An efficient methodology for the synthesis of 3-styryl coumarins

Article abstract of DOI:10.1590/S0103-50532012000400014

Regioselective and highly efficient Heck arylation of 3-vinyl-6,7- dimethoxycoumarin has been developed to afford 3-styryl coumarins in good to very high yields. The increase in conjugation reflects on the absorbance of the synthesized compounds revealing all pronounced bathochromic shifts and hyperchromic effects.

Full text of DOI:10.1590/S0103-50532012000400014

J. Braz. Chem. Soc., Vol. 23, No. 4, 688-693, 2012.
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Article
A
An Efficient Methodology for the Synthesis of 3-Styryl Coumarins
Sérgio M. A. Martins,a Paula C. S. Brancob and António M. D. R. L. Pereira*,a
aCentro de Química, Departamento de Química, Universidade de Évora,
Rua Romão Ramalho, 59, 7000-671 Évora, Portugal
bREQUIMTE, Departamento de Química, Faculdade de Ciências e Tecnologia (FCT),
Universidade Nova de Lisboa, 2829-516 Caparica, Portugal
Foi desenvolvida a arilação de Heck, regiosseletiva e altamente eficiente, de 3-vinil-6,7-
dimetoxicumarina, para a obtenção de 3-estiril cumarinas com bons a excelentes rendimentos. O
aumento da conjugação nos produtos sintetizados reflete na absorvância, revelando todos desvios
batocrômicos pronunciados e efeitos hipercrômicos.
Regioselective and highly efficient Heck arylation of 3-vinyl-6,7-dimethoxycoumarin has been
developed to afford 3-styryl coumarins in good to very high yields. The increase in conjugation
reflects on the absorbance of the synthesized compounds revealing all pronounced bathochromic
shifts and hyperchromic effects.
Keywords: 3-vinyl coumarin, 3-styryl coumarin, Heck reaction, palladium, fluorescent dyes
Introduction
synthesis of diversified 3-aryl coumarin using Heck
coupling reactions between coumarin and arylhalides.17
One can anticipate that the extension of the p-delocalized
system will lead to compounds showing a more promising
fluorescent behavior. In relation to this, the introduction of
an unsaturated fragment between the coumarin ring and
the aromatic group attached to the 3-position appears to be
an exciting task for which the Heck reaction is a suitable
tool. Previously,18 the palladium-catalysed insertion of
3-bromocoumarin into a number of alkenes, cycloalkenes
and alkynes was already tried. More recently the approach
of Bäuerle and co-workers19 for the parallel synthesis of
a 3-substituted coumarin compounds library rely also on
palladium catalyzed reaction between 3-bromocoumarin
and appropriated arylvinyl substrates. This work is
however limited to the unsubstituted 3-bromocoumarin
or to nitrogen substituted ones. A similar approach was
used by Kirsch and co-workers20 for the preparation of
oxygen substituent 3-styryl coumarins. The presence of
oxygen substituent groups in coumarins is promising
in relation to likely biological activity. Starting with
6,7-dihydroxycoumarin (esculetin) a natural product
with high biological activity4 we propose to use
Heck coupling reaction into the esculetin derivative,
3-vinyl-6,7-dimethoxycoumarin and 3-bromo-6,7-
dimethoxycoumarin, to afford 3-styryl coumarins.
Coumarins (or benzopyranones), whether naturally
occurring or synthetic, have attracted the interest of the
scientific community due to their broad pharmacological
activities,1 suchasantiprotozoal,2 anticancer,3 antibacterial,4
among others.5 Depending on the nature and substitution
pattern, coumarins show exceptional optical properties,6
as they constitute the largest class of fluorescent dyes,7
widely used as emission layers in organic light-emitting
diodes (OLED),8 optical brighteners,9 nonlinear optical
chromophores,10 fluorescent whiteners,11 fluorescent
labels and probes for physiological measurement12 and
more recently, in labelling13 and caging.14 Developments
from the last decade show that the introduction of
appropriated substituents into the coumarin ring
contribute to structures with improved photophysical
and spectroscopic proprieties.15 Many articles dealing
with their synthesis, reactivity and spectral profile have
been published. In particular, it seems that the presence
of an aryl or heteroaryl moiety on the 3-position of the
coumarinic system induces specific activities.16 We have
recently reported a particularly useful, easy and concise
*e-mail: amlp@uevora.pt

Vol. 23, No. 4, 2012
Martins et al.
