified by column chromatography (silica gel, PE–EtOAc, 4:1); this
gave 6bb.
5-(3-Acetoxyprop-1-ynyl)-2-[4-(benzyloxy)-3-methoxyphenyl]-
7-methoxybenzofuran (7bb); Typical Procedure for the Synthe-
sis of 5-(3-Acetoxypropynyl)benzofurans 7 by Sonogashira
Coupling
A mixture of 6bb (660 mg, 1.5 mmol), [PdCl2(NCPh)2] (58 mg,
0.15 mmol), [t-Bu3PH]BF4 (170 mg, 0.60 mmol), CuI (61 mg, 0.32
mmol), propargyl acetate (1 mL), Et3N (1 mL), and DMF (5 mL)
was introduced into a three-necked flask. After being degassed, the
mixture was stirred and heated at 90 °C for 20 h. The reaction was
quenched with 10% aq NaHCO3 (30 mL) and extracted with CH2Cl2
(3 × 30 mL). The combined organic layer was washed with 10% aq
NH4OH until the purple color disappeared and then washed with
distilled H2O to neutral. After being dried (Na2SO4), the organic
layer was concentrated. The crude material was purified by column
chromatography (silica gel, PE–EtOAc, 3:1); this gave 7bb.
White solid; yield: 0.82 g (94%); mp 154.0–155.6 °C.
IR (KBr): 1613, 1513, 1476, 1208 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.32–7.47 (m, 6 H), 7.30 (d,
J = 1.7 Hz, 2 H), 6.93–6.95 (m, 1 H), 6.90 (d, J = 1.7 Hz, 1 H), 6.82
(s, 1 H), 5.22 (s, 2 H), 4.03 (s, 3 H), 4.00 (s, 3 H).
Synthesis 2010, No. 7, 1181–1187 © Thieme Stuttgart · New York

PAPER
Synthesis of Ailanthoidol and Egonol
1185
White solid; yield: 488 mg (71%); mp 147–148.8 °C (Lit.3a 149–
151 °C).
IR (KBr): 2952, 2131, 1741, 1457, 1377, 1221 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.38 (d, J = 7.2 Hz, 2 H), 7.24–
7.32 (m, 5 H), 7.21 (s, 1 H), 6.81–6.88 (m, 2 H), 6.73 (s, 1 H), 5.13
(s, 2 H), 4.61 (s, 2 H), 3.95 (s, 3 H), 3.92 (s, 3 H), 2.04 (s, 3 H).
IR (KBr): 3400, 2932, 1744, 1604, 1467, 1376, 1241, 1146 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.40 (d, J = 7.3 Hz, 2 H), 7.29 (s,
1 H), 6.89–6.96 (m, 2 H), 6.82 (s, 1 H), 5.44 (s, 1 H), 4.39 (t, J = 6.7
Hz, 2 H), 4.00 (s, 3 H), 3.96 (s, 3 H), 2.71 (t, J = 7.9 Hz, 2 H), 2.16
(s, 3 H), 1.65–1.69 (m, 2 H).
5-(3-Acetoxypropyl)-7-methoxy-2-(3,4-methylenedioxyphe-
nyl)benzofuran (11ba)
5-(3-Acetoxyprop-1-ynyl)-7-methoxy-2-(3,4-methylenedioxy-
phenyl)benzofuran (7ba)
White solid; mp 131.0–132.8 °C.
White solid; mp 94.5–96.0 °C (Lit.6c 94–95 °C).
IR (KBr): 1746, 1462, 1373, 1237 cm–1.
IR (KBr): 2952, 2130, 1747, 1454, 1378, 1225 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.39–7.41 (dd, J = 10.2, 2.1 Hz, 1
H), 7.27–7.32 (m, 2 H), 6.90 (s, 1 H), 6.88 (d, J = 10.0 Hz, 1 H),
6.79 (s, 1 H), 6.02 (s, 2 H), 4.27 (t, J = 6.7 Hz, 2 H), 4.03 (s, 3 H),
2.67 (t, J = 7.9 Hz, 2 H), 2.16 (s, 3 H), 1.49–1.55 (m, 2 H).
1H NMR (400 MHz, CDCl3): d = 7.39 (dd, J = 8.2, 1.6 Hz, 1 H),
7.26–7.31 (m, 2 H), 6.87–6.89 (m, 2 H), 6.78 (s, 1 H), 6.01 (s, 2 H),
4.68 (s, 2 H), 4.02 (s, 3 H), 2.11 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 170.1, 167.8, 157.0, 148.4, 148.2,
145.4, 132.2, 124.0, 119.5, 115.9, 115.7, 110.1, 108.6, 105.6, 101.3,
99.8, 97.0, 88.7, 56.3, 51.9, 20.6.
5-(3-Acetoxypropyl)-2-(3,4-dimethoxyphenyl)-7-methoxyben-
zofuran (11bc)
White solid; mp 91–92 °C (Lit.7 90–91 °C).
MS (EI): m/z (%) = 364 (25) [M+], 306 (30), 170 (80), 151 (90).
