Concise synthesis of licochalcone a through water-accelerated [3,3]-sigmatropic rearrangement of an aryl prenyl ether

Article abstract of DOI:10.1055/s-0030-1258381

Claisen-Schmidt condensation of 4-(tetrahydropyran-2-yloxy)acetophenone with 2-methoxy-4-[(3-methylbut-2-en-1-yl)oxy]benzaldehyde gave a THP-protected chalcone ether. Removal of the THP group under mild acidic conditions gave the corresponding chalcone ether, which underwent a water-accelerated Claisen rearrangement under microwave irradiation or heating in a sealed tube in aqueous ethanol to give a good yield of licochalcone A, which has diverse biological activities; no product of deprenylation or abnormal Claisen rearrangement was formed. The abnormal Claisen rearrangement of -substituted allyl aryl ethers is known to be a problem in [3,3]-sigmatropic rearrangement reaction; this, however, was not detected in our water-accelerated system.

Full text of DOI:10.1055/s-0030-1258381

370
PAPER
Concise Synthesis of Licochalcone A through Water-Accelerated
[3,3]-Sigmatropic Rearrangement of an Aryl Prenyl Ether
Concise
S
a
ynthesis of
e
L
icochalco
-
ne
A
Ho Jeon,a Mi Ran Kim,b Jong-Gab Jun*a,b
a
Institute of Natural Medicine, Hallym University, Chuncheon 200-702, South Korea
Department of Chemistry and Institute of Applied Chemistry, Hallym University, Chuncheon 200-702, South Korea
Fax +82(33)2563421; E-mail: jgjun@hallym.ac.kr
b
Received 20 October 2010; revised 16 November 2010
droxyacetophenone (3) gave the chalcone prenyl ether (4).
This underwent a [3,3]-sigmatropic rearrangement with
acetic anhydride in N,N-diethylaniline to give the acety-
Abstract: Claisen–Schmidt condensation of 4-(tetrahydropyran-2-
yloxy)acetophenone with 2-methoxy-4-[(3-methylbut-2-en-1-
yl)oxy]benzaldehyde gave a THP-protected chalcone ether. Re-
moval of the THP group under mild acidic conditions gave the cor-
responding chalcone ether, which underwent a water-accelerated
Claisen rearrangement under microwave irradiation or heating in a
sealed tube in aqueous ethanol to give a good yield of licochalcone
A, which has diverse biological activities; no product of deprenyla-
tion or abnormal Claisen rearrangement was formed. The abnormal
Claisen rearrangement of g-substituted allyl aryl ethers is known to
be a problem in [3,3]-sigmatropic rearrangement reaction; this,
however, was not detected in our water-accelerated system.
4"
5"
1"
2"
O
O
β
6
3
6'
3'
1
2
5'
1'
2'
5
α
3"
HO
MeO
OH
4
HO
MeO
OH
4'
OH
licochalcone A
O
licochalcone B
Key words: rearrangements, condensation, natural products, lico-
chalcone A
O
HO
MeO
OH
HO
MeO
OH
Licochalcones A–E and the closely related compound
echinatin (Figure 1) were isolated and identified from the
root of Glycyrrhiza inflata (licorice).1 The crude extract of
this root finds commercial use as a food additive because
it contains the sweetening principle glycyrrhizin. Lico-
chalcones A–E and echinatin are interesting retrochal-
cones that are distinguished from ordinary chalcones by
the absence of an oxygen functionality at the C-2¢ and C-
6¢ positions.1a They have been reported to have various bi-
ological activities, such as antitumor,2 antiparasitic,3 anti-
leishmanial,4 antioxidative,5 superoxide-scavenging,6 and
antibacterial activities,7 as well as tyrosine-protein phos-
phatase non-receptor type 1-inhibitory activity.8 Also, lic-
ochalcone A has been used as a drug to treat various
abdominal spasmodic symptoms, and it was recently re-
ported that it is a potent regulator of pathological vascular
conditions such as restenosis.9 Licochalcone A has also
been shown to have antimalarial activity.10 The discovery
by our collaborators that licochalcone A has anti-inflam-
matory activity7 and antimetastatic effects2 prompted us
to develop a practical method for the preparation of this
compound.
