New developments in the synthesis of (e)-8-styrylflavones

Article abstract of DOI:10.1055/s-0034-1380208

A novel route for the synthesis of new (E)-8-styrylflavones is reported. This methodology involves the regio- and stereoselective Heck cross-coupling reaction of 8-iodoflavones and styrene derivatives. The Heck precursors, 8-iodoflavones, were obtained through an efficient regioselective one-pot oxidative cyclization-iodination reaction of (E)-2′-hydroxychalcones by applying the iodine/dimethyl sulfoxide system.

Full text of DOI:10.1055/s-0034-1380208

SYNLETT
0
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6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
© Georg Thieme Verlag Stuttgart · New York
2015, 26, 1379–1384
letter
1379
O. D. C. C. De Azevedo et al.
Letter
Synlett
New Developments in the Synthesis of (E)-8-Styrylflavones
OMe
Orlando D. C. C. De Azevedo
Raquel S. G. R. Seixas*
Artur M. S. Silva*
R2
Heck reaction
one-pot
oxidative cyclization-
iodination reaction
R1
R1
OMe
MeO
OMe
Department of Chemistry & QOPNA, University of Aveiro,
Campus Universitário de Santiago, 3810-193 Aveiro, Portugal
raquel.grevy@ua.pt
I
R1
MeO
O
O
O
PdCl2, K2CO3
TBAB, KCl
NMP, 100 °C
MeO
OMe
O
OMe
artur.silva@ua.pt
I2, DMSO
reflux
OMe
OMe
O
R2
OH
R1 = H, OMe
75–77%
87–93%
OMe
2 = H, OMe
R
Received: 14.03.2015
Accepted: 03.04.2015
In recent years, there have been reported several studies
on the application of Heck reactions in the synthesis of
alkenylated chromones and flavones (including styrylfla-
vones). Dawood performed the synthesis of 3-styryl-4H-
chromen-4-one through a Heck cross-coupling reaction of
3-bromo-4H-chromen-4-one with styrene using benzothi-
azole oxime based palladium(II) precatalysts, in the pres-
ence of triethylamine, under thermal and microwave heat-
ing.12 Patonay et al. have demonstrated that 3-, 6-, 7-, or 8-
bromochromones can be coupled successfully under modi-
fied Jeffery’s conditions to various terminal alkenes in a dia-
stereoselective fashion.13,14 Under similar conditions, 3-, 6-,
or 7-bromoflavones can also be treated with multiple ter-
minal alkenes, including styrene derivatives, to give the
corresponding alkenylated flavones in moderate to good
yields.15 Luthman et al. have efficiently coupled methyl ac-
rylate to the 3-, 6-, and 8-positions of flavone scaffolds us-
ing microwave heating as an alternative energy source.16
Silva et al. performed an efficient Heck cross-coupling reac-
tion of 3-bromoflavones with styrene derivatives, under
microwave irradiation, leading to the corresponding (E)-3-
styrylflavones.17 Besides Heck reaction, other methods for
the synthesis of styrylflavones are reported in the litera-
ture, including Wittig reaction of 3-methylflavone18 and
condensation of 1-(2-hydroxyphenyl)-3-phenylpropane-
1,3-diones with phenylacetaldehydes.19
Published online: 04.05.2015
DOI: 10.1055/s-0034-1380208; Art ID: st-2015-d0184-l
Abstract A novel route for the synthesis of new (E)-8-styrylflavones is
reported. This methodology involves the regio- and stereoselective
Heck cross-coupling reaction of 8-iodoflavones and styrene derivatives.
The Heck precursors, 8-iodoflavones, were obtained through an effi-
cient regioselective one-pot oxidative cyclization–iodination reaction of
(E)-2′-hydroxychalcones by applying the iodine/dimethyl sulfoxide sys-
tem.
Keywords palladium, Heck reaction, styrylflavones, iodoflavones, cy-
clodehydrogenation
Flavones are an important class of flavonoids based on a
2-aryl-4H-chromen-4-one framework.1,2 These compounds
are widespread in the plant kingdom as secondary metabo-
lites2 and can be found in all parts of plants.3 They are also
part of the human diet, being present in various herbs, veg-
etables, and fruits.4
Depending on their substitution pattern, flavones ex-
hibit several biological properties,5 being the antioxidant
activity one of the most explored.6,7 Easily dissociable phe-
nolic hydroxyl groups, maximum extended conjugated sys-
tem, and electron-donating substituents in the aromatic
rings are crucial structural features to a potent antioxidant
activity.8 Flavones possessing a 3′,4′-dihydroxy substitution
at the B ring are highly active antioxidants and, as the num-
ber of hydroxyl groups increases, their scavenging potential
also increases.9 Like flavones, 2- and 3-styrylchromones
(the vinylogues of flavones and isoflavones, respectively)
possess multiple activities with potential therapeutic appli-
cations.10,11
Iodoflavones can be excellent Heck precursors, and they
are typically iodinated at 3-, 6-, or 8-positions. Synthesis of
6,8-diiodoflavones can be performed by oxidative cycliza-
tion–iodination of 2′-benzyloxy-6′-hydroxychalcones with
iodine/dimethyl sulfoxide or by iodination of 5-hydroxy- or
5,7-dihydroxyflavones, using iodine/dimethyl sulfoxide20 or
I2 in a mixture of acetic acid/nitric acid,21 respectively. Al-
ternatively, 6,8-diiodoflavones can be synthesized by diace-
toxyiodobenzene-catalyzed iodination of 2′-hydroxychal-
cones with tetra-n-butylammonium iodide in acetic acid in
The interesting biological properties of flavones and
styrylchromones led us to attempt the synthesis of new fla-
vones bearing a styryl moiety.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 1379–1384