IR (KBr): 2925, 1747, 1462, 1376, 1237 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.37–7.39 (dd, J = 6.4, 2.0 Hz, 1
H), 7.28 (d, J = 2.0 Hz, 1 H), 7.19 (s, 1 H), 6.82–6.89 (m, 2 H), 6.27
(s, 1 H), 4.26 (t, J = 6.9 Hz, 2 H), 3.96 (s, 3 H), 3.92 (s, 3 H), 3.87
(s, 3 H), 2.70 (t, J = 7.9 Hz, 2 H), 2.17 (s, 3 H), 1.48–1.56 (m, 2 H).
Anal. Calcd for C21H16O6: C, 69.23; H, 4.43. Found: C, 69.46; H,
4.70.
5-(3-Acetoxyprop-1-ynyl)-2-(3,4-dimethoxyphenyl)-7-methoxy-
benzofuran (7bc)
White solid; mp 196.0–197.6 °C.
IR (KBr): 2953, 2131, 1750, 1457, 1377 cm–1.
5-(3-Acetoxypropyl)-2-(3,4-methylenedioxyphenyl)benzofuran
(11ca)
White solid; mp 95.5–97 °C (Lit.8b 97.8 °C).
1H NMR (400 MHz, CDCl3): d = 7.40–7.47 (m, 3 H), 7.06–7.09 (m,
3 H), 4.67 (s, 2 H), 3.99 (s, 3 H), 3.87 (s, 3 H), 3.82 (s, 3 H), 2.05 (s,
3 H).
13C NMR (100 MHz, CDCl3): d = 169.6, 156.6, 149.9, 149.1, 145.3,
142.0, 132.1, 121.9, 117.8, 115.5, 115.3, 112.1, 109.8, 108.4, 100.3,
96.9, 89.7, 56.2, 55.7, 55.6, 51.5, 20.3.
IR (KBr): 1746, 1462, 1373, 1237cm–1.
1H NMR (400 MHz, CDCl3): d = 7.66 (s, 1 H), 7.25–7.39 (m, 4 H),
6.88 (d, J = 8.1 Hz, 1 H), 6.80 (s, 1 H), 6.02 (s, 2 H), 4.27 (t, J = 6.7
Hz, 2 H), 2.67 (t, J = 7.9 Hz, 2 H), 2.16 (s, 3 H), 1.49–1.55 (m, 2 H).
5-(3-Hydroxypropyl)-7-methoxy-2-(3,4-methylenedioxyphe-
nyl)benzofuran (Egonol, 2a); Typical Procedure for the Synthe-
sis of 5-(3-Hydroxypropyl)benzofurans 2a–c by Hydrolysis
5-(3-Acetoxypropyl)benzofuran 11ba (180 mg, 0.5 mmol) was add-
ed to a soln of NaOH (100 mg, 2.5 mmol) in MeOH (15 mL). The
mixture was refluxed until the hydrolysis was completed (as moni-
tored by TLC) and was evaporated to dryness. The residue was dis-
solved in distilled H2O (30 mL), and the soln was neutralized with
3% aq HCl and extracted with EtOAc (3 × 20 mL). The organic lay-
er was dried (Na2SO4) and concentrated. The residue was purified
by column chromatography (silica gel, PE–EtOAc, 3:1); this gave
egonol (2a).
White solid; yield: 150 mg (92%); mp 117–119 °C (Lit.7 115–116
°C).
IR (KBr): 3338, 2924, 1459, 1378, 1234, 1056 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.39–7.41 (dd, J = 8.4, 2.0 Hz, 1
H), 7.27–7.32 (m, 2 H), 6.87–6.90 (m, 2 H), 6.79 (s, 1 H), 6.02 (s, 2
H), 4.03 (s, 3 H), 3.62 (t, J = 6.8 Hz, 2 H), 3.06 (s, 1 H), 2.65 (t,
J = 7.9 Hz, 2 H), 1.51–1.56 (m, 2 H).
MS (EI): m/z (%) = 380 (30) [M+], 365 (45), 337 (90), 139 (55).
Anal. Calcd for C22H20O6: C, 69.46; H, 5.30. Found: C, 69.65; H,
5.52.
5-(3-Acetoxyprop-1-ynyl)-2-(3,4-methylenedioxyphenyl)benzo-
furan (7ca)
White solid; mp 122.5–124.0 °C.
IR (KBr): 2924, 2130, 1747, 1439, 1378, 1229, 1034 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.60 (s, 1 H), 7.19–7.32 (m, 4 H),
6.81–6.83 (d, J = 8.1 Hz, 1 H), 6.74 (s, 1 H), 5.96 (s, 2 H), 4.69 (s,
2 H), 2.10 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 171.2, 157.1, 153.4, 148.4, 148.2,
131.3, 126.7, 124.1, 123.2, 119.4, 115.9, 112.4, 108.8, 105.5, 101.4,
99.5, 95.6, 90.1, 52.0, 20.7.
MS (EI): m/z (%) = 334 (35) [M+], 291 (95), 197 (40), 168 (60).
Anal. Calcd for C20H14O5: C, 71.85; H, 4.22. Found: C, 71.61; H,
4.49.
