An efficient microwave-promoted route to (Z)-stilbenes from trans-cinnamic acids: Synthesis of combretastatin A-4 and analogues

Article abstract of DOI:10.1055/s-0029-1217981

cis-Stilbenes were synthesized from trans-cinnamic acids, involving ethylenic-bond bromination and a subsequent one-pot microwave-promoted stereoselective debrominative decarboxylation-Suzuki cross-coupling strategy. This sequence represents a useful way to prepare a variety of combretastatin A-4 derivatives.

Full text of DOI:10.1055/s-0029-1217981

LETTER
2789
An Efficient Microwave-Promoted Route to (Z)-Stilbenes from
trans-Cinnamic Acids: Synthesis of Combretastatin A-4 and Analogues
S
ynthesis of Combreta
a
statin
A
-4 rc-Antoine Bazin,a,1 Marie Jouanne,a Hussein El-Kashef,b Sylvain Rault*a
a
Centre d’Etudes et de Recherche sur le Médicament de Normandie (CERMN), UPRES EA-4258, FR CNRS INC3M,
Université de Caen Basse-Normandie, U.F.R. des Sciences Pharmaceutiques, Boulevard Becquerel, 14032 Caen Cedex, France
Fax +33(2)31931188; E-mail: sylvain.rault@unicaen.fr
b
Chemistry Department, Faculty of Science, Assiut University, Assiut 71516, Egypt
Received 18 June 2009
the other hand, the cis-b-bromostyrene derivatives can be
obtained by stereoselective reduction of b,b-dibromo-
styrenes using tributyltin hydride and tetrakis(triphenyl-
phosphine)palladium(0)12 or by the debrominative
decarboxylation of an anti-2,3-dibromo-3-arylalkanoic
acid.13
Abstract: cis-Stilbenes were synthesized from trans-cinnamic ac-
ids, involving ethylenic-bond bromination and a subsequent one-
pot microwave-promoted stereoselective debrominative decarboxy-
lation–Suzuki cross-coupling strategy. This sequence represents a
useful way to prepare a variety of combretastatin A-4 derivatives.
Key words: cis-stilbenes, cinnamic acids, combretastatin A-4, de-
brominative decarboxylation, Suzuki–Miyaura cross-coupling
reaction
As a part of our ongoing program directed to the synthesis
of stilbene derivatives, we have recently published an
original one-pot microwave-promoted Hunsdiecker–
Suzuki reaction for the synthesis of trans-stilbenes from
trans-cinnamic acids.14 The success of this methodology
prompted us to transpose it for the synthesis of the other
geometrical isomers cis-stilbenes.
Combretastatin A-4 (CA-4) is the most important cis-stil-
bene naturally occurring product isolated from the bark of
the South African tree Combretum caffrum (Figure 1).2
This compound strongly inhibits the polymerization of tu-
bulin by interacting with the colchicine binding site on tu-
bulin.3 It possesses a highly potent antitumor activity.2,4
Combretastatin A-4 in the form of a water-soluble phos-
phate prodrug (CA-4P, Figure 1), is currently in phase II
and III clinical trials for the treatment of solid tumours.5–7
Because of its simple structure, a large number of CA-4
analogues has been synthesized and evaluated in SAR
studies.8
Thus we wish to report herein a new strategy for the syn-
thesis of some unknown cis-stilbenes, CA-4 analogues,
from trans-cinnamic acids as depicted in Scheme 1.
Firstly, the trans-3,4,5-trimethoxycinnamic acid (1a),
used as a starting material, was brominated15 to give the
corresponding 2,3-dibromo-3-(3,4,5-trimethoxyphenyl)pro-
panoic acid (2a). The latter compound was subjected to
stereoselective debrominative decarboxylation under mi-
crowave irradiation, following the procedure described by
Kuang,16 giving the cis-vinylbromide 3a in a good yield.