OH
licochalcone C
licochalcone D
O
O
HO
MeO
OH
HO
MeO
OH
licochalcone E
echinatin
Figure 1 Structures of the licochalcones
Me2SO4, KHCO3
acetone, reflux, 4 h
OHC
MeO
OHC
74%
O
HO
O
1
2
O
Ac2O, PhNEt2
sealed tube
185 °C, 4 h
O
HO
3
20%
HO
MeO
O
KOH, EtOH
r.t., 72 h
37%
Three previous routes to the total synthesis of licochal-
cone A have been reported. In the first route, methylation
of 2-hydroxy-4-[(3-methylbut-2-en-1-yl)oxy]benzalde-
hyde (1) at the 2-position to form the protected aldehyde
2 followed by Claisen–Schmidt condensation11 with 4-hy-
4
O
EtOH
NaOH
licochalcone A
75%
AcO
MeO
OAc
SYNTHESIS 2011, No. 3, pp 0370–0376
Advanced online publication: 22.12.2010
x
x
.
x
x
.2
0
1
1
5
DOI: 10.1055/s-0030-1258381; Art ID: F18510SS
© Georg Thieme Verlag Stuttgart · New York
Scheme 1 Licochalcone A synthesis: route 1

PAPER
Concise Synthesis of Licochalcone A
371
lated chalcone 5 in 20% yield. Removal of the acetyl ylbut-2-ene under basic conditions gave the aryl prenyl
group under basic conditions then gave licochalcone A in ether 2 in 75% yield. The [3,3]-sigmatropic reaction of
a 4% overall yield (four steps) (Scheme 1).12a
ether 2 was studied in various refluxing solvents at atmo-
spheric pressure with conventional heating (entries 1–4).
Because this reaction was not very successful, we at-
tempted to accelerate the reaction by performing it at a
higher pressure in a thick-walled pressure vessel (entries
8–18). Although single solvents with high boiling points
were used, the reaction failed to proceed (entries 8–11).
Another group used a similar procedure involving a [3,3]-
sigmatropic rearrangement.12b They dissolved aldehyde 2
in propionic anhydride and N,N-dimethylaniline, and
heated the mixture to 200 °C for 2.5 hours in a sealed tube.
Acid hydrolysis and Claisen–Schmidt condensation11
with 4-hydroxyacetophenone (3) gave licochalcone A
(Scheme 2).
Table 1 [3,3]-Sigmatropic Rearrangement of Prenyl Ether 2 to Re-
arranged Benzaldehyde 6
OHC
H+
(EtCO)2O, PhNMe2
Entry Solvent
Temp
(°C)
Time
(h)
Ratiod Yield of 6d
(6:7) (%)
2
50%
sealed tube
200 °C, 2.5 h
OH
MeO
1a
2a
valeric acid
reflux
reflux
reflux
reflux
180
24
48
48
12
24
10
12
10
10
10
10
10
10
10
24
24
15
15
0.5
0.5
0.5
1.5
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
6
3
xylene
licochalcone A
EtOH
3a
toluene
dry HCl
35%
4a
DMF
Scheme 2 Licochalcone A synthesis: route 2
5a
DMF–H2O (4:1)
EtOH
In the third route, treatment of 2-chloro-4-methoxyace-
tophenone with tosylmethyl isocyanide (TOSMIC) gave a
nitrile compound that was methylated and subjected to an
SN2 reaction followed by a series of functional-group
transformations to give the required prenylated benzalde-
6a
reflux
180
7a
EtOH–H2O (4:1)
valeric acid
xylene
8b
reflux
130
9b
hyde, which was converted into licochalcone
A
(Scheme 3).13
10b
11b
12b
13b
14b
15b
16b
17b
18b
19c
20c
21c
22c
DMF
130
toluene
reflux
reflux
130
CN
CN
O
Cl
EtOH
Cl
Cl
TOSMIC
MeI, NaH
DMF
DMF–H2O (4:1))
AcOH–H2O (7:2)
EtOH–H2O (4:1)
EtOH–H2O (4:1)
EtOH–H2O (4:1)
EtOH–H2O (4:1)
DMF
KOtBu, tBuOH
OMe
OMe
OMe
130
80
130
80:20 40
70:30 20
Cl
licochalcone A
180
OHC
210
–
–
–
–
–
–
–
–
OMe
210
prenylated benzaldehyde
DMF–H2O (5:1)
210
Scheme 3 Licochalcone A synthesis: route 3
acetone–H2O (4:1) 210
EtOH–H2O (4:1) 210
The existing Claisen rearrangements of prenyl ether 4 and
2 to give 5 and 6, respectively (Schemes 1 and 2, respec-
tively) were very useful for constructing the backbone of
licochalcone A, but the reported yields were generally
low. The route using TOSMIC (Scheme 3) is interesting,
but involves seven steps. We therefore focused on meth-
ods for improving the yield of the Claisen rearrangement
step.