5-(3-Acetoxypropyl)-2-(4-hydroxy-3-methoxyphenyl)-7-meth-
oxybenzofuran (10); Typical Procedure for the Synthesis of 5-
(3-Acetoxypropyl)benzofurans 10 and 11 by Catalytic Hydroge-
nation
Benzofuran 7bb (700 mg, 1.5 mmol) was dissolved in MeOH (15
mL). Pd/C (10%, 0.13 g) was added and the reaction mixture was
stirred under H2 (1 atm) at r.t. After compound 7bb had been con-
sumed (as monitored by TLC), the reaction mixture was filtered and
then evaporated to dryness. The residue was purified by column
chromatography (silica gel, PE–EtOAc, 3:1); this gave 10.
2-(3,4-Dimethoxyphenyl)-5-(3-hydroxypropyl)-7-methoxyben-
zofuran (Homoegonol, 2b)
White solid; mp 118–119 °C (Lit.7 120–122 °C).
IR (KBr): 3329, 2924, 1460, 1377, 1307, 1254, 1224 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.37–7.40 (dd, J = 6.4, 2.0 Hz, 1
H), 7.28 (d, J = 1.9 Hz, 1 H), 7.22 (d, J = 1.7 Hz, 1 H), 6.82–6.87
(m, 2 H), 6.76 (s, 1 H), 3.96 (s, 3 H), 3.92 (s, 3 H), 3.87 (s, 3 H), 3.42
(t, J = 6.7 Hz, 2 H), 3.04 (s, 1 H), 2.69 (t, J = 7.9 Hz, 2 H), 1.48–
1.57 (m, 2 H).
White solid; yield: 470 mg (85%); mp 76–78 °C (Lit.3a 80–80.5 °C).
Synthesis 2010, No. 7, 1181–1187 © Thieme Stuttgart · New York

1186
X.-F. Duan et al.
PAPER
5-(3-Hydroxypropyl)-2-(3,4-methylenedioxyphenyl)benzofu-
ran (Demethoxyegonol, 2c)
rified by flash column chromatography (silica gel, CH2Cl2); this
gave ailanthoidol (1).
White solid; yield: 130 mg (82%); mp 195–196 °C (Lit.3a 199–201
°C).
White solid; mp 116–118 °C (Lit.8b 118–119 °C).
IR (KBr): 3338, 2924, 1459, 1378, 1234, 1056 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.66 (s, 1 H), 7.34–7.39 (m, 3 H),
7.29 (d, J = 1.6 Hz, 1 H), 6.89–6.90 (d, J = 8.2 Hz, 1 H), 6.78 (s, 1
H), 6.02 (s, 2 H), 3.51 (t, J = 6.8 Hz, 2 H), 3.06 (s, 1 H), 2.65 (t,
J = 7.9 Hz, 2 H), 1.49–1.55 (m, 2 H).
IR (KBr): 3326, 3170, 2925, 1604, 1463, 1377, 1148 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.46 (d, J = 7.2 Hz, 1 H), 6.45 (s,
1 H), 7.30 (s, 1 H), 6.93–6.96 (m, 1 H), 6.89 (d, J = 1.7 Hz, 1 H),
6.82 (s, 1 H), 6.59 (d, J = 16.3 Hz, 1 H), 5.72 (d, J = 16.3 Hz, 1 H),
4.21 (s, 2 H), 4.00 (s, 3 H), 4.04 (s, 3 H), 3.42 (s, 1 H).
Ailanthoidol (1)
5-(3-Acetoxyprop-1-ynyl)-2-(4-hydroxy-3-methoxyphenyl)-7-
methoxybenzofuran (8)
Acknowledgment
TiCl4 (0.09 mL, 0.8 mmol) was added dropwise by a syringe to a
soln of 7bb (320 mg, 0.7 mmol) in CH2Cl2 (25 mL) at r.t. The mix-
ture was stirred until completion of the reaction (as monitored by
TLC). The reaction mixture was quenched by the slow addition of
distilled H2O (1 mL) and treated with activated carbon. After the re-
sulting mixture had been filtered and concentrated, the residue was
subjected to flash column chromatography (silica gel, PE–EtOAc,
3:1); this gave 8.
We gratefully acknowledge the support of the National Nature Sci-
ence Foundation of China (grant 20672014) and the Beijing Key
Subject Program, and Dr. Yao Ma for revising this manuscript.
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White solid; yield: 230 mg (88%); mp 141–142.6 °C.
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Anal. Calcd for C21H18O6: C, 68.85; H, 4.95. Found: C, 68.59; H,
4.68.
2-(4-Hydroxy-3-methoxyphenyl)-5-(3-hydroxyprop-1-ynyl)-7-
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White solid; yield: 180 mg (93%); mp 136–138 °C.
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(E)-2-(4-Hydroxy-3-methoxyphenyl)-5-(3-hydroxyprop-1-
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Synthesis 2010, No. 7, 1181–1187 © Thieme Stuttgart · New York

PAPER
Synthesis of Ailanthoidol and Egonol
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Synthesis 2010, No. 7, 1181–1187 © Thieme Stuttgart · New York