Compound 3a was then allowed to react with phenylbo-
ronic acid 4a via a Suzuki cross-coupling reaction to give
the cis-stilbene 5a (Scheme 1).
MeO
A
MeO
B
OMe
OR
CA-4 R = H
OMe
CA-4P R = PO3Na
Br
MeO
MeO
CO2H
MeO
MeO
CO2H
Figure 1 Combretastatin A-4 and its water-soluble phosphate pro-
drug CA-4P
a
b
Br
OMe
1a
OMe
2a
Several methods have been reported for the synthesis of
these compounds, based on the utility of these methods in
giving access to a stereospecific cis-geometrical isomer.
The most common ones are, the Wittig reaction between
a phosphonium salt and an aromatic aldehyde,9 and also
the stereoselective reduction of diarylalkynes.10 More-
over, the Suzuki cross-coupling reaction of cis-b-bro-
mostyrenes gives a straightforward access to cis-stilbenes
and provides a great molecular diversity due to the com-
mercially available boronic acid building blocks.3c,11 On
MeO
MeO
c
Br
MeO
MeO
OMe
5a
OMe
3a
Scheme 1 Reagents and conditions: (a) Br2, CHCl3, r.t., 2 h, 82%;
(b) Et3N, DMF, 140 °C, MW, 1 min, 77%; (c) phenylboronic acid,
Pd(PPh3)4, K2CO3, DME–H2O (2:1), 100 °C, MW, 15 min, 80%.
SYNLETT 2009, No. 17, pp 2789–2794
Advanced online publication: 25.09.2009
DOI: 10.1055/s-0029-1217981; Art ID: G19009ST
© Georg Thieme Verlag Stuttgart · New York
x
x
.x
x
.2
0
0
9
The choice of the cinnamic acid 1a as a starting material
came in the light of the SAR studies of CA-4 derivatives
which revealed that the trimethoxy substituents of ring A

2790
M.-A. Bazin et al.
LETTER
Table 1 Solvent Optimization for a One-Pot Reaction
solvent 1,
base 1,
4a, Pd(PPh3)4,
solvent 2, base 2,
2a
3a
5a
140 °C, MW,
1 min
100 °C, MW,
15 min
Entry
Solvent 1
DME–H2O (2:1)
DMF
Base 1
Solvent 2
Base 2
Product
1
2
3
K2CO3
Et3N
DME–H2O (2:1)
DMF
K2CO3
(E)-5aa
b
K3PO4×H2O
K2CO3
–
DMF
Et3N
DME–H2O (2:1)
(Z)-5a (64%)c
a Determined by 1H NMR (400 MHz).
b Ill-defined products.
c Isolated yield (two steps from 2a).
are essential for the activity, meanwhile ring B is amena- the one-pot reaction gave ill-defined products. These fail-
ble to substitutions.17
ures urged us to choose standard conditions for each step.
Thus, when DMF was kept to a minimum in the first step,
and then when Suzuki cross-coupling reagents were add-
ed in a large volume of the solvent DME–H2O (2:1) in the
second step, the target cis-stilbene 5a was successfully
obtained in a good yield (64%, entry 3). This result con-
firms the mechanism proposed by Kuang13 for debromi-
native decarboxylation by trans-b-elimination in the first
step of our reaction when DMF–Et3N was used leading to
a cis-bromostyrene. On the other hand, probably a unimo-
lecular elimination process occurred when DME–H2O
and K2CO3 were employed leading to a trans-isomer.
Second, we studied the possibility of carrying out the two
reactions, the debrominative decarboxylation and the
Suzuki cross-coupling reaction in a one-pot procedure in
the same vial under microwave irradiation. This method-
ology has not been reported before. To the best of our
knowledge, only a single paper has reported a one-pot
synthesis involving a debrominative decarboxylation and
a Pd-catalyzed Sonogashira cross-coupling reaction.16
The attempted trials of our study are depicted in Table 1.