85:15 52
a Conventional heating at atmospheric pressure.
b Sealed-tube furnace reactor.
c Microwave irradiation (300 W).
d Yield after purification by silica gel chromatography.
Because these results were not promising, we changed the
solvent to an organic solvent–water mixture (entries 5, 7,
13–18). It is known that water can accelerate certain types
of organic reactions, such as Diels–Alder reactions, 1,3-
Our strategy began with determining the optimal condi-
tions for synthesis of the prenylated benzaldehyde 6
(Scheme 4 and Table 1). Simple prenylation of 4-hy-
droxy-2-methoxybenzaldehyde (7) with 1-bromo-3-meth-
Synthesis 2011, No. 3, 370–376 © Thieme Stuttgart · New York

372
J.-H. Jeon et al.
PAPER
O
γ
O
OHC
MeO
OHC
MeO
Br
β
OH
O
α
acetone, K2CO3
reflux, 1.5 h, 75%
HO
MeO
O
HO
MeO
licochalcone A
OH
7
2
4
[3,3]-sigmatropic
rearrangement
O
OHC
MeO
+
7
OHC
MW (300 W) or
sealed-tube furnace
reaction
OH
+
MeO
O
THPO
6
2
8
Scheme 4 [3,3]-Sigmatropic rearrangement reaction
Scheme 5 Retrosynthetic analysis of licochalcone A
dipolar cycloadditions, cycloaddition reactions of azodi-
carboxylates, Claisen rearrangements, Passerini reactions,
Ugi reactions, nucleophilic opening of three-membered
rings, nucleophilic substitution reactions, transition-
metal-induced reactions, metal-free C–C bond-forming
processes, bromination reactions, oxidations, and reduc-
tions.14a,b It has also been reported that polar solvents can
accelerate the rates of [1,3]- and [3,3]-sigmatropic reac-
tions.14c–e We therefore examined the aqueous organic sol-
vent systems for the [3,3]-sigmatropic rearrangement
reaction of the aryl prenyl ether 2.
The aryl ether
2
underwent Claisen–Schmidt
condensation11 with 4-[(tetrahydropyran-2-yl)oxy]ace-
tophenone (8) to give the protected chalcone 9 in 81%
yield. Removal of the tetrahydropyranyl group under
mildly acidic conditions (1 M HCl, EtOH, r.t., 30 min)
gave the chalcone ether 4 in 95% yield. The [3,3]-sigmat-
ropic rearrangement reactions of chalcone ether 4 in etha-
nol–water (4:1 v/v) under microwave irradiation at 300 W
for 1.5 hours gave the desired licochalcone A in 86% yield
with no deprenylated or abnormal Claisen-rearrangement
products. Similarly, when the reaction was performed
with the same solvent system in a sealed-tube in a furnace
for 8 hours at 130 °C, the product was obtained in 82%
yield (Scheme 6).
Even though reaction in ethanol–water (4:1 v/v) at 130 °C
(entry 16) gave the desired product 6 in a 40% yield within
twenty-four hours, the deprenylated phenol 7 was always
recovered, and this was the biggest obstacle to optimiza-
tion of the reaction.15 When we decreased the reaction
temperature to 80 °C (entry 15), the reaction did not pro-
ceed at all within twenty-four hours, and when we in-
creased the temperature to 180 °C (entry 17), the reaction
proceeded within fifteen hours, but the yield of 6 de-
creased as a result of increased deprenylation to give 7.
When the temperature was raised to 210 °C (entry 18), de-
composed materials were the main products after fifteen
hours.
The Claisen rearrangement of 2 to 6 resulted in significant
deprenylation compared with the same rearrangement of
4 to licochalcone A, where no deprenylation occurred.
The difference in the degree of deprenylation between the
two reactions may arise from structural differences. We
initially suspected that the phenol moiety of 4 might in-
hibit deprenylation during the rearrangement by acting as
a radical scavenger. However, when the Claisen rear-
rangement of 2 to 6 was performed under identical condi-
tions, the addition of hydroquinone as a radical scavenger
showed no helpful effect in protecting against deprenyla-
tion. We now believe that the direct attachment of the car-
bonyl group to the phenyl ring of compound 2 may
significantly reduce the electron density of the aromatic
ring system. For this reason, the 2 shows less [3,3]-sigma-
tropic rearrangement than does the chalcone ether 4.
