Original one-pot microwave-promoted Hunsdiecker-Suzuki strategy: straightforward access to trans-1,2-diarylethenes from cinnamic acids

Article abstract of DOI:10.1016/j.tetlet.2007.04.114

An original strategy combining a Hunsdiecker-type bromodecarboxylation and a Suzuki cross-coupling reaction starting from various cinnamic acids has been developed in one-pot and under microwave heating to give trans-1,2-diarylethenes in few minutes.

Full text of DOI:10.1016/j.tetlet.2007.04.114

Tetrahedron Letters 48 (2007) 4347–4351
Original one-pot microwave-promoted
Hunsdiecker–Suzuki strategy: straightforward access to
trans-1,2-diarylethenes from cinnamic acids
Marc-Antoine Bazin, Laıla El Kihel, Jean-Charles Lancelot and Sylvain Rault*
¨
Centre d’Etudes et de Recherche sur le Me´dicament de Normandie, UPRES EA-3915, U.F.R. des Sciences Pharmaceutiques,
Universite´ de Caen Basse-Normandie, 5, rue Vaube´nard, 14032 Caen Cedex, France
Received 27 February 2007; revised 15 March 2007; accepted 23 April 2007
Available online 27 April 2007
Abstract—An original strategy combining a Hunsdiecker-type bromodecarboxylation and a Suzuki cross-coupling reaction starting
from various cinnamic acids has been developed in one-pot and under microwave heating to give trans-1,2-diarylethenes in few
minutes.
ꢀ 2007 Elsevier Ltd. All rights reserved.
Substituted trans-1,2-diarylethenes or trans-stilbenes are
of interest in many cases from a pharmacological point
of view.1 In particular, hydroxylated trans-stilbenes such
as resveratrol or piceatannol display a variety of biolog-
ical actions including antioxidant, anti-inflammatory
activities and anticarcinogenic effects.2–4 Photophysical
properties of trans-stilbenes (photoisomerization,5 fluo-
rescence)6 have also been widely studied.
cular diversity. The carbon–carbon double bond forma-
tion is the key step in the synthesis of trans-stilbenes and
needs a high level of geometrical control. Conventional
synthetic methods start from arylaldehydes engaged to-
wards various partners in different reactions such as
Wittig–Horner reaction,7 Julia olefination8 or Mc Mur-
ry olefination.1a More recent strategies involve Pd-cata-
lyzed Heck,9 Stille10 or Suzuki11 cross-coupling
reactions, phosphonium salts homocoupling reactions12
or Ru-catalyzed cross metathesis.13 However, none of
these methods is really general due to the difficult avail-
ability of some raw materials.
R'''
OH
R
HO
Y
As Suzuki cross-coupling reactions are one of our labo-
ratory interests14 and considering that arylboronic acids
are widely available, we thought about a general proce-
dure using these Suzuki reactions starting from (E)-b-
arylvinyl bromides. This strategy was all the more justi-
fied that we could use a Hunsdiecker-type reaction to
obtain the latter compounds started from (E)-a,b-unsat-
urated aromatic carboxylic acids.15 Moreover, the stere-
oselective access to trans-b-halostyrenes under catalytic
conditions has been optimized16 and few Suzuki cross-
coupling reactions using those compounds in the synthe-
sis of substituted trans-1,2-diarylethenes have been
reported.17 That is the reason why we developed a
strategy combining the Hunsdiecker-type bromodecarb-
oxylation and the Suzuki cross-coupling reaction. Fur-
thermore, as only two one-pot strategies have been
developed combining Hunsdiecker reaction and Pd-
catalyzed Heck18 or Sonogashira19 cross-coupling
R'
R''
OH
Resveratrol (Y=H)
Piceatannol (Y=OH)
trans-Stilbenes
(trans-1,2-diarylethenes)
Thus, due to the large amount of interest in such com-
pounds, we decided to achieve their synthesis using an
original pathway which could also allow a great mole-
Keywords: Hunsdiecker bromodecarboxylation; Suzuki cross-coupling;
trans-1,2-Diarylethenes; Microwave-assisted synthesis.