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O. D. C. C. De Azevedo et al.
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Synlett
the presence of sodium perborate as a terminal oxidant.22
The regioselective 8-iodination of 5,7-dibenzyloxyflavone
can be accomplished using iodine/dimethyl sulfoxide.23
Similarly, 5,7-dimethoxyflavone can be iodinated at 8-posi-
tion using iodine in a mixture of acetic acid/nitric acid,24 N-
iodosuccinimide,25 or iodine monochloride.26 On the other
hand, the regioselective 6-iodination of 5-hydroxy-7-me-
thoxyflavones can be performed using N-iodosuccinimide25
or iodine with thallium(I) salts.27 In addition, 3-iodofla-
vones may be synthesized by using iodine monochloride,28
iodine/cerium ammonium nitrate,29 lithium diisopropyl-
amide followed by iodine30 and bis(trifluoroacetoxyio-
do)benzene/iodine.31
In the present communication we report a new strategy
for the synthesis of novel (E)-8-styrylflavones based on the
selective one-pot oxidative cyclization–iodination of (E)-2′-
hydroxychalcones followed by the Heck reaction of the ob-
tained 8-iodoflavones (Scheme 1).
The preparation of the iodinated partner, in this case
the 8-iodoflavones, started with the selective dimethylation
of 2′,4′,6′-trihydroxyacetophenone (1) in good yield (82%),
following a modification of the Khanna and Seshadri’s
method (Scheme 1).10a,32,33 Then, (E)-2′-hydroxychalcones
3a,b34 were synthesized in good yields (77% and 61%, re-
R1
MeO
OMe
O
OMe
HO
OH
O
(i)
(ii)
3a R1 = H
R1
OH
OH
3b R1 = OMe
O
1
OMe
(iii)
2a R1 = H
OMe
2b R1 = OMe
R1
R2
4''
3''
5''
6''
OMe
I
2''
R1
3'
1''
MeO
O
β
OMe
(iv)
4'
2'
1'
α
8
R2
MeO
O
8a
5'
2
7
6'
OMe O
4
3
4a R1 = H
6
4a
OMe
5
4b R1 = OMe
7a R2 = H
7b R2 = OMe
OMe
O
8a R1 = H, R2 = H
8b R1 = OMe, R2 = H
isolated byproducts:
8c R1 = OMe, R2 = OMe
OMe
4'
3'
isolated byproducts:
I
2'
5'
7
5'''
4'''
MeO
7a
1'
MeO
O
R1
6'
6'''
6
α
2
1'''
1''
3'''
3'
2''
OMe
4'
5
3
OH
R2
3a
2'
1'
4
2'''
O
8
OMe
MeO
O
8a
5'
2
7
5
6'
OMe
3
4
6
I
4a
5
MeO
O
O
OMe
O
9a R1 = H, R2 = H
9b R1 = OMe, R2 = H
I
9c R1 = OMe, R2 = OMe
OMe
6
OMe
MeO
O
OMe
O
10
Scheme 1 Reagents and conditions: (i) Me2SO4, K2CO3, acetone, reflux, 20 min; (ii) NaOH (aq, 60%), MeOH, r.t., 3–4 h; (iii) I2, DMSO, reflux, N2, 45 min;
(iv) Pd cat., solvent, temperature, K2CO3, KCl, TBAB, 24 h, N2.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 1379–1384