We therefore turned our attention to use of microwave
heating (entries 19–22).16 The best results were obtained
in ethanol–water (4:1 v/v) with heating at 300 W for 1.5
hours (entry 22). In this case a 52% yield of 6 was ob-
tained; however, the problem of deprenylation still oc-
curred. It is well known that the [3,3]-sigmatropic
rearrangement of g-substituted allyl aryl ether systems is
often complicated as a result of abnormal rearrangement
leading to structural isomerization of the migrating
group.17 In the case of our substrate, no observable abnor-
mal rearranged product was obtained. It is noteworthy that
the reported method14c using trimethylaluminum with wa-
ter or phenylboronic acid gave only the [1,3]-sigmatropic
rearrangement product together with the deprenylated
phenol 7. As the reaction was not well optimized, we de-
cided to change our entire synthesis plan, as shown in
Scheme 5.
O
8 (1.0 equiv)
NaOH (2.0 equiv)
2 (1.0 equiv)
O
MeO
EtOH, r.t., 12 h
81%
THPO
9
EtOH–H2O (4:1, v/v), 210 °C
MW (300 W), 1.5 h, 86%
EtOH
1 M HCl
licochalcone A
4
or EtOH–H2O (4:1, v/v)
sealed tube, 130 °C, 8 h, 82%
r.t., 0. 5 h
95%
We thought that the microwave reaction would be better
Scheme 6 Total synthesis of licochalcone A by a microwave or
for converting the chalcone ether (4) into licochalcone A.
sealed-tube reaction
Synthesis 2011, No. 3, 370–376 © Thieme Stuttgart · New York

PAPER
Concise Synthesis of Licochalcone A
373
Although we did not observe any abnormal Claisen rear-
ranged product of 4, for the sake of comparison we exam-
ined this reaction by using Fukuyama’s method with silyl
trapping agents and N,N-diethylaniline as a solvent
(Scheme 7, Table 2).17b
β
δ
OH
O
Ph3P, DEAD, CH2Cl2
α
γ
0 °C, 5 min → r.t., 2 h
90%
11
HO
10
O
OH
OH
α
β
silyl agent, PhNEt2
licochalcone A
sealed tube
γ
α
δ
+
HO
MeO
O
11
β
δ
γ
conditions II
4
13
12
Scheme 7 [3,3]-Sigmatropic rearrangement reaction with silyl
agent
Scheme 8 Test reaction for abnormal Claisen rearrangement. Con-
ditions I: EtOH–H2O (4:1), MW (300 W); conditions II: EtOH–H2O
(4:1), stainless-steel bomb reactor; conditions III: N,N-diethylaniline,
TMSN=C(Me)OTMS (20 equiv) trapping agent.
When we used hexamethyldisilazane (HMDS) as a trap-
ping agent, we obtained only the decomposed products
(entry 1, Table 2). When the reaction was performed at a
lower temperature (185 °C) in the presence of the hexa-
methyldisilazane (entry 2), licochalcone A was obtained
in 8% yield and the deprenylated product was obtained in
4% yield. The highest yield of licochalcone A (56%) with-
out any deprenylation was obtained when N,O-bis(tri-
methylsilyl)acetamide [TMSN=C(Me)OTMS] was used
as a trapping agent (entry 3).
as entry 3. We concluded that our water-accelerated Claisen
reactions do not produce abnormal rearrangement prod-
ucts when the reaction is performed under microwave
conditions or in a thermal bomb.
Table 3 Study of Aromatic Claisen Rearrangement Reaction of 11
Entry Conditionsa
Temp
(°C)
Time
(h)
Ratiob
(12/13)
Yieldc
(%)
Table 2 [3,3]-Sigmatropic Rearrangement Reaction of Chalcone 4
in the Presence of Silyl Agents
1
2
3
4
I
210
130
180
200
3
8
5
5
100:0
–
40
–
Entry Silyl agenta
(equiv)
Temp
(°C)
Time
(h)
Yieldb
II
II
III
100:0
100:0
54
52
1
2
3
HMDS (10)
230
185
185
8.5
4.5
5.0
-
8
HMDS (10)
a For details, see the caption to Scheme 8.
b Determined by 1H NMR.
TMSN=C(Me)OTMS (20)
56
c Yield after purification by silica gel chromatography.
a The reaction was performed in a stainless-steel bomb with N,N-di-
ethylaniline as the solvent.
b Yield after purification by silica gel chromatography.