Thus, when a single solvent was used for both reactions,
the attempted reaction failed to give the target product
(entries 1 and 2). Treatment of 2a with K2CO3 in DME–
H2O (2:1) gave the trans-isomer of 5a, while using DMF
as a solvent and K3PO4·H2O as a base in the second step,18
Table 2 Synthesis of CA-4 Derivatives
Br
1) Et3N, DMF,
140 °C, MW, 1 min
MeO
MeO
CO2H
Ar(Het)
(Het)Ar
DME–H2O (2:1),
2) B(OH)2
Br
2b–i
Pd(PPh3)4, K2CO3,
100 °C, MW, 15 min
OMe
5a–h
MeO
OMe
OMe
4b
Entry
1
Substrate
Product
Z/E ratioa
Yield (%)b
MeO
MeO
Br
CO2H
80:20
76
Br
OMe
OMe
2b
5a
MeO
Br
CO2H
MeO
2
90:10
52
Br
Me
Me
2c
5b
Synlett 2009, No. 17, 2789–2794 © Thieme Stuttgart · New York

LETTER
Synthesis of Combretastatin A-4
2791
Table 2 Synthesis of CA-4 Derivatives (continued)
Br
1) Et3N, DMF,
140 °C, MW, 1 min
MeO
MeO
CO2H
Ar(Het)
(Het)Ar
DME–H2O (2:1),
2) B(OH)2
Br
2b–i
Pd(PPh3)4, K2CO3,
100 °C, MW, 15 min
OMe
5a–h
MeO
OMe
OMe
4b
Entry
3
Substrate
Product
Z/E ratioa
Yield (%)b
MeO
Br
CO2H
MeO
>95:5
46
OMe
Br
F3C
CF3
2d
5c
MeO
Br
CO2H
O
MeO
4
5
6
90:10
85:15
60:40
53
OMe
Br
O
O
O
2e
5d
MeO
Br
CO2H
MeO
63
OMe
Br
2f
5e
MeO
Br
CO2H
MeO
42c
Br
OMe
OMe
OMe
AcO
OMe
OMe
OH
2g
5f
MeO
Br
CO2H
MeO
7
8
75:25
80:20
41c
Br
MeO
OH
OAc
OMe
2h
5g
MeO
Br
CO2H
21
MeO
S
S
Br
2i
5h
a Determined by 1H NMR.
b Isolated yield (two steps from 2).
c NaOH was used as base.
For a typical one-pot microwave-promoted debrominative DME–H2O (2:1, 8 mL). Then microwave heating was re-
decarboxylation–Suzuki cross-coupling procedure,19 started for 15 minutes at 100 °C. This short-time proce-
Et3N was added to 2,3-dibromoalkanoic acids 2 in DMF dure allowed the synthesis of various trimethoxystilbenes
(1 mL) in a 10 mL vial. After completion of the debromi- in good yield.
native decarboxylation reaction (microwave heating,
140 °C, 1 min), Suzuki cross-coupling reagents were add-
ed: the boronic acid, K2CO3 or NaOH, Pd(PPh3)4, and
It is noteworthy that the cis-stilbene 5a could be obtained
alternatively by the same one-pot methodology, starting
Synlett 2009, No. 17, 2789–2794 © Thieme Stuttgart · New York

2792
M.-A. Bazin et al.