Corresponding author. Tel.: +33 (0)2 31 56 59 10; fax: +33 (0)2 31 93
*
11 88; e-mail: sylvain.rault@unicaen.fr
0040-4039/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.04.114

4348
M.-A. Bazin et al. / Tetrahedron Letters 48 (2007) 4347–4351
R'
B(OH)2
3
R'
CO2H
Br
, Pd catalyst
NBS, AcOLi
solvent, base,
MW 5-15 min
solvent, MW 1-5 min
R
R
R
1
2
4
Scheme 1.
reactions, we also studied a one-pot microwave-pro-
moted methodology (Scheme 1).
The Hunsdiecker-type reaction was carried out with var-
ious cinnamic acids and the Suzuki coupling step was
carried out with commercially available boron reagents
including phenylboronic acid 3a, 2-fluorophenylboronic
acid 3b, 4-cyanophenylboronic acid 3c and 2-thienyl-
boronic acid 3d.
Since a one-pot strategy needs to be adaptive to two
different reaction conditions, the choice of the solvent
turned out to be essential to achieve accurately the
two steps in the same vessel. The Hunsdiecker-type bro-
modecarboxylation was settled with trans-cinnamic acid
1a. The most common solvent mixture used in this reac-
tion is acetonitrile–water 97:3. This system gives from
very good to excellent yields of trans-b-bromostyrenes.
Unfortunately, this mixture is not compatible with the
Suzuki reaction conditions. All the attempts we carried
out in these conditions failed. So we studied new mix-
tures of solvents and we finally found that DME–water
mixtures could be used for the two reactions: a DME–
water 9:1 mixture for the Hunsdiecker-type bromode-
carboxylation and a DME–water 2:1 mixture for the
Suzuki cross-coupling reaction (Tables 1 and 2). Finally
we adjusted a one-pot protocol. The bromodecarboxyl-
ation was achieved in DME–water 9:1 for the first step.
Addition of water to reach DME–water 2:1 and Suzuki
cross-coupling reagents permits the second step.
Thus, a series of cinnamic acids was first treated with
N-bromosuccinimide and a catalytic amount of lithium
acetate in 10 mL of DME–water (9:1) for 1–5 min under
microwave heating at 100 ꢁC to afford the correspond-
ing (E)-b-bromostyrenes. After cooling and carbon
dioxide removal, boronic acid, tetrakis(triphenylphos-
phine)palladium(0), potassium carbonate and 3 mL of
water were added to the mixture and heated for few min-
utes under microwave heating at 100 ꢁC.20 The results
summarized in Table 3 show that trans-1,2-diarylethenes
4a–h were obtained in moderate to good yields. The final
yield was mainly conditioned by the yield of the first
step. Indeed, cinnamic acids carrying strong electron-
donating groups such as methoxy (entries 2–5) provided
easily trans-b-bromostyrenes, whereas cinnamic acids
carrying electron-withdrawing groups (1f and 1g) gave
products in lower yields and with a longer heating time
(entries 6–7). This analysis was clearly established by
Kuang and co-workers.15p Compound 4d was obtained
using NaOH as the base in the Suzuki cross-coupling
reaction instead of K2CO3 to remove completely the
acetate function (entry 4). We also applied our sequence
to 3-(2-thienyl)acrylic acid 1h to afford 4h in moderate
yield (entry 8). In this way, we tried to synthesize the
original trans-1,2-dihetarylethene 4i starting from 3-(3-
furyl)acrylic acid 1i; however, the first step failed due
to the bromination of the furan nucleus by NBS (entry 9).