To summarize, we have developed a practical route to
licochalcone A through the water-accelerated Claisen re-
arrangement reaction of prenyl ether 4. This route will
permit the scale-up of the synthesis of this promising lead
molecule for various cancer treatments.2 Because of the
low overall yield of the previous multistep total synthesis
with its low-yielding Claisen rearrangement step, this
compounds was previously obtained mainly by extraction
from the roots of G. inflata. The water-accelerated Claisen
rearrangement in an ethanol–water cosolvent system
should improve the crucial step of the synthesis without
producing any deprenylated or abnormal Claisen-
rearranged products.
Because we could not find any possible abnormal Claisen
rearrangement products of 6 or licochalcone A, we exam-
ined another aromatic ether system 11, which is known to
be very vulnerable to the abnormal Claisen rearrangement
reaction (Scheme 8 and Table 3).
The g-alkyl substituted aryl ether (11), prepared by a phe-
nolic Mitsunobu reaction,18 underwent a water-accelerat-
ed [3,3]-sigmatropic rearrangement when subjected to
microwave irradiation (300 W) for three hours to give the
Claisen product 12 in 40% yield, without any of the ab-
normal rearranged product 13 (conditions I, entry 1).
When the same solvent system was used in a stainless-
steel bomb reactor (conditions II) at 130 °C for eight
hours, the reaction was not successful (entry 2), but when
the temperature was raised to 180 °C for five hours, the re-
action proceeded well, giving 54% of 12 without any con-
tamination by 13 (entry 3). As a control experiment, we
prepared a genuine sample of 12 under Fukuyama condi-
tions (conditions III, entry 4), which gave the same result
All chemicals were purchased from Sigma-Aldrich Chemicals and
were used without further purification unless noted otherwise. 13
C
NMR spectra were recorded on a Bruker Avance II 150-MHz FT-
1
NMR spectrometer, whereas H NMR spectra were recorded on a
Varian Mercury-300 MHz FT-NMR spectrometer. Chemical shifts
(d) are reported in parts per million (ppm) relative to TMS, and the
coupling constants (J) are give in Hz. CDCl3 was used as both a sol-
vent and internal standard. IR spectra were recorded on a Shimadzu
Synthesis 2011, No. 3, 370–376 © Thieme Stuttgart · New York

374
J.-H. Jeon et al.
PAPER
IR-435 spectrometer. An Anthon Parr microwave synthesis system
(Synthos-3000) equipped with a wireless pressure and temperature
sensor was used, operating at a power of 300 W. The sample tem-
perature was ramped to 210 °C for 1 min and kept at this tempera-
ture for the desired time while the pressure was increased to 40 bar.
For GC/MS, an Agilent 7890A gas chromatograph linked to an Ag-
ilent 5975C mass spectrometer system equipped with a HP-5MS
capillary column (30 m × 0.25 mm; 0.25 mm film thickness) was
used. The GC oven temperature was programmed from 80 °C (3
min hold) at a rate of 10 °C/min to 300 °C (10 min hold); the inlet
temperature was at 250 °C, and the sample-injection mode was
splitless. The mass ion source was EI and the ionization voltage was
70 eV. The ion-source temperature was 280 °C and scan range was
50–500 m/z. The solvent delay time was 3 min. The CI mass spectra
were recorded on a Jeol JMS-600 Mass spectrometer with methane
as the reagent gas. The energy of the electron beam was 70 eV.
Flash chromatography was carried out on Merck 60 silica gel (230–
400 mesh). TLC was performed on DC-Plastikfolien 60, F254
(Merck; layer thickness 0.2 mm) plastic-backed silica gel plates that
were visualized with UV light (254 nm) or by staining with p-anis-
aldehyde.
The reaction time was 8 h. The product was purified by flash col-
umn chromatography [EtOAc–hexane (1:4)]; yield: 203 mg (82%).
Method 3: [3,3]-Sigmatropic Reaction with a Silyl Reagent
TMSN=C(Me)OTMS (0.5 mL, 2.13 mmol, 20 equiv), chalcone
prenyl ether 4 (36 mg, 0.106 mmol), and PhNEt2 (2 mL) were
placed in a stainless-steel bomb. The bomb was tightly sealed,
placed in an electric-furnace at 185 °C for 5 h, cooled to r.t., and dis-
assembled. The crude mixture was transferred to a separatory fun-
nel by washing with Et2O (50 mL). The organic phase was washed
with 3 M HCl (2 × 20 mL) and brine (20 mL) then dried (MgSO4),
filtered, and concentrated. The residue was purified by flash column
chromatography [silica gel, EtOAc–hexane (1:6)]; yield: 20 mg
(56%).
The spectral data for this compound agreed well with the literature
values.1b
Rf = 0.2 (EtOAc–hexane, 1:2).