LETTER
from trans-cinnamic acid and using 3,4,5-trimethoxyphe- As we mentioned above the Z/E stereoselectivity is first
nylboronic acid as a coupling agent in the Suzuki cross- governed by debrominative decarboxylation reaction con-
coupling reaction. To investigate the scope of this proto- ditions. In agreement with the literature,13 anti-2,3-dibro-
col, a variety of CA-4 analogues 5a–h was synthesized mo-3-arylpropanoic acids carrying electron-withdrawing
using different anti-2,3-dibromoalkanoic acids, readily groups (e.g., 4-trifluoromethyl, entry 3) gave high Z/E
available from trans-a,b-unsaturated carboxylic acids, ratios. On the contrary, the Z/E stereoselectivity was re-
and the same trimethoxyphenylboronic acid (Table 2). duced when the aromatic ring was substituted with
The use of the latter boronic acid fulfills the criterion of electron-donating groups (entries 2 and 4). This is why
the biological activity due to the presence of the three CA-4 (5g) and iso-CA-4 (5f) were obtained in moderate
methoxy groups of ring A and provides a cheaper reac- yields (41% and 42%, respectively). This methodology
tion.
Table 3 Synthesis of Substituted (Z)-Stilbenes
Br
CO2H
1) Et3N, DMF, 140 °C, MW, 1 min
(Het)Ar
Br
2) 4a,c–g; DME–H2O (2:1),
Pd(PPh3)4, K2CO3, 100 °C, MW,
15 min
R
R
2b,g,j–k
5i–n
Entry
anti-2,3-Dibromo-3-phenylpropanoic acid Boronic acid
Product
Z/E ratioa Yield (%)b
Br
B(OH)2
B(OH)2
B(OH)2
B(OH)2
CO2H
1
2
3
4
95:5
95:5
95:5
80:20
61
52
86
43
Br
Br
4a
4c
4d
4e
2b
2b
2b
5i
5j
F
Br
CO2H
Br
Br
CO2H
CO2H
t-Bu
Br
Br
5k
MeS
NO2
NO2
5l
2j
Br
B(OH)2
CO2H
MeO
5
6
60:40
80:20
28c
Br
AcO
OMe
OMe
OH
4f
2g
5m
Br
B(OH)2
CO2H
N
36
Br
MeO
OMe
OMe
OMe
4g
2k
5n
a Determined by 1H NMR (400 MHz).
b Isolated yield (two steps from 2).
c NaOH was used as base.
Synlett 2009, No. 17, 2789–2794 © Thieme Stuttgart · New York

LETTER
Synthesis of Combretastatin A-4
2793
(7) Horsman, M. R.; Siemann, D. W. Cancer Res. 2006, 66,
11520.
also allowed the synthesis of original cis-stilbenes such as
the thiophene derivative 5h in an acceptable yield.
(8) (a) Nam, N.-H. Curr. Med. Chem. 2003, 10, 1697.
(b) Hsieh, H.-P.; Liou, J.-P.; Mahindroo, N. Curr. Pharm.
Des. 2005, 11, 1655. (c) Tron, G. C.; Pirali, T.; Sorba, G.;
Pagliai, F.; Busacca, S.; Genazzani, A. A. J. Med. Chem.
2006, 49, 3033. (d) Mahindroo, N.; Liou, J.-P.; Chang,
J.-Y.; Hsieh, H.-P. Expert Opin. Ther. Pat. 2006, 16, 647.
(9) (a) Davis, P. D. WO 200112579, 2001. (b) Seyedi, F.; Gale,
J.; Haider, R.; Hoare, J.; Baldwin, A. WO 2002006279,
2002. (c) Mutti, S.; Lavigne, M.; Malejonock, I.; Casimir,
J.-P. WO 2003084919, 2003. (d) Maya, A. B. S.; Pérez-
Melero, C.; Mateo, C.; Alonso, D.; Fernández, J. L.; Gajate,
C.; Mollinedo, F.; Peláez, R.; Caballero, E.; Medarde, M.
J. Med. Chem. 2005, 48, 556. (e) Pettit, G. R.; Rhodes, M.
R.; Herald, D. L.; Hamel, E.; Schmidt, J. M.; Pettit, R. K.