Table 1. Solvent optimization in the Hunsdiecker-type bromodecarb-
oxylation
NBS, LiOAc
Br
CO2H
Ph
Ph
solvent, MW 1 min
1a
2a
Entry
Cinnamic
acid
Solvent
Yield of
2aa (%)
1
2
3
1a
1a
1a
Acetonitrile–water 97:3
DME–water 9:1
DME–water 2:1
81
78
62
In most cases, we observed or isolated a secondary prod-
uct resulting in the intermediary trans-b-bromostyrene
homocoupling. This has been proved. The bromo-
decarboxylation carried out with 1b in the presence of
tetrakis(triphenylphosphine)palladium(0) gave the yet
unknown dimer 5b (Scheme 2).
a Isolated yields.
Table 2. Solvent optimization in the Suzuki cross-coupling reaction
This sequence could be surely extended to (2E,4E)-5-
arylpenta-2,4-dienoic acids. The first attempt using 2-
fluorophenylboronic acid was successful (Table 4).
PhB(OH)2, K2CO3
Ph
Br
Ph
Ph
Pd(PPh3)4, solvent, MW 5 min
2a
4a
Entry
trans-b-
Bromostyrene
Solvent
Yield of
In conclusion, we have developed an original one-pot
microwave-promoted Hunsdiecker–Suzuki strategy giv-
ing a straightforward access to trans-1,2-diarylethenes
from cinnamic acids in few minutes. Further study con-
cerning these compounds and preliminary biological
evaluation are currently under progress.
4aa (%)
1
2
3
2a
2a
2a
Acetonitrile–water 97:3
DME–water 9:1
DME–water 2:1
0
43
72
a Isolated yields.

M.-A. Bazin et al. / Tetrahedron Letters 48 (2007) 4347–4351
Table 3. One-pot Hunsdiecker–Suzuki reaction starting from cinnamic acids
4349
Entry
Cinnamic acid
Boronic acid
Product
MW (min)
Yielda (%)
B(OH)2
CO2H
Step 1: 1
Step 2: 5
46b
71b
64
1
1a
3a
4a
CO2H
B(OH)2
2
3
4
Step 1: 1
Step 2: 5
MeO
OMe
OMe
MeO
BnO
HO
OMe
3a
1b
1c
OMe
OMe
OMe
OMe
4b
CO2H
B(OH)2
Step 1: 1
Step 2: 5
BnO
OMe
3a
4c
CO2H
B(OH)2
Step 1: 1
Step 2: 10
70c,d
AcO
OMe
3a
1d
4d
CO2H
S
5
Step 1: 1
Step 2: 15
43
B(OH)
MeO
OMe
2 3d
S
MeO
1e
4e
B(OH)2
CO2H
F
6
7
Step 1: 5
Step 2: 15
12
21
F3C
F
1f
F3C
3b
4f
B(OH)2
CN
CO2H
Step 1: 5
Step 2: 15
Cl
1g
Cl
CN
4g
3c
B(OH)2
S
8
9
Step 1: 1
Step 2: 10
41
CO2H
CO2H
S
1h
1i
CN
4h
CN
3c
Step 1: 5
0
S
B(OH)
2 3d
O
S
O
4i
a Isolated yields.
b Products 4a and 4b are spectroscopically identical to the reported literature (Ref. 21).
c NaOH was used as the base.
d Product 4d is spectroscopically identical to the reported literature (Ref. 22).

4350
M.-A. Bazin et al. / Tetrahedron Letters 48 (2007) 4347–4351
OMe
OMe
MeO
CO2H
Br
NBS, LiOAc, Pd(PPh3)4
+
DME-H2O (9:1), MW 30 min
OMe
OMe
OMe
MeO
MeO
MeO
5b
18% (determined by 1H NMR spectroscopy)
OMe
OMe
OMe
1b
2b
Scheme 2.
Table 4. One-pot Hunsdiecker–Suzuki reaction starting from (2E,4E) phenylpenta-2,4-dienoic acid 1j
Entry
a,b-Unsaturated carboxylic acid
Boronic acid
Product
MW (min)
Yielda (%)
37
B(OH)2
F
CO2H
1
Step 1: 1
Step 2: 10
1j
F
3b
4j
a Isolated yield.