1H NMR (300 MHz, CDCl3): d = 1.50 (s, 6 H, 4¢¢,5¢¢-dimethyl), 3.90
(s, 3 H, OMe), 5.35 (d, J = 10.5 Hz, 1 H, H¢¢3), 5.40 (d, J = 17.1 Hz,
1 H, H3¢¢), 5.63 (br s, 1 H, OH), 6.20 (dd, J = 17.1, 10.4 Hz, 1 H,
H2¢¢), 6.45 (s, 1 H, H3), 6.93 (d, J = 8.1 Hz, 2 H, H3¢ and H5¢), 7.47
(s, 1 H, H6), 7.57 (d, J = 15.9 Hz, 1 H, Ha), 7.98 (d, J = 8.5 Hz, 2 H,
H2¢, H6¢), 8.03 (d, J = 15.9 Hz, 1 H, Hb).
13C NMR (75 MHz, CDCl3): d = 27.5, 27.5, 41.0, 56.0, 100.8,
110.7, 115.2, 115.7, 116.3, 119.3, 128.3, 130.1, 131.5, 132.0, 132.0,
142.3, 149.0, 160.5, 161.3, 163.4, 191.9.
5-(1,1-Dimethylprop-2-en-1-yl)-4-hydroxy-2-methoxybenzal-
dehyde (6)
Method 1: Microwave Reaction; Typical Procedure
Aryl prenyl ether 2 (230 mg, 1.05 mmol) was dissolved in EtOH–
H2O (4:1 v/v) in the PTFE–TFM liner of an Anthon Parr MW syn-
thesis system, the screw cap was tightened, and the vessel was sub-
jected to irradiation at 300 W. After 1 min ramping time to 210 °C,
the vessel was maintained at 210 °C and 40 bar for 1.5 h and then
cooled to r.t. The screw cap was then loosened and the mixture was
transferred to a 100-mL round-bottom flask. The solvent was then
evaporated in vacuo. EtOAc (30 mL) was added and the organic
phase was washed with deionized distilled H2O (20 mL) and brine
(10 mL). The organic phase was dried (MgSO4), filtered, and con-
centrated under reduced pressure. The residue was purified by flash
column chromatography [silica gel, EtOAc–hexane (1:4)] to give a
white solid; yield: 120 mg (52%); mp 194–196 °C (dec.).
2-Methoxy-4-[(3-methylbut-2-en-1-yl)oxy]benzaldehyde (2)
This compound was prepared according to the known
procedure12c,19 and obtained as a white solid, mp 47–50 °C;20
Rf = 0.30 (EtOAc–hexane, 1:3).
(2E)-3-{2-Methoxy-4-[(3-methylbut-2-en-1-yl)oxy]phenyl}-1-
[4-(tetrahydro-2H-pyran-2-yloxy)phenyl]prop-2-en-1-one (9)
A two-necked round-bottom flask was charged with a soln of alde-
hyde 2 (700 mg, 3.18 mmol) and ketone 8 (700 mg, 3.18 mmol) in
EtOH (30 mL). NaOH (254 mg, 6.36 mmol) was added slowly and
the mixture was stirred at r.t. for 12 h until the reaction was com-
plete (TLC). The crude mixture was concentrated in vacuo and ex-
tracted with EtOAc. The organic phase was washed with H2O (10
mL) and brine (10 mL) then dried (MgSO4) and concentrated in
vacuo. The residue was purified by column chromatography [silica
gel, EtOAc–hexane (1:7)] to give an oily liquid; yield: 1087 mg
(81%); Rf = 0.36 (EtOAc–hexane, 1:4).
Method 2: Furnace Reaction; Typical Procedure
Compound 2 (200 mg, 0.91 mmol) was dissolved in EtOH–H2O
(4:1 v/v, 10 mL) in a 35-mL Ace pressure tube with PTFE bushes
and an FETFE O-ring seal. The tube was then placed in an electric
furnace at 130 °C for 24 h. When the tube had cooled to r.t., the
screw-cap was loosened, and the contents were worked up in the
same way as for the MW reaction; yield: 80 mg (40%).
IR (neat): 3744, 2935, 2872, 2366, 1745, 1656, 1572, 1510 cm–1.