689
Results and Discussion
Also, and as expected, iodo halides gave a better result, with
an increment of approximately 3 fold more than bromo
halides (Table 1) which reflects the easiness of the oxidative
addition of ArI to the palladium(0) complex.24
The strategy for the synthesis of 3-styryl substituted
coumarins (1a-d) was outlined by two different synthetic
routes via Heck coupling reactions (Scheme 1): routeA, the
halogenated counterpart is the coumarin (2) and route B,
the vinylcoumarin (3) is the substrate for the insertion
reaction of aryl halides.
To carry out the synthesis of 3-styryl coumarins the
synthesis of 3-bromo-6,7-dimethoxycoumarin21 (2) was
essential which was accomplished with oxone22 and HBr
on reaction with 6,7-dimethoxicoumarin (4) (Scheme 2).
Compound 2 was obtained in high yield (96%). The
6,7-dimethoxycoumarin (4) was easily obtained by
methylation with diazomethane of 6,7-dihydroxycoumarin
(esculetin). Subsequent Suzuki cross-coupling reaction
of 2 with potassium vinyltrifluoroborate23 allowed
6,7-dimethoxy-3-vinylcoumarin (3), the scaffold used on
route B, to be obtained in 95% yield (Scheme 2).
With both substrates in hand we endeavor a set of
palladium coupling reactions. To substrate 2, were applied
several Heck catalyst systems including those referred in
literature18-20 but the results were as discouraging as those
here presented in Table 1 (route A). These results are
consistent with the reactivity of coumarins at the 3-position
that is largely dependent on the substitution pattern as
any change on the arrangement of substituents leads to
unpredictable results. Comparing both results obtained in
route A and B we found that route B (although involving
one more step) provide us with a more clean reaction which
facilitates products isolation and purification allowing the
3-styrylcoumarins to be obtained in higher yields (Table 1).
Table 1. Yields of 3-styrylcoumarins (1)
route B / %
Compound
route A / %
X = Br
25
X = I
88
1a
1b
1c
1d
85
10
37
96
24
32
90
trace
15
52
The method proved to have applicability as varying R
with electron-withdrawing and electron-donating groups
(Scheme 1) diverse compounds could be synthesized in a
straightforward procedure. The electronic delocalization
induced by the methoxy groups at the 6 and 7-positions
allows the coumarin to have a distinctive behavior for
the Heck coupling reactions which enhances this work
and make it very useful for this particular family of
compounds. Likewise this work presents an interesting
approach to generate 3-vinyl coumarins as it relies in
natural available substrates, which complements our
recently reported procedure which is dependent on the
availability of 2-hydroxy aldehydes.25 Also both highlight
the importance of 3-vinyl coumarins for the synthesis of
diverse 3-styryl coumarins. The Heck catalytic system
involving CH3CO2Ag as sequestering agent of halide,
indicates a cationic mechanism for the coordination-
insertion step, i.e., the coordination of 3 should take place
R
MeO
MeO
Br
O
+
R
O
2
MeO
Pd(Ph3)4 (0.5 mol%)
AgOAc, DMF, (80 ºC, 72 h)
MeO
O
O
MeO
MeO
R
1a, R = H
1b, R = NO2
+
1c, R = CHO
1d, R = OMe
O
O
X
X = Br, I
3
Scheme 1. Synthesis of 3-styryl coumarins (1) by Heck reaction through halogenated coumarins (route A) and vinyl coumarins (route B).
MeO
R
MeO
MeO
MeO
MeO
Br
O
PdCl2(dppf).CH2Cl2 (2 mol%)
CH2CHBF3K, NEt3, n-PrOH
OXONE
HBr
MeO
O
O
O
O
O
4
2 (96%)
3 (95%)
Scheme 2. Synthesis of 3-bromo-6,7-dimethoxycoumarin (2) and 3-vinyl-6,7-di-methoxycoumarin (3).