9. (a) Gooben, L. J.; Paetzold, J.; Winkel, L. Synlett 2002,
1721–1723; (b) Arvela, R. K.; Leadbeater, N. E. J. Org.
Chem. 2005, 70, 1786–1790.
Acknowledgements
We gratefully acknowledge the financial support from
10. Choi, H.; Jung, I.; Song, K. H.; Song, K.; Shin, D.-S.;
Kang, S. O.; Ko, J. Tetrahedron 2006, 62, 9059–9065.
11. (a) Farinola, G. M.; Fiandanese, V.; Mazzone, L.; Naso,
F. J. Chem. Soc., Chem. Commun. 1995, 2523–2524; (b)
Molander, G. A.; Bernardi, C. R. J.Org. Chem. 2002, 67,
8424–8429; (c) Cella, R.; Stefani, H. A. Tetrahedron 2006,
62, 5656–5662; (d) Navarro, O.; Marion, N.; Mei, J.;
Nolan, S. P. Chem. Eur. J. 2006, 12, 5142–5148.
´
Laboratoires PCAS and the ‘Conseil Regional de
Basse-Normandie’.
References and notes
`
1. (a) Vessieres, A.; Top, S.; Pigeon, P.; Hillard, E.; Boube-
12. Ngwendson, J. N.; Atemnkeng, W. N.; Schultze, C. M.;
Banerjee, A. Org. Lett. 2006, 8, 4085–4088.
13. (a) Chang, S.; Na, Y.; Shin, H. J.; Choi, E.; Jeong, L. S.
Tetrahedron Lett. 2002, 43, 7445–7448; (b) Velder, J.;
Ritter, S.; Lex, J.; Schmalz, H.-G. Synthesis 2006, 2, 273–
278.
14. (a) Bouillon, A.; Voisin, A. S.; Robic, A.; Lancelot, J.-C.;
Collot, V.; Rault, S. J. Org. Chem. 2003, 68, 10178–10180;
(b) Voisin, A. S.; Bouillon, A.; Berenguer, I.; Lancelot,
J.-C.; Lesnard, A.; Rault, S. Tetrahedron 2006, 62, 11734–
ker, L.; Spera, D.; Jaouen, G. J. Med. Chem. 2005, 48,
3937–3940; (b) Sanoh, S.; Kitamura, S.; Sugihara, K.;
Kohta, R.; Ohta, S.; Watanabe, H. J. Health Sci. 2006, 52,
613–622; (c) Heynekamp, J. J.; Weber, W. M.; Hunsaker,
L. A.; Gonzales, A. M.; Orlando, R. A.; Deck, L. M.;
Vander Jagt, D. L. J. Med. Chem. 2006, 49, 7182–7189; (d)
Li, Y.-Q.; Li, Z.-L.; Zhao, W.-J.; Wen, R.-X.; Meng,
Q.-W.; Zeng, Y. Eur. J. Med. Chem. 2006, 41, 1084–1089.
2. Ovesna, Z.; Kozics, K.; Bader, Y.; Saiko, P.; Handler, N.;
Erker, T.; Szekeres, T. Oncol. Rep. 2006, 16, 617–624.
3. Richard, N.; Porath, D.; Radspieler, A.; Schwager, J. Mol.
Nutr. Food Res. 2005, 49, 431–442.
´
11739; (c) Gerard, A.-L.; Bouillon, A.; Mahatsekake, C.;
Collot, V.; Rault, S. Tetrahedron Lett. 2006, 47, 4665–
4669.
4. Jang, M.; Cai, L.; Udeani, G. O.; Slowing, K. V.; Thomas,
C. F.; Beecher, C. W. W.; Fong, H. H. S.; Farnsworth, N.
R.; Kinghorn, A. D.; Mehta, R. G.; Moon, R. C.; Pezzuto,
J. M. Science 1997, 275, 218–220.
15. For Hunsdiecker-type halodecarboxylations in various
conditions, see: (a) Johnson, R. G.; Ingham, R. K. Chem.