The spectral data for the compound agreed well with those reported
in the literature.6,12b
1H NMR (300 MHz, CDCl3): d = 1.40–2.20 (m, 12 H), 3.62 (m, 1
H), 3.85 (m, 1 H), 3.88 (s, 3 H), 4.55 (d, J = 6.9 Hz, 2 H), 5.48 (m,
2 H), 5.52 (m, 1 H), 6.48 (d, J = 1.9 Hz, 1 H), 6.53 (dd, J = 8.8, 1.9
Hz, 1 H), 7.10 (d, J = 8.8 Hz, 2 H, para protons), 7.54 (d, J = 15.6
Hz, 1 H, Ha), 7.99 (d, J = 8.8 Hz, 2 H, para protons), 8.02 (d,
J = 15.6 Hz, 1 H, Hb).
13C NMR (75 MHz, CDCl3): d = 18.1, 18.5, 25.0, 25.7, 30.0, 55.3,
61.9, 64.8, 95.8, 98.9, 105.8, 115.7, 116.9, 118.9, 119.8, 130.2,
130.4, 132.0, 138.3, 139.3, 159.9, 160.2, 161.8, 189.0.
Rf = 0.2 (EtOAc–hexane, 1:3).
1H NMR (300 MHz, CDCl3): d = 1.44 (s, 6 H), 3.87 (s, 3 H), 5.35
(dd, J = 10.8, 1.0 Hz, 1 H), 5.38 (dd, J = 17.6, 1.0 Hz, 1 H), 6.17
(dd, J = 17.6, 10.8 Hz, 1 H), 6.42 (s, 1 H), 6.60 (s, 1 H), 7.77 (s, 1
H), 10.27 (s, 1 H, CHO).
(2E)-3-[5-(1,1-Dimethylprop-2-en-1-yl)-4-hydroxy-2-methoxy-
phenyl]-1-(4-hydroxyphenyl)prop-2-en-1-one (Licochalcone A)
Method 1: Microwave Reaction
MS (ESI, 70 eV): m/z 423.6 [M + H]+.
Licochalcone A was prepared from compound 4 (131 mg, 0.39
mmol) by following the typical procedure given for compound 6.
The reaction time was 1.5 h. Purification by flash column chroma-
tography [EtOAc–hexane (1:4)] gave an amorphous solid, yield:
114 mg, (86%).
HRMS (ESI): m/z [M + H]+ calcd for C26H31O5: 423.2093; found:
423.2172.
(2E)-1-(4-Hydroxyphenyl)-3-{2-methoxy-4-[(3-methylbut-2-en-
1-yl)oxy]phenyl}prop-2-en-1-one (4)
1 M HCl (100 mL) was added to a soln of ketone 9 (500 mg, 1.19
mmol) in EtOH (5 mL) in a one-necked round-bottom flask, and the
mixture was stirred at r.t. for 0.5 h until the reaction was complete
(TLC). Sat. aq NaHCO3 was then added until the pH was almost
Method 2: Sealed-Tube Reaction
Licochalcone A was prepared from compound 4 (248 mg, 0.73
mmol) by following the typical procedure given for compound 6.
Synthesis 2011, No. 3, 370–376 © Thieme Stuttgart · New York

PAPER
Concise Synthesis of Licochalcone A
375
neutral (pH paper). The solvent was evaporated under reduced pres-
sure and the crude mixture was extracted with EtOAc (2 × 20 mL).
The organic layer was washed with H2O (10 mL) and brine (10 mL)
then dried (MgSO4), filtered, and concentrated. The residue was pu-
rified by column chromatography [silica gel, EtOAc–hexane (1:5)]
to give a yellowish solid; yield: 382 mg (95%); mp 95–96 °C (Lit.12a
94–95 °C); Rf = 0.3 (EtOAc–hexane, 1:2).
Method 3: [3,3]-Sigmatropic reaction with silyl agent
TMSN=C(Me)OTMS (2.38 mL, 9.65 mmol, 20 equiv), ether 11 (85
mg, 0.48 mmol), and PhNEt2 (2 mL) were placed in a stainless-steel
bomb that was tightly closed and heated in an electric furnace at
200 °C for 5 h. The bomb was then cooled to r.t. and disassembled.
The crude mixture was transferred to separatory funnel by washing
with Et2O (50 mL). The organic phase was washed with 3 M HCl
(20 mL × 2) and brine (20 mL) then dried (MgSO4), filtered, and
concentrated. The residue was purified by flash column chromatog-
raphy [silica gel, EtOAc–hexane (1:8)] to give an oily liquid; yield:
44 mg (52%). The Rf value and 1H NMR spectrum were identical to
those of compound obtained under MW conditions.
