Synthesis of biaryl-styrene monomers by microwave-assisted Suzuki coupling

Article abstract of DOI:10.1016/j.tetlet.2009.07.117

Biaryl-styrenic monomers are prepared via Suzuki coupling as functional monomers in the synthesis of molecularly imprinted polymers. Traditional thermal Suzuki approaches are hampered by competition between Suzuki, Heck and homo-coupling reactions. Microw

Full text of DOI:10.1016/j.tetlet.2009.07.117

Tetrahedron Letters 50 (2009) 5894–5895
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Tetrahedron Letters
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Synthesis of biaryl-styrene monomers by microwave-assisted Suzuki coupling
*
Hazit A. Zayas, Michael C. Bowyer, Christopher P. Gordon, Clovia I. Holdsworth, Adam McCluskey
School of Environmental and Life Sciences, University of Newcastle, Callaghan, NSW 2308, Australia
a r t i c l e i n f o
a b s t r a c t
Article history:
Biaryl-styrenic monomers are prepared via Suzuki coupling as functional monomers in the synthesis of
molecularly imprinted polymers. Traditional thermal Suzuki approaches are hampered by competition
between Suzuki, Heck and homo-coupling reactions. Microwave-assisted approaches facilitated rapid
access to the desired Suzuki products whilst suppressing both Heck and homo-couplings of 4-vinylbo-
ronic acid.
Received 15 May 2009
Revised 16 July 2009
Accepted 20 July 2009
Available online 24 July 2009
Crown Copyright Ó 2009 Published by Elsevier Ltd. All rights reserved.
Keywords:
Suzuki coupling
Microwave-assisted synthesis
Styrenic monomers
4-Vinylboronic acid
The preparation of molecularly imprinted polymers (MIPs) for
selective recognition of molecules of interest involves a judicious
choice of functional monomers that are complementary to, and
therefore, capable of selectively binding the target molecule.1,2 In
order to increase our group’s library of functional monomers, we
synthesized a number of styrenic monomers 1a–f, capable of
(either under an air or N2 atmosphere).10 Contrary to reports by
De et al., our styrenic systems are sensitive to air.9
Suzuki coupling (air atmosphere) of 4-bromophenol and 2 af-
fords 3 (12%, 18 h reaction time) and none of the desired 1a. The
potentially interacting with selected targets by
or H-bonding interactions (Fig. 1).
p–p stacking and/
Typically, access to such biaryl systems is via Suzuki cross-cou-
pling of aryl bromides and 4-vinylphenylboronic acid 2 (Scheme 1).
Whilst the Suzuki protocol has been widely used for aryl–aryl bond
formation, its application for the preparation of styrene-based aryl
compounds has been very limited. Given the known propensity for
tetrakis(triphenylphosphine)palladium (Pd(PPh3)4) to generate un-
wanted side-products, we commenced our study using Pd(DI-
PHOS)2.3 Generally, Suzuki couplings are characterized by the
persistence of side-reactions comprising a self-coupling of the
boronic acid (3) and the equivalent Heck coupling (4) (Scheme
1).4,5 The presence of the vinylic moiety obviously increases the
probability of Heck coupling.
N
N
OH
N
CO2H
OH
1a
1b
1c
1d
1e
1f
Figure 1. Target styrenyl biaryl functional monomer systems.
Herein we report the synthesis of the biaryl-styrenic functional
monomers 1a–f via microwave irradiation of the Suzuki coupling
mixture under a variety of conditions whilst minimizing the for-
mation of by-products.6–9
a
Our initial efforts employed traditional thermal Suzuki coupling
+
Ar-Br
1a - 1f
+
+
conditions.9 Thus,
a mixture of 4-vinylphenylboronic acid 2
(1.0 mmol) and aryl bromide (1.0 mmol), 1 mol % of Pd(DIPHOS)2
and 2 M K2CO3 (2.4 mmol) in THF (4 mL) was heated at reflux
B(OH)2
Ar
2
4a-f
3
* Corresponding author. Tel.: +61 2 4921 6486; fax: +61 2 4921 5472.
E-mail address: Adam.McCluskey@newcastle.edu.au (A. McCluskey).
Scheme 1. Suzuki coupling (a) Pd(DIPHOS)2, 2 M K2CO3, THF,
D, N2, 5 d.
0040-4039/$ - see front matter Crown Copyright Ó 2009 Published by Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.07.117