Rev. 1956, 56, 219–269; (b) Berman, J. D.; Price, C. C. J.
Org. Chem. 1958, 23, 102–103; (c) Barton, D. H. R.;
Lacher, B.; Zard, S. Z. Tetrahedron Lett. 1985, 26, 5939–
5942; (d) Graven, A.; Jørgensen, K. A.; Søren, D.;
Stanczak, A. J. Org. Chem. 1994, 59, 3543–3546; (e)
Chowdhury, S.; Roy, S. Tetrahedron Lett. 1996, 37, 2623–
2624; (f) Chowdhury, S.; Roy, S. J. Org. Chem. 1997, 62,
199–200; (g) Naskar, D.; Chowdhury, S.; Roy, S. Tetra-
hedron Lett. 1998, 39, 699–702; (h) Homsi, F.; Rousseau,
G. Tetrahedron Lett. 1999, 40, 1495–1498; (i) Kuang, C.;
Senboku, H.; Tokuda, M. Synlett 2000, 1439–1442; (j)
You, H.-W.; Lee, K.-J. Synlett 2001, 105–107; (k) Roy, S.
C.; Guin, C.; Maiti, C. Tetrahedron Lett. 2001, 42, 9253–
9255; (l) Sinha, J.; Layek, S.; Mandal, G. C.; Bhattachar-
jee, M. Chem. Commun. 2001, 1916–1917; (m) Das, J. P.;
Roy, S. J. Org. Chem. 2002, 67, 7861–7864; (n) Ye, C.;
Shreeve, J. M. J. Org. Chem. 2004, 69, 8561–8563; (o)
5. Waldeck, D. H. Chem. Rev. 1991, 91, 415–436.
6. (a) Chaudhuri, M. K.; Ganguly, S. C. J. Phys. C (Solid
State Phys.) 1969, 2, 1560–1565; (b) Singh, A. K.;
Kanvah, S. J. Chem. Soc., Perkin Trans. 2 2001, 395–401.
7. (a) Bachelor, F. W.; Loman, A. A.; Snowdon, L. R. Can.
J. Chem. 1970, 48, 1554–1557; (b) Cushman, M.; Naga-
rathnam, D.; Gopal, D.; Chakraborti, A. K.; Lin, C. M.;
Hamel, E. J. Med. Chem. 1991, 34, 2579–2588; (c) Kim, S.;
Seus, P.; Meier, H. Eur. J. Org. Chem. 2004, 8, 1761–1764;
(d) Murias, M.; Handler, N.; Erker, T.; Pleban, K.; Ecker,
G.; Saiko, P.; Szekeres, T.; Jaeger, W. Bioorg. Med. Chem.
2004, 12, 5571–5578.
8. (a) Alonso, D. A.; Fuensanta, M.; Najera, C.; Varea, M. J.
Org. Chem. 2005, 70, 6404–6416; (b) Mirk, D.; Grassot,
J.-M.; Zhu, J. Synlett 2006, 1255–1259.

M.-A. Bazin et al. / Tetrahedron Letters 48 (2007) 4347–4351
4351
Kuang, C.; Senboku, H.; Tokuda, M. Tetrahedron 2005,
61, 637–642; (p) Kuang, C.; Yang, Q.; Senboku, H.;
Tokuda, M. Synthesis 2005, 8, 1319–1325.
