A one-pot synthesis of unsymmetrical bis-styrylbenzenes

Article abstract of DOI:10.1016/j.tetlet.2009.08.083

An efficient and widely applicable one-pot synthesis of unsymmetrical (E,E)-bis-styrylbenzenes using successive Heck and Horner-Wadsworth-Emmons reactions is described.

Full text of DOI:10.1016/j.tetlet.2009.08.083

Tetrahedron Letters 50 (2009) 6228–6230
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A one-pot synthesis of unsymmetrical bis-styrylbenzenes
*
Daniel P. Flaherty, Yuxiang Dong, Jonathan L. Vennerstrom
University of Nebraska Medical Center, College of Pharmacy, 986025 Nebraska Medical Center, Omaha, NE 68198-6025, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient and widely applicable one-pot synthesis of unsymmetrical (E,E)-bis-styrylbenzenes using
successive Heck and Horner–Wadsworth–Emmons reactions is described.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 17 July 2009
Revised 20 August 2009
Accepted 24 August 2009
Available online 28 August 2009
Keywords:
Bis-styrylbenzenes
Alzheimer’s disease
Heck reaction
Horner–Wadsworth–Emmons reaction
Alzheimer’s disease (AD)1 is a common neurodegenerative disor-
der in theelderly.2,3 Hallmarksof thisdiseaseare senile plaque depo-
sition containing aggregated b-amyloid (Ab) protein, neurofibrillary
tangles (NFTs), reactive astrocytes and activated microglia in the
brain parenchyma.4,5 Based on the Ab-binding dye Congo red,6
bis-styrylbenzene derivatives such as (E,E)-1-fluoro-2,5-bis(3-car-
boxy-4-hydroxystyryl)benzene (FSB)7 and (E,E)-1,4-bis(4-hydroxy-
styryl)benzene8 have been identified as potent Ab-binding ligands
with potential for the early diagnosis of AD using positron emission
tomography (PET) and magnetic resonance imaging (MRI). FSB has
also been reported to inhibit Ab fibril aggregation.9
One-step syntheses of symmetrical bis-styrylbenzenes using
classic Wittig (Horner–Wadsworth–Emmons or HWE) couplings
between benzaldehydes and ylides derived from tetraethyl p-xyly-
lenediphosphonates have been described.7,8 Other reports describe
double HWEreactionsequencesthatcouldbeappliedtothe synthesis
of unsymmetrical bis-styrylbenzenes, but these require intervening
adjustmentof oxidation state,10,11 adding extra steps to the synthesis.
Othersyntheses12–14 employ alternatingHWEand Heckreactions ina
step-wise manner to form polymeric bis-styrylbenzenes known as
oligo(phenylenevinylene)s; in these syntheses, unsymmetrical bis-
styrylbenzene are often synthetic intermediates. Another report15
describes a one-pot sequential Heck cross-coupling using aryl diha-
lides to form unsymmetrical bis-styrylbenzenes.
and widely applicable synthesis of unsymmetrical bis-styrylbenz-
enes. Herein, we report a one-pot16 synthesis of unsymmetrical
bis-styrylbenzenes 4a–4i through successive Heck/HWE reactions
in good yields (60–84%).
The first step in this procedure (Scheme 1) is a Heck coupling
reaction between diethyl 4-iodobenzyl phosphonate (1) and a sty-
rene (2a–2c) (2 mol equiv) to form the 4-substituted diethyl (E)-(4-
‘X’-styrylbenzyl) phosphonates in situ. This Heck reaction is based
on an existing protocol17 optimized for our purposes using
Pd(OAc)2 (3 mol %), phenylurea (6 mol %) and potassium carbonate
(2 mol equiv) in DMF16 with stirring at 110 °C. Attempted Heck
reactions with the bromo analogue of 1 under these conditions
were unsuccessful. The reaction is monitored by testing small ali-
quots with GC–MS until 1 is consumed, typically in 22 h. After ver-
ification of the disappearance of 1, the reaction is cooled to 80 °C
with continued stirring while benzaldehydes 3a–3e (1.1 mol equiv)
and sodium methoxide (30% w/v solution in methanol) (2 mol
equiv) are added. After continued stirring for 1 h, the reaction is
stopped by a water quench at which time products 4a–4i precipi-
tate and are filtered and rinsed with water and ether (Table 1).
In order to show applicability for styrenes containing electron-
donating and electron-withdrawing groups, we tested the method
with 4-methoxymethoxystyrene 2b and 4-methoxycarbonylsty-
rene 2c in the Heck coupling step and 4-methoxybenzaldehyde
3d and 4-cyanobenzaldehyde 3a in the HWE step. These reactions
produced the desired products, 4f–4i in slightly lower yields com-
pared to those with styrene. The formation of 4h required 2 mol
equiv of 3d.18
The structure–activity relationship (SAR) of this class of
compounds for binding to Ab fibrils and the inhibition of Ab aggre-
gation is based on data obtained only from symmetrical bis-styryl-
benzenes. With this in mind, we identified the need for an efficient
The one-pot method was compared to a sequential HWE/Heck
two-step19 pathway12–14 to form bis-styrylbenzenes 4a–4d from
the isolated intermediate styrylbenzenes 5a–5d20 (Scheme 2). This
* Corresponding author. Tel.: +1 402 559 5362; fax: +1 402 559 9543.
E-mail address: jvenners@unmc.edu (J.L. Vennerstrom).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.08.083