690
An Efficient Methodology for the Synthesis of 3-Styryl Coumarins
J. Braz. Chem. Soc.
+
+
+
Coumarin
+
- X-
+X-
Ph3P PPh3
Pd
Ph3P PPh3
Ph3P PPh3
Ph3P PPh3
Pd
Pd
Pd
Ar
Coumarin
Ar
Ar
X
Ar
Coumarin
-
Coumarin
5
6
Scheme 3. Proposed mechanism for the coordination-insertion step (route B).
via dissociation of the anionic ligand (X–), and a cationic
palladium(II) complex 6 is formed (Scheme 3).24
Conclusions
The reactivity of the cationic complex 5 depends on
the charge density of the unsaturated system reacting
faster with electron rich ones which is the case of the vinyl
coumarin 3 (poor π-acceptors and good σ-donors). The
faster formation of 6 will account for the success of the
methodology. In both cases the reaction is regioselective
and the 2’-arylethenyl coumarins are obtained exclusively.
Changing reaction conditions as the amount of catalyst,
the base and the solvent revealed that the system
6,7-dimethoxy-3-vinylcoumarin (3) (1.1 equiv.) / aryl
halide (1.0 equiv.) / Pd(PPh3)4 (5 mol %) / CH3CO2Ag
(1.1 equiv.) / DMF / 80 ºC / 72 h, was the most efficient to
furnish the desired 3-styryl coumarins 1. The increase in
conjugation reflects on the absorbance of the synthesized
compounds, revealing all pronounced bathochromic shifts
and hyperchromic effects (Table 2, Figure 1).
In summary, with the objective to increase the
delocalized p-electron system, new 3-styrylcoumarin
derivatives with potential industrial applications, such
as new antioxidants and fluorescent chemosensors, were
developed by a simple and efficient synthetic strategy
involving Heck coupling reactions. The starting material
for these reactions, the 6,7-dihydroxycoumarin, is a natural
product with high biological activity which can perspective
these compounds as promising ones.
Experimental
All commercial reagents were used as received unless
otherwise mentioned. For analytical and preparative thin-
layer chromatography, Merck, 0.2 mm and 0.5 mm Kieselgel
GF 254 percoated were used, respectively. The spots were
visualized using UV light and phosphomolybdic acid
solution followed by heating. Medium performance liquid
chromatography and flash column chromatography were
performed using Merck, Kieselgel 60 with 0.063-0.200 mm
and 0.040-0.063 mm, respectively. UV-Vis absorption
spectra were recorded on a Thermo Electron Corporation
(Nicolet Evolution 300) spectrophotometer for solutions
in acetonitrile. 1H and 13C NMR spectra were recorded on
a Bruker ARX 400 spectrometer at 400 and 100.62 Hz,
Table 2. Absorption properties of selected coumarins
Coumarin
λmaxa / nm
342
εmaxa / (L mol-1 cm-1)
12580
4
2
356
17370
3
361
20280
1a
374
25120
1b
408
32650
1
1c
398
29720
respectively. H shifts are reported relative to internal
TMS. Carbon shifts are given relative to the 13C signal
of CDCl3 (δ 77.0 ppm) or (CD3)2CO (δ 29.8 ppm) as
reference. Mass spectra were recorded at the Laboratório
deAnálises, Requimte, Faculdade de Ciências e Tecnologia,
Universidade Nova de Lisboa using a Micromass GC-TOF
apparatus and the high resolution mass spectra were
recorded at the Mass Spectrometry Unit at the University
of Santiago de Compostela, Spain. The electron impact
mass spectra were recorded using a magnetic Micromass
Autospec apparatus.
1d
392
28880
alongest wavelength transition.
Procedure for the bromination of 6,7-dimethoxycoumarin
with oxone® and HBr
To a mixture of 6,7-dimethoxycoumarin (619 mg,
3.0 mmol, 1.0 equiv.) and oxone® (1.29 g, 4.2 mmol)
Figure 1. UV-Vis spectra of the 3-styryl coumarins and their precursor
(2.5×10-5 mol L-1, in acetonitrile).

Vol. 23, No. 4, 2012
Martins et al.
691
in CH2Cl2 (12 mL) was added 2 mol L-1 HBr (3.3 mL,
6.6 mmol) in one portion resulting a dark red colored
solution. After stirring 16 h at r.t., the color disappeared
and Et3N (1.25 mL, 9.0 mmol) was added cautiously.After
stirring for further 1 h, the reaction mixture was diluted with
CH2Cl2, and washed with H2O. The organic layer was dried
(Na2SO4), filtered, and concentrated under vacuum. The
residue was purified by flash column chromatography on
silica gel (230-400 mesh; hexane/CH2Cl2 gradient) to yield
3-bromo-6,7-dimethoxycoumarin (821 mg, 2.88 mmol,
96%).
on silica gel (230-400 mesh; hexane/CH2Cl2 gradient) to
afford the corresponding products.