H. A. Zayas et al. / Tetrahedron Letters 50 (2009) 5894–5895
5895
introduction of an N2 atmosphere, under otherwise identical reac-
tion conditions, gave 1a (11%) and 3 (3%). Nevertheless, even under
N2, the reactions were still very slow requiring five days to obtain
the optimal cross-coupling yields (Table 1). Excellent yields of biar-
yl products 1b (86%) and 1c (78%) were obtained using this modi-
fied approach. However, the yields observed for acidic analogues
1a (13%), 1f (0%) and basic analogues 1d (41%) and 1e (30%) were
synthetically unsatisfactory. Additionally, we were unable to di-
rectly prepare 1f from 4-bromobenzoic acid. Carboxylate protec-
tion (benzyl ester) was necessary to effect the desired Suzuki
coupling. Subsequent saponification afforded 1f.11 The yield varia-
tion is consistent with the expected reactivity of the substituted
aryl bromides towards electrophilic substitution. Previous studies
have shown that arylboronic acid homo-coupling increases in the
presence of oxygen and competes with the Suzuki cross-coupling
in open air conditions.5 This is consistent with our findings with
the degree of homo-coupling reduced, but not eliminated by care-
ful control of the reaction atmosphere. Additionally, we note that
the low yield of 1a (13%) is a function of the acidity of 4-
bromophenol.
efficient conversion into the desired Suzuki product (>98%) in all
cases thereby demonstrating the flexibility of our approach.
In this Letter we have demonstrated the ease of synthesis of
biaryl-styrenic functional monomers. Careful control of the micro-
wave synthesis conditions facilitates quantitative conversion into
the desired coupling product suppressing the potentially compet-
ing pathway that leads to the Heck products. This work suggests
that the Suzuki coupling in the presence of vinylic moieties is syn-
thetically feasible and opens the way to the synthesis of a wide
range of novel monomer systems for molecularly imprinted poly-
mer systems.
Acknowledgements
The authors acknowledge the financial support of the Australian
Research Council and the National Health and Medical Research
Council. H. Zayas acknowledges the UNI-PRS postgraduate funding
from the University of Newcastle.
References and notes
Given the dual issues of low yields and long reaction times we
next turned our attention to the use of microwave heating as a pos-
sible means to improve both issues. Microwave-assisted Suzuki
couplings have already been reported,12–14 but to the best of our
knowledge, the method has not yet been applied to cross-coupling
of vinylic aryls.
1. Arshady, R.; Mosbach, K. Macromol. Chem. Phys. 1981, 182, 687–692.
2. McCluskey, A.; Holdsworth, C. I.; Bowyer, M. C. Org. Biomol. Chem. 2007, 5,
3233–3244.
3. Leadbeater, N. E. R.; Sarah, M. Tetrahedron 1999, 55, 11889–11894.
4. Moreno-Mañas, M.; Pérez, M.; Pleixats, R. J. Org. Chem. 1996, 61, 2346–2351.
5. Knowles, J. P.; Whiting, A. Org. Biomol. Chem. 2007, 5, 31–44.
6. Hajduk, P. J.; Sheppard, G.; Nettesheim, D. G.; Olejniczak, E. T.; Shuker, S. B.;
Meadows, R. P.; Steinman, D. H.; Carrera, G. M., Jr.; Marcotte, P. A.; Severin, J.;
Walter, K.; Smith, H.; Gubbins, E.; Simmer, R.; Holzman, T. F.; Morgan, D. W.;
Davidsen, S. K.; Summers, J. B.; Fesik, S. W. J. Am. Chem. Soc. 1997, 119, 5818–
5827.
7. Sellner, H.; Faber, C.; Rheiner, P. B.; Seebach, D. Chem. Eur. J. 2000, 6, 3692–
3705.
8. Ueno, I. In Proceedings of the International Symposium on Ion Exchange in
Korea, and 22nd Annual Meeting of JAIE, 2006, 67, 67.
Microwave irradiation of benzyl 4-bromobenzoate in PhCH3/
H2O (1:1) with Pd(DIPHOS)2/K2CO3 returned an identical yield of
1f as that observed with the equivalent thermal reaction (Table
1). Given the reduced reaction times, we examined the synthesis
of 1a, a reaction that proceeded very poorly (13%) in the thermal