J. Med. Chem. 2005, 48, 4087. (f) Simoni, D.; Romagnoli,
R.; Giannini, G.; Alloati, D.; Pisano, C. WO 2005007635,
2005. (g) Chang, J.-Y.; Yang, M.-F.; Chang, C.-Y.; Chen,
C.-M.; Kuo, C.-C.; Liou, J.-P. J. Med. Chem. 2006, 49,
6412. (h) Harrowven, D. C.; Guy, I. L.; Howell, M.;
Packham, G. Synlett 2006, 2977.
(10) (a) Lindlar, H.; Dubuis, R. Org. Synth. 1966, 46, 89; Org.
Synth., Coll. Vol. V, 1973, 880. (b) Fürstner, A.; Nikolakis,
K. Liebigs Ann. Chem. 1996, 12, 2107. (c) Lawrence, N. J.;
Ghani, F. A.; Hepworth, L. A.; Hadfield, J. A.; McGown,
A. T.; Pritchard, R. G. Synthesis 1999, 1656. (d)Wei,L.-L.;
Wei, L.-M.; Pan, W.-B.; Leou, S.-P.; Wu, M.-J. Tetrahedron
Lett. 2003, 44, 1979. (e) Nakamura, H.; Kuroda, H.; Saito,
H.; Suzuki, R.; Yamori, T.; Maruyama, K.; Haga, T.
ChemMedChem 2006, 1, 729. (f) Lara-Ochoa, F.; Espinosa-
Pérez, G. Tetrahedron Lett. 2007, 48, 7007. (g) Giraud, A.;
Provot, O.; Hamzé, A.; Brion, J.-D.; Alami, M. Tetrahedron
Lett. 2008, 49, 1107.
1
In each case, the Z/E ratio was determined by H NMR,
and it was possible to isolate the pure Z-isomers using sil-
ica gel column chromatography.
Finally, for the sake of evaluating the scope and limita-
tions of this methodology, a series of various substituted
(Z)-stilbenes was synthesized. The results are presented in
Table 3.
The reaction sequence provided different results depend-
ing on the substitution of the phenyl ring of the arylpro-
panoic acid 2. Unsubstituted acids (entries 1–3) gave good
yields and excellent Z/E ratios (ca. 95:5). The presence of
electron-withdrawing (entry 4) or electron-donating (en-
try 6) groups lead to a loss of the stereoselectivity and
yield. In the case of the nitro derivative (entry 4), the de-
crease of both yield and selectivity is probably due to a
loss of reactivity during the Suzuki step since the first step
afforded the (Z)-b-bromostyrene in a high stereoselectivi-
ty as reported.13,16
In conclusion, we have developed a new and efficient
microwave-promoted synthesis of cis-stilbenes, CA-4 an-
alogues, using trans-cinnamic acids as starting materials.
The scope and limitations of this new methodology has
been studied. Our procedure proved to be very useful to
prepare a library of CA-4 analogues whose biological
evaluation is in progress.
(11) (a) Hadfield, J. A.; McGown, A. T.; Gaukroger, K.;
Hepworth, L. A.; Lawrence, N. J. WO 200249994, 2002.
(b) Katayama, H.; Nagao, M.; Ozawa, F.; Ikegami, M.; Arai,
T. J. Org. Chem. 2006, 71, 2699. (c) Wakioka, M.; Nagao,
M.; Ozawa, F. Organometallics 2008, 27, 602.
Acknowledgment
Dr. Rémi Legay is gratefully acknowledged for his assistance in
measurement of mass spectra.
(12) Uenishi, J.; Kawahama, R.; Shiga, Y.; Yonemitsu, O.; Tsuji,
References and Notes
J. Tetrahedron Lett. 1996, 37, 6759.
(13) Kuang, C.; Senboku, H.; Tokuda, M. Tetrahedron Lett.
2001, 42, 3893; and references cited therein.
(14) Bazin, M.-A.; El Kihel, L.; Lancelot, J.-C.; Rault, S.
Tetrahedron Lett. 2007, 48, 4347.