3-Vinyl-6,7-dimethoxycoumarin (3)
1H NMR (400 MHz, CDCl3): 3.91 (s, 3H, OCH3), 3.94
(s, 3H, OCH3), 5.41 (d, 1H, J 11.3 Hz, H-2’), 6.11 (d,1H,
J 17.6 Hz, H-2’’), 6.69 (dd, 1H, J 17.6, 11.3 Hz, H-1’),
6.82 (s, 1H, H-8), 6.86 (s, 1H, H-5), 7.63 (s, 1H, H-4).
13C NMR (100 MHz, CDCl3): 56.3 (2×OCH3), 99.6 (C-8),
107.8 (C-5), 111.9 (C-4a), 118.1 (C-2’), 112.0 (C-3), 130.7
(C-1’), 137.7 (C-4), 146.4 (C-6), 149.1 (C-8a), 152.6 (C-7),
160.6 (C-2). MS (EI+) m/z (%): 232 [M]+ (100).
Procedure for the Suzuki reaction of 3-bromo-6,7-
dimethoxycoumarin and potassium vinyltrifluoroborate
(E)-6,7-Dimethoxy-3-styrylcoumarin (1a)
1H NMR (400 MHz, CDCl3): 3.93 (s, 3H, OCH3),
3.94 (s, 3H, OCH3), 6.83 (s, 1H, H-8), 6.88 (s, 1H, H-5),
7.10 (d, 1H, J 16.3 Hz, H-1’), 7.26-7.29 (m, 1H, H-6’),
7.34-7.37 (m, 2H, H-5’, H-7’), 7.51-7.53 (m, 2H, H-4’,
H-8’), 7.54 (d, 1H, J 16.3 Hz, H-2’), 7.73 (s, 1H, H-4).
13C NMR (100 MHz, CDCl3): 56.3 (2×OCH3), 99.6 (C-8),
107.7 (C-5), 112.3 (C-4a), 122.0 (C-3), 122.4 (C-1’), 126.8
(C-4’, C-8’), 128.1 (C-6’), 128.7 (C-5’, C-7’), 132.3 (C-2’),
137.1 (C-4, C-3’), 146.5 (C-6), 148.8 (C-8a), 152.5 (C-7),
160.8 (C-2). MS (EI+) m/z (%): 308 [M]+ (100). HRMS
(EI+) calc. for C19H16O4 [M]+ 308.1049, found 308.1049.
Under an nitrogen atmosphere, a mixture of
potassium vinyltrifluoroborate (60 mg, 0.448 mmol),
PdCl2(dppf).CH2Cl2 (6 mg, 0.007 mmol), 3-bromo-6,7-
dimethoxycoumarin (2) (106 mg, 0.373 mmol), and
NEt3 (37.7 mg, 0.373 mmol) in n-PrOH (6 mL) was
stirred at reflux for a period of 15 min. After cooling
to r.t., the reaction mixture was diluted with CH2Cl2, and
washed with H2O. The organic layer was dried (Na2SO4),
filtered, and concentrated under vacuum. The residue was
purified by flash column chromatography on silica gel
(230-400 mesh; CH2Cl2/EtOAc gradient) to yield 3-vinyl-
6,7-dimethoxycoumarin (3) (82 mg, 0.353 mmol, 95%).
(E)-6,7-Dimethoxy-3-(4-nitrostyryl)coumarin (1b)
1H NMR (400 MHz, CDCl3): 3.95 (s, 3H, OCH3), 3.97
(s, 3H, OCH3), 6.86 (s, 1H, H-8), 6.90 (s, 1H, H-5), 7.20
(d, 1H, J 16.2, H-1’), 7.64 (d, 2H, J 8.8, H-4’, H-8’), 7.70
(d, 1H, J 16.2, H-2’), 7.78 (s, 1H, H-4), 8.21 (d, 2H, J 8.8,
H-5’, H-7’). 13C NMR (100 MHz, CDCl3): 56.4 (2xOCH3),
99.6 (C-8), 107.8 (C-5), 112.0 (C-4a), 120.7 (C-3), 124.1
(C-5’, C-7’), 127.1 (C-1’,C-4’, C-8’), 130.0 (C-2’), 139.7
(C-4), 143.7 (C-3’), 146.7 (C-6), 147.0 (C-6’), 149.3
(C-8a), 153.3 (C-7), 160.3 (C-2). MS (EI+) m/z (%): 353
[M]+ (48), 323 [M-(2×CH3)]+ (100). HRMS (EI+) calc. for
C19H15NO6 [M]+ 353.0899, found 353.0900.