for 1 min. After removal of carbon dioxide and a thin-
layer chromatography control, 2-thienylboronic acid 4d
(1.47 g, 11.52 mmol), Pd(PPh3)4 (0.56 g, 0.48 mmol),
K2CO3 (3.32 g, 24.01 mmol) and water (3 mL) were added
to the mixture. The vial was sealed, purged with argon
through the vial’s septum and heated at 100 ꢁC under
microwave irradiation for 15 min. The aqueous layer was
extracted with ethyl acetate (2 · 50 mL). The combined
organic layers were washed with brine, dried over MgSO4,
filtered, and evaporated under reduced pressure. The
crude product was purified by silica gel chromatography
using EtOAc/cyclohexane (1:9) as eluent. Recristallization
from methanol afforded 4e as pale yellow needles (1.02 g,
Yield: 43%). 2-[(E)-2-(3,4-dimethoxyphenyl)vinyl]thio-
phene 4e: mp 109 ꢁC (methanol); 1H NMR (400 MHz,
CDCl3): 3.90 (s, 3H, OMe), 3.94 (s, 3H, OMe), 6.85 (d,
J = 8.8 Hz, 1H), 6.88 (d, 3J = 16.0 Hz, 1H, olefinic-H),
16. (a) Chowdhury, S.; Roy, S. J. Org. Chem. 1997, 62, 199–
200; (b) Kuang, C.; Senboku, H.; Tokuda, M. Synlett
2000, 1439–1442; (c) Das, J. P.; Roy, S. J. Org. Chem.
2002, 67, 7861–7864.
17. (a) Graukroger, K.; Hadfield, J. A.; Hepworth, L. A.;
Lawrence, N. J.; McGown, A. T. J. Org. Chem. 2001, 66,
8135–8138; (b) Hadfield, J. A.; McGown, A. T.; Gaukr-
oger, K.; Hepworth, L. A.; Lawrence, N. J. WO
2002049994, 2002; (c) Yamada, Y. M. A.; Takeda, K.;
Takahashi, H.; Ikegami, S. Org. Lett. 2002, 4, 3371–3374;
(d) Arvela, R. K.; Leadbeater, N. E.; Sangi, M. S.;
Williams, V. A.; Granados, P.; Singer, R. D. J. Org.
Chem. 2005, 70, 161–168; (e) Katayama, H.; Nagao, M.;
Ozawa, F.; Ikegami, M.; Arai, T. J. Org. Chem. 2006, 71,
2699–2705; (f) Dhudshia, B.; Thadani, A. N. Chem.
Commun. 2006, 668–670; (g) Babudri, F.; Cardone, A.;
Cioffi, C. T.; Farinola, G. M.; Naso, F.; Ragni, R.
Synthesis 2006, 8, 1325–1332.
18. Naskar, D.; Roy, S. Tetrahedron 2000, 56, 1369–1377.
19. Kuang, C.; Yang, Q.; Senboku, H.; Tokuda, M. Tetra-
hedron 2005, 61, 4043–4052.
20. Typical procedure: In a microwave vial with a magnetic stir
bar was introduced a mixture of trans-3,4-dimethoxycin-
namic acid 1e (2.00 g, 9.60 mmol), LiOAc (0.13 g,
1.92 mmol), and NBS (1.80 g, 10.09 mmol) in a DME–
H2O mixture (10 mL, 9:1). The vial was sealed and heated
at 100 ꢁC under microwave irradiation (Biotage Initiator)
3
6.98–7.04 (m, 4H), 7.11 (d, J = 16.0 Hz, 1H, olefinic-H),
7.17 (d, J = 4.6 Hz, 1H) ppm; 13C NMR (100 MHz,
CDCl3): 56.0 (OMe), 56.1 (OMe), 108.7, 111.4, 119.8,
120.2, 124.0, 125.6, 127.7, 128.3, 130.2, 143.2, 149.1,
149.3 ppm; IR (KBr) 3413, 1597, 1580, 1519, 1507, 1264,
1230, 1154, 1137, 1025, 946, 816, 685 cmÀ1; MS-EI: m/z
(%) = 246 (100) [M+], 231 (86), 171 (61), 115 (24).
HRMS–EI: m/z [M+] calcd. for C14H14O2S: 246.0724,
found: 246.0714.
21. Parrish, J. P.; Jung, Y. C.; Shin, S., II; Jung, K. W. J. Org.
Chem. 2002, 67, 7127–7130.
22. Chhor, R. B.; Singh, K. A.; Nosse, B.; Tandon, V. K.
Synth. Commun. 2003, 33, 2519–2530.