D. P. Flaherty et al. / Tetrahedron Letters 50 (2009) 6228–6230
6229
Y
1) Pd(OAc)2, phenylurea
K2CO3, DMF, 110 ºC, 22 h
X
PO(OEt)2
I
+
O
2)
Y
X
2
1
4a - 4i
H
3
2a, X = H
2b, X = OCH2OMe
2c, X = COOMe
NaOCH3, DMF,
80 ºC, 1 h
3d, R = 4-OMe
3a, R = 4-CN
3b, R = 4-NO2
3e, R = 3-COOMe-4-OCH2OMe
3c, R = 4-OCH2OMe
Scheme 1. Heck/HWE one-pot synthesis of unsymmetrical bis-styrylbenzenes 4a–4i.
Table 1
Overall yields of bis-styrylbenzenes 4a–4i from one-pot (Scheme 1) and two-pot (Scheme 2) syntheses
Compound
X
Y
Yield (one-pot)
Yield (two-pot)a
4a
4b
4c
4d
4e
4-H
4-H
4-H
4-H
4-H
4-Cyano
4-Nitro
84
84
79
75
76
65
58
50
64
—
4-Methoxymethoxy
4-Methoxy
3-Methoxycarbonyl
4-Methoxymethoxy
4-Methoxy
4-Cyano
4-Methoxy
4-Cyano
4f
4-Methoxymethoxy
4-Methoxymethoxy
4-Methoxycarbonyl
4-Methoxycarbonyl
60
64
62b
76
—
—
—
—
4g
4h
4i
a
Yields based on the isolated products of sequential HWE and Heck reaction.
2 mol equiv of aldehyde utilized in second step.
b
Y
Memorial AFPE pre-doctoral fellowship and a Nancy and Ronald
Reagan Alzheimer’s Scholarship Award for financial support.
3a - 3d
1
I
NaOCH3, DMF,
80 ºC, 1 h
5a - 5d
Supplementary data
Y
2a
Experimental procedures for 2b, 2c, 3c and 3e. Experimental
procedures and characterization of compounds 4a–4i and 5a–5d.
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2009.08.083.
Pd(OAc)2, phenylurea
K2CO3, DMF, 110 ºC, 22 h
4a - 4d
Scheme 2. HWE/Heck two-pot synthesis of 4a–4e.
References and notes
process requires an extra isolation step between the HWE and
Heck couplings leading to potentially lower yields from compound
losses during work-up. Indeed, even using the previously described
optimized Heck reaction conditions, the sequential HWE/Heck
two-pot pathway gave lower overall yields than the one-pot meth-
od (Table 1).
Other reaction variants similarly gave lower yields or failed
altogether. For example, 4f–4i were synthesized in a reverse se-
quence HWE/Heck one-pot reaction, but yields were significantly
lower in the range of 43–60%. Finally, attempts to perform a one-
pot double Heck reaction with 1-bromo-4-iodobenzene failed, pre-
sumably due to the lack of reactivity of the bromo styrene
intermediates.
In conclusion, this Letter describes the first one-pot synthesis of
unsymmetrical bis-styrylbenzenes using a Heck/HWE sequence.
The yields are shown to be comparable or higher than those re-
ported from HWE/Heck two-pot reactions.12–14 This method
should be applicable to the synthesis of structurally diverse
unsymmetrical bis-styrylbenzenes and could lead to advances in
the SAR of this class of compounds in AD studies.
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16. Representative one-pot procedure: diethyl 4-iodobenzyl phosphonate (1)
(0.23 g, 0.65 mmol) and vinylbenzene 2a (0.14 g, 1.3 mmol) were mixed with
palladium (II) acetate (0.004 g, 0.02 mmol), phenylurea (0.005 g, 0.04 mmol)
and potassium carbonate (0.18 g, 1.3 mmol) in DMF (5 mL) and were stirred at
110 °C for 22 h. The reaction temperature was then lowered to 80 °C and to this
mixture were added 4-cyanobenzaldehyde (3a) (0.094 g, 0.72 mmol) and 30%
w/v sodium methoxide in MeOH (0.27 mL, 1.4 mmol). The reaction was stirred
for 1 h at 80 °C and then cooled to rt and quenched with H2O (15 mL). The solid
was then filtered and rinsed with H2O and ether to yield (E,E)-1-styryl-4-(4-
cyanostyryl)benzene (4a) (0.17 g, 84%).
Acknowledgements
We thank UNMC, an American Foundation for Pharmaceutical
Education (AFPE) pre-doctoral fellowship, a Josiah Kirby Lilly, Sr.