General procedure for the Heck reactions
Route A
Under an nitrogen atmosphere, a mixture of 3-bromo-
6,7-dimethoxycoumarin (2) (285 mg, 1.0 mmol, 1.0 equiv.),
styrene derivative (1.1 equiv.), Pd(PPh3)4 (5 mol %), and
CH3CO2Ag (1.1 equiv.) in DMF (2.0 mL) was stirred at
80 ºC for a period of 72 h. The reaction mixture was diluted
with EtOAc, and washed with H2O. The organic layer was
dried (Na2SO4), filtered, and concentrated under vacuum.
The residue was purified by flash column chromatography
on silica gel (230-400 mesh; hexane/CH2Cl2 gradient) to
afford the corresponding products.
(E)-6,7-Dimethoxy-3-(4-formylstyryl)coumarin (1c)
1H NMR (400 MHz, CDCl3): 3.92 (s, 3H, OCH3), 3.95
(s, 3H, OCH3), 6.84 (s, 1H, H-8), 6.89 (s, 1H, H-5), 7.20
(d, 1H, J 16.3, H-1’), 7.63 (d, 1H, J 16.3, H-2’), 7.64 (d,
2H, J 7.6, H-4’, H-8’), 7.78 (s, 1H, H-4), 7.85 (d, 2H, J 7.6,
H-5’, H-7’), 9.97 (CHO). 13C NMR (100 MHz, CDCl3):
56.3 (OCH3), 56.4 (OCH3), 99.6 (C-8), 107.9 (C-5), 112.1
(C-4a), 121.1 (C-3), 126.0 (C-1’), 127.1 (C-5’, C-7’), 130.1
(C-4’, C-8’), 131.0 (C-2’), 135.6 (C-6’), 138.9 (C-4), 143.2
(C-3’), 146.7 (C-6), 149.2 (C-8a), 153.1 (C-7), 160.4 (C-2),
191.5 (CHO). MS (EI+) m/z (%): 336 [M]+ (72). HRMS
(EI+) calc. for C20H16O5 [M]+ 336.0998, found 336.1006.
Route B
Under an nitrogen atmosphere, a mixture of 3-vinyl-
6,7-dimethoxycoumarin (3) (232 mg, 1.0 mmol, 1.1 equiv.),
aryl halide (1.0 equiv.), Pd(PPh3)4 (5 mol %), and
CH3CO2Ag (1.1 equiv.) in DMF (2.0 mL) was stirred at
80 ºC for a period of 72 h. The reaction mixture was diluted
with EtOAc, and washed with H2O. The organic layer was
dried (Na2SO4), filtered, and concentrated under vacuum.
The residue was purified by flash column chromatography

692
An Efficient Methodology for the Synthesis of 3-Styryl Coumarins
J. Braz. Chem. Soc.
(E)-6,7-Dimethoxy-3-(4-methoxylstyryl)coumarin (1d)
1H NMR (400 MHz, CDCl3): 3.83 (3H, s, OCH3), 3.93
(3H, s, OCH3), 3.94 (3H, s, OCH3), 6.83 (1H, s, H-8), 6.87
(1H, s, H-5), 6.89 (2H, d, J 8.6, H-5’, H-7’), 6.97 (1H, d,
J 16.2, H-1’), 7.46 (2H, d, J 8.6, H-4’, H-8’), 7.49 (1H,
d, J 16.2, H-2’), 7.68 (1H, s, H-4). 13C NMR (100 MHz,
CDCl3): 55.3 (OCH3), 56.3 (2xOCH3), 99.6 (C-8), 107.6
(C-5), 112.4 (C-4a), 114.1 (C-5’, C-7’), 120.2 (C-1’), 122.2
(C-3), 128.1 (C-4’, C-8’), 129.9 (C-3’), 131.8 (C-2’), 136.1
(C-4), 146.5 (C-6), 148.6 (C-8a), 152.3 (C-7), 159.7 (C-6’),
160.9 (C-2). MS (EI+) m/z (%): 338 [M]+ (100). HRMS
(EI+) calc. for C20H18O5 [M]+ 338.1154 found 338.1156.
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