(15) Del Ponte, G.; Costa Arcanjo, F.; Botteghi, C. J. Mol. Catal.
A: Chem. 2003, 192, 35.
(1) Current address: Université de Nantes, Nantes Atlantique
Universités, IICiMed EA1155, UFR des Sciences
Pharmaceutiques, Laboratoire de Chimie Thérapeutique, 1
Rue Gaston Veil, BP 53508, 44000 Nantes, France.
(2) Pettit, G. R.; Singh, S. B.; Hamel, E.; Lin, C. M.; Alberts,
D. S.; Garcia-Kendall, D. Experientia 1989, 45, 209.
(3) (a) Pettit, G. R.; Singh, S. B.; Niven, M. L.; Hamel, E.;
Schmidt, J. M. J. Nat. Prod. 1987, 50, 119. (b) Pettit, G. R.;
Singh, S. B.; Boyd, M. R.; Hamel, E.; Pettit, R. K.; Schmidt,
J. M.; Hogan, F. J. Med. Chem. 1995, 38, 1666.
(c) Gaukroger, K.; Hadfield, J. A.; Hepworth, L. A.;
Lawrence, N. J.; McGown, A. T. J. Org. Chem. 2001, 66,
8135. (d) Hsieh, H.-P.; Liou, J.-P.; Lin, Y.-T.; Mahindroo,
N.; Chang, J.-Y.; Yang, Y.-N.; Chern, S.-S.; Tan, U.-K.;
Chang, C.-W.; Chen, T.-W.; Lin, C.-H.; Chang, Y.-Y.;
Wang, C.-C. Bioorg. Med. Chem. Lett. 2003, 13, 101.
(4) Chaudhary, A.; Pandeya, S. N.; Kumar, P.; Sharma, P. P.;
Gupta, S.; Soni, N.; Verma, K. K.; Bhardwaj, G. Mini-Rev.
Med. Chem. 2007, 12, 1186.
(16) Kuang, C.; Yang, Q.; Senboku, H.; Tokuda, M. Tetrahedron
2005, 61, 4043.
(17) For example, see: (a) Cushman, M.; Nagarathnam, D.;
Gopal, D.; Chakraborti, A. K.; Lin, C. M.; Hamel, E. J. Med.
Chem. 1991, 34, 2579. (b) Cushman, M.; Nagarathnam, D.;
Gopal, D.; He, H.-M.; Lin, C. M.; Hamel, E. J. Med. Chem.
1992, 35, 2293. (c) Medarde, M.; Ramos, A.; Caballero, E.;
Peláez-Lamamié de Clairac, R.; López, J. L.; Grávalos,
D. G.; San Feliciano, A. Eur. J. Med. Chem. 1998, 33, 71.
(d) Hatanaka, T.; Fujita, K.; Ohsumi, K.; Nakagawa, R.;
Fukuda, Y.; Nihei, Y.; Suga, Y.; Akiyama, Y.; Tsuji, T.
Bioorg. Med. Chem. Lett. 1998, 8, 3371. (e) Gaukroger, K.;
Hadfield, J. A.; Lawrence, N. J.; Nolan, S.; McGown, A. T.
Org. Biomol. Chem. 2003, 1, 3033.
(5) (a) Patterson, D. M.; Rustin, G. J. S. Clin. Oncol. 2007, 19,
443. (b) Lippert, J. W. III. Bioorg. Med. Chem. 2007, 15,
605. (c) Hinnen, P.; Eskens, F. A. L. M. Br. J. Cancer 2007,
96, 1159. (d) Cai, S. X. Recent Pat. Anti-Cancer Drug
Discov. 2007, 2, 79.
(18) For Suzuki–Miyaura cross-coupling reactions using K3PO4
as base in DMF, see: (a) Watanabe, T.; Miyaura, N.; Suzuki,
A. Synlett 1992, 207. (b) Cailly, T.; Fabis, F.; Rault, S.
Tetrahedron 2006, 62, 5862.