case. Microwave irradiation as per the synthesis of 1f (THF:H2O;
30 min, 150 W/100 °C) gave 1a in 33% yield, a significant improve-
ment over the thermal reaction. Raising the reaction temperature
to 150 °C resulted only in a significant loss of solvent with no
improvement in reaction outcome. Whilst, importantly, there
was no evidence of the homo-coupling product 3, as one might
have anticipated, the major species (at 66%) was the Heck product
4f. Switching to the less volatile THF/H2O (1:1) mixed solvent sys-
tem facilitated control of the reaction temperature at 150 °C
(100 W, 30 min) and essentially quantitative conversion to 1a. Sub-
sequent experimentation showed the same outcome in THF/H2O
(1:1) at 100 °C, and all further synthesis was conducted at this
temperature (Table 1).10 These data clearly demonstrate a highly
9. De, D.; Krogstad, D. J. Org. Lett. 2000, 2, 879–882.
10. In
vinylphenylboronic acid (1.0 mmol), Pd(DIPHOS)2 (1 mol %) and 2 M K2CO3
(2.4 mmol) in THF/H2O (1:1, 6 mL) in 10-mL microwave vessel with
magnetic stirrer was degassed and purged with nitrogen prior to microwave
irradiation. Microwave irradiation was conducted in CEM Discover
a typical synthesis: A mixture of aryl bromide (1.0 mmol), 4-
a
a
a
microwave. The vessel was placed in the microwave sample cavity and
sealed with a pressure lock. The microwave source was turned on and was set
to 100 °C using 100 W of power to heat the reaction mixture for 30 min. The
reaction mixture was allowed to cool before the addition of EtOAc (10 mL) and
was filtered through Celite. The filtrate was evaporated to dryness, after which
the residue was dissolved in water, extracted with EtOAc (2 Â 10 mL), and the
combined organic layers were dried over Na2SO4 prior to rotary evaporation.
The product was purified by silica gel flash chromatographyCompound 1d: 1H
NMR (300 MHz, CDCl3) d 2.96 (s, 6H, N(CH3)2), 5.23 (d, J = 10.9 Hz, 1H, vinyl H),
5.75 (d, J = 17.6 Hz, 1H, vinyl H), 6.72 (ddd, J = 9.3, 6.6, 4.6 Hz, 2H, vinyl H and
Arom. H), 6.93 (dd, J = 8.7, 1.4 Hz, 1H, Arom. H), 7.28 (t, J = 7.8 Hz, 2H, Arom H),
7.44 (d, J = 8.4 Hz, 2H, Arom H), 7.55 (d, J = 8.2 Hz, 2H, Arom. H); 13C NMR
(75 MHz, CDCl3): d 40.4, 113.0, 113.8, 125.9, 127.0, 127.3, 130.5, 135.1, 136.7,
140.1, 150.3. IR (ATR) 3080, 2972, 2882, 2843, 2796, 1912, 1881, 1603, 1501,
Table 1
Conversion (%) of styrenic compounds 1a–f prepared under thermal conditions and
microwave-assisted Suzuki coupling catalyzed by Pd(DIPHOS)2.
1352, 1227, 992, 890, 751, 539 cmÀ1
. HRMS: calcd for C16H17N m/
z = 223.13610; found 223.13615; mp 170 °C (dec).Compound 1e: 1H NMR
(300 MHz, DMSO-d6) d 2.94 (s, 6H, N(CH3)2), 5.23 (d, J = 10.9 Hz, 1H, vinyl H),
5.80 (d, J = 17.7 Hz, 1H, vinyl H), 6.74 (dd, J = 15.2, 8.5 Hz, 1H, vinyl H), 6.80 (d,
J = 8.9 Hz, 2H, Arom. H), 7.46–7.58 (m, 6H, Arom H); 13C NMR (75 MHz, CDCl3):
d 41.2, 111.8, 112.3, 114.1, 116.2, 127.0, 127.9, 129.9, 137.1, 142.2, 142.3 (2C),
151.5. IR (ATR) 3080, 3028, 2983, 2888, 2805, 1918, 1816, 1598, 1563, 1487,
Product
Thermal
THFa,b
Microwave
PhCH3/H2O (1:1)b,c
THF/H2O (1:1)b,d
1a
1b
1c
1d
1e
1f
13b
86
78
33
>98
>98
>98
>98
>98
>98
>98
>98
80
85
>98
1354, 993, 903, 836, 772, 691, 626 cmÀ1
z = 223.13610; found 223.13618; mp 44–47 °C.
. HRMS: calcd for C16H17N m/
41
30
>98e
11. Hostetler, E. D.; Terry, G. E.; Burns, H. D. J. Lab. Comp. Radiopharm. 2005, 48,
629–634.
12. Blettner, C. G.; König, W. A.; Stenzel, W.; Schotten, T. J. Org. Chem. 1999, 64,
3885–3890.
13. Bai, L.; Wang, J.-X.; Zhanga, Y. Green Chem. 2003, 5, 615–617.
14. Namboodiri, V. V.; Varma, R. S. Green Chem. 2001, 3, 146–148.
a
THF reflux, N2, 5 d.
b
c
GC and 1H NMR yields.
THF/H2O (1:1) at 100 °C for 30 min (100 W).
PhCH3/H2O (1:1) at 100 °C for 30 min (100 W).
Commenced with benzyl 4-bromobenzoate followed by saponification.
d
e