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D. P. Flaherty et al. / Tetrahedron Letters 50 (2009) 6228–6230
17. Cui, X.; Zhou, Y.; Wang, N.; Liu, L.; Guo, Q.-. X. Tetrahedron Lett. 2007, 48, 163.
18. Several attempts to synthesize 4h with 1.1 mol equiv of 3d using the one-pot
procedure resulted in low yields of the desired product and recovery of the
(E)-(4-methoxycarbonylstyrylbenzyl) phosphonate starting material. The
lower reactivity of 3d may be due to its less electrophilic carbonyl carbon.
19. Representative two-pot procedure: Step 1: diethyl 4-iodobenzyl phosphonate (1)
(0.57 g, 1.6 mmol), 4-cyanobenzaldehyde 3a (0.21 g, 1.6 mmol) and 30% w/v
sodium methoxide in MeOH (0.62 mL, 3.3 mmol) were added to DMF (5 mL)
and were stirred for 1 h at 80 °C. The reaction was quenched with water,
filtered and rinsed with water to yield (E)-4-iodostyrylcyanobenzene (5a)
(0.42 g, 79%). Step 2: Iodostyrene 5a (0.13 g, 0.38 mmol) and 2a (0.07 g,
0.68 mmol) were mixed with palladium (II) acetate (0.003 g, 0.010 mmol),
phenylurea (0.003 g, 0.021 mmol) and potassium carbonate (0.094 g,
0.68 mmol) in DMF (5 mL) and stirred at 110 °C for 22 h. The reaction was
then quenched with H2O (15 mL) and filtered to yield (E,E)-1-styryl-4-(4-
cyanostyryl)benzene (4a) (0.086 g, 82%).
20. Using a HWE reaction, we were able to isolate 5c in 90% yield using sodium
methoxide at 80 °C compared to a previously reported (Kung, H. F.; Lee, C.-W.;
Zhuang, Z.-P.; Kung, M.-P.; Hou, C.; Plssl, K. J. Amer. Chem. Soc. 2001, 123,
12740.) 30% yield using sodium hydride at room temperature.