(19) General Procedure for the One-Pot Synthesis of 5a–n
(6) West, C. M. L.; Price, P. Anti-Cancer Drugs 2004, 15, 179.
In a 10 mL microwave vial were introduced a magnetic stir
Synlett 2009, No. 17, 2789–2794 © Thieme Stuttgart · New York

2794
M.-A. Bazin et al.
LETTER
bar, a anti-2,3-dibromo-3-arylpropanoic acid 2 (5.0 mmol,
1.00 equiv), and Et3N (1.05 equiv) in DMF (1 mL). The vial
was sealed, and the suspension was then heated at 140 °C for
1 min. After CO2 removal were added a boronic acid 4 (1.20
equiv), K2CO3 (2.50 equiv) or NaOH (3.50 equiv), Pd(PPh3)4
(0.05 equiv), and DME–H2O (2:1, 8 mL). The vial was
sealed and purged with argon through the septum inlet. The
suspension was then heated at 100 °C for 15 min. The
resulting mixture was acidified with 1 N HCl. H2O and Et2O
were added, and the aqueous layer was extracted with Et2O
(3 × 30 mL). The combined organic layers were washed with
H2O, dried over MgSO4, filtered, and evaporated. The crude
product was then purified by silica gel chromatography
(eluent: cyclohexane–EtOAc) to afford (Z)-stilbene 5 as a
pure compound. Compound trans-5 was isolated too, to
determine the Z/E ratio.
CDCl3): d = 3.71 (s, 6 H, 2 × OMe), 3.85 (s, 3 H, OMe), 5.92
(s, 2 H, OCH2O), 6.42 (d, J = 11.7 Hz, 1 H, =CH), 6.48 (d,
J = 11.7 Hz, 1 H, =CH), 6.51 (s, 2 H, Har), 6.73 (d, J = 8.8
Hz, 1 H, Har), 6.79–6.81 (m, 2 H, Har). 13C NMR (100 MHz,
CDCl3): d = 55.9 (2 C, 2 × OMe), 60.9 (OMe), 100.9, 105.9
(2 C), 108.1, 109.0, 122.9, 129.1, 129.4, 131.1, 132.5, 137.1,
146.6, 147.3, 152.9 (2 C). ESI-MS: m/z = 315 [M + H]+.
HRMS (EI): m/z calcd for C18H18O5: 314.1154; found:
314.1165.
Compound 5m: yellow solid; yield 0.17 g (45%); mp 58 °C.
IR (KBr): n = 3417, 2956, 1605, 1511, 1465, 1274, 1241,
1175, 1029, 870 cm–1. 1H NMR (400 MHz, CDCl3): d = 3.67
(s, 3 H, OMe), 3.79 (s, 3 H, OMe), 5.58 (s, 1 H, OH), 6.42
(part A of AB system, 3JAB = 11.7 Hz, 1 H, =CH), 6.45 (part
B of AB system, 3JAB = 11.7 Hz, 1 H, =CH), 6.77–6.79 (m,
5 H, Har), 7.22 (d, J = 8.8 Hz, 1 H, Har). 13C NMR (100 MHz,
CDCl3): d = 55.2 (OMe), 55.7 (OMe), 111.1, 113.5, 114.1,
122.4, 126.1, 127.4, 128.3, 128.7, 130.1, 144.7, 146.0,
158.5. ESI-MS: m/z = 257 [M + H]+. HRMS (EI): m/z calcd
for C16H16O3: 256.1099; found: 256.1109.
Selected Data
Compound 5d: orange solid; yield 0.51 g (63%); mp 78 °C.
IR (KBr): n = 2931, 2831, 1581, 1510, 1487, 1454, 1330,
1235, 1129, 1024, 1006, 846 cm–1. 1H NMR (400 MHz,
Synlett 2009, No. 17, 2789–2794 © Thieme Stuttgart · New York

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