The spectral data for this compound agreed well with those reported
in the literature.12a
1H NMR (300 MHz, DMSO-d6): d = 1.73 (s, 3 H), 1.75 (s, 3 H),
3.88 (s, 3 H), 4.60 (d, J = 7 Hz, 2 H), 5.43 (m, 1 H), 6.60 (d, J = 8
Hz, 2 H), 6.87 (d, J = 8 Hz, 2 H), 7.70 (d, J = 16 Hz, 1 H, Ha), 7.85
(d, J = 8 Hz, 1 H), 7.92 (d, J = 16 Hz, 1 H, Hb), 7.99 (d, J = 8 Hz, 2
H), 10.31 (br s, 1 H, OH).
13C NMR (75 MHz, DMSO-d6): d = 17.9, 25.3, 55.6, 64.5, 98.7,
106.6, 115.0, 115.7, 118.8, 119.3, 129.2, 129.5, 130.5, 137.2, 159.3,
161.5, 161.6, 161.8, 186.8.
Acknowledgment
This research was supported financially by the Ministry of Educa-
tion, Science, and Technology (MEST) and by the Korea Institute
for Advancement of Technology (KIAT) through the Human Re-
source Training Project for Regional Innovation (4R09-0301-003-
S000100), and by the Priority Research Centers Program through
the National Research Foundation of Korea (NRF) funded by the
Ministry of Education, Science, and Technology (2010-0029642).
[(2E)-Hex-2-en-1-yloxy]benzene(11): Test Reaction for Check-
ing Abnormal Claisen Rearrangement Reaction
A two-necked round-bottomed flask was charged with PhOH (516
mg, 5.48 mmol), (E)-hex-2-en-1-ol (692 mg, 6.91 mmol), Ph3P
(1.87 g, 7.13 mmol), a 40% soln of DEAD in toluene (3.25 mL, 7.13
mmol), and anhyd CH2Cl2 (15 mL) with cooling in an ice bath
(4 °C). The mixture was stirred for an additional 5 min at 4 °C and
then gradually warmed to r.t. and stirred for 2 h. It was then trans-
ferred to a separatory funnel and the organic phase was washed with
brine (20 mL) then dried (MgSO4), filtered, and concentrated in
vacuo. The residue was purified by column chromatography [silica
gel, EtOAc–hexane (1:20)] to give an oily liquid; yield: 869 mg
(90%); Rf = 0.70 (EtOAc–hexane, 1:10).
1H NMR (300 MHz, CDCl3): d = 7.30–7.50 (m, 2 H), 6.90–7.00 (m,
3 H), 5.75–5.90 (m, 1 H), 5.60–5.75 (m, 1 H), 4.44–4.47 (dd,
J = 5.7, 1.2 Hz, 2 H), 2.03–2.10 (m, 2 H), 1.36–1.49 (m, 2 H), 0.88–
0.93 (t, J = 7.5 Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 13.8, 22.2, 34.5, 68.7, 114.5,
120.4, 124.8, 129.3, 135.3, 158.5.
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2-(1-Propylprop-2-en-1-yl)phenol (12)
Method 1: MW reaction
The compound was prepared according to the typical procedure de-
scribed above for compound 6. The reaction time was 3 h. Purifica-
tion by flash column chromatography [silica gel, EtOAc–hexane
(1:8)] gave an oily liquid; yield: 40 mg (40%); Rf = 0.2 (EtOAc–
hexane, 1:8).
1H NMR (300 MHz, CDCl3): d = 7.05–7.20 (m, 2 H), 6.72–6.84 (d,
J = 7.8 Hz, 1 H). 5.90–6.60 (m, 2 H), 4.95–5.20 (m, 1 H), 5.00 (s, 1
H, OH), 3.49–3.56 (m, 1 H), 1.70–1.77 (m, 2 H), 1.23–1.39 (m, 2
H), 0.89–0.94 (t, J = 7.5 Hz, 3 H).
13C NMR (150 MHz, CDCl3): d = 14.0, 20.7, 35.5, 43.5, 114.8 (vi-
nylic C=C), 116.2, 120.9, 127.4, 128.5, 129.5, 141.5 (vinylic C=C),
153.7.
Method 2: Stainless Steel Bomb Reaction
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mL) was placed in a stainless-steel bomb reactor that was placed in-
side an electric furnace at 180 °C and heated for 5 h, then cooled to
r.t. The reactor was disassembled and the product was worked up as
described for the MW reaction; yield: 67 mg (54%). The Rf value
and 1H NMR spectrum were identical to those of the compound ob-
tained under MW conditions.
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Synthesis 2011, No. 3, 370–376 © Thieme Stuttgart · New York