1381
O. D. C. C. De Azevedo et al.
Letter
Synlett
spectively) by a base-catalyzed aldol condensation of the
obtained acetophenone with benzaldehyde derivatives
2a,b, using sodium hydroxide in methanol (Scheme 1).35
In order to prepare the iodinated flavones to be used as
Heck precursors we attempted the one-pot oxidative cy-
clization–iodination of (E)-2′-hydroxychalcones 3a,b by ap-
plying the I2/DMSO system. Optimatizion of reaction condi-
tions by changing the amount of iodine, temperature, and
reaction time, was performed based on the 1H NMR spectra
of the crude reaction mixture. Molar quantity of iodine is
determinant in the composition of the resulting reaction
mixture. Best results were achieved using one equivalent of
I2 in refluxing DMSO for 45 min.36 Under these conditions,
8-iodoflavone 4a was isolated in good yield (77%, Scheme
1). Increasing the amount of iodine to two or three equiva-
lents did not promote diiodination, resulting in lower yields
of 8-iodoflavone 4a together with an increase of degrada-
tion compounds and the identification of α-hydroxy-7-
iodo-4,4′,6-trimethoxyaurone 537 as a byproduct. Oxidative
cyclization–iodination reaction of (E)-2′-hydroxychalcone
3a can be performed at 130 °C, although better perfor-
mances were attained in refluxing DMSO. Increasing the re-
action time to 90 min led to a substantial decrease of 8-
iodoflavone 4a yield (43%) with no significant improvement
of 3,8-diiodo-4′,5,7-trimethoxyflavone 638 yield (4% → 9%),
resulting in higher degradation products. Under the opti-
mized conditions, 8-iodoflavone 4b39 was synthesized in
good yield (75%) from (E)-2′-hydroxychalcone 3b. It is wor-
thy to note that in all the assays performed the iodination
occurred regioselectively at C-8, the 6-iodoflavone isomer
was never isolated, which is consistent with related stud-
ies.21,23,24
Following our interest on the synthesis of new 8-styryl-
flavones, we studied the Heck reaction of 8-iodoflavones
4a,b with styrenes 7a,b. Optimization of the experimental
conditions was performed with 8-iodoflavone 4a and 4-
methoxystyrene 7a under Jeffery’s conditions, already de-
scribed for the coupling of bromoflavones with several
alkenes13,14 (Table 1, entries 1–9). Among the different pal-
ladium catalysts used, palladium(II) led generally to better
results than palladium(0) (Table 1, entries 1, 3–7). PdCl2
had the largest effect on the reaction yield giving the ex-
pected (E)-8-styrylflavone 8a40 in very good yield (83%, Ta-
ble 1, entry 7). Of the two polar aprotic solvents tested, 1-
methylpyrrolidin-2-one (NMP) had the best performance
leading to a slight improvement of (E)-8-styrylflavone 8a
yield (83% → 87%, Table 1, entries 7 and 8).
Table 1 Optimization of the Heck Reaction Conditions in the Synthesis
of (E)-8-Styrylflavones 8a–ca
Entry
Product
Catalyst
Solvent
Temp (°C) Yield (%)
1
2
8a
8a
8a
8a
8a
8a
8a
8a
8a
8b
8c
PdCl2(PPh3)2
PdCl2(PPh3)2
Pd2(dba)3
Pd(PPh3)4
Pd(acac)2
Pd(OAc)2
PdCl2
DMF
DMF
DMF
DMF
DMF
DMF
DMF
NMP
NMP
NMP
NMP
100
130
100
100
100
100
100
100
155
100
100
70
72
45
53
65
66
83
87
47
90
93
3
4
5
6
7
8
PdCl2
9
PdCl2
10
11
PdCl2
PdCl2
a All the reactions were performed in a 0.09 mmol scale of 8-iodoflavone 4
in the presence of the appropriate styrene 7 (0.45 mmol), Pd cat. (6 mol%),
K2CO3 (0.14 mmol), KCl (0.09 mmol), TBAB (0.14 mmol) for 24 h under N2.
use of PdCl2 (6 mol%), K2CO3 (1.5 equiv), KCl (1 equiv), TBAB
(1.5 equiv), and NMP at 100 °C.41 These optimized condi-
tions were applied to the other derivatives leading to (E)-8-
styrylflavones 8b and 8c in excellent yields (90% and 93%,
Table 1, entries 10 and 11).
Heck cross-coupling reaction of 8-iodoflavones 4a,b
with styrenes 7a,b is regioselective to the C-β of the styrene
which is activated by conjugation and less steric hindered,
although in most assays, 8-[1-(4-metoxyphenyl)vinyl]-
4′,5,7-trimethoxyflavone 9a,42 as well as 9b,c, were isolated
as byproducts in very low yields (traces to 11%).
4′,5,7-Trimethoxyflavone 10,43 formed by palladium-
catalyzed dehalogenation of 8-iodoflavone 4a, was only ob-
served when using PdCl2(PPh3)2 or Pd(PPh3)4 (2% and <13%,
respectively, Table 1, entries 1 and 4).
1
The most important features in the H NMR spectra of
(E)-8-styrylflavones 8a–c are the presence of: i) two sin-
glets at δ = 6.62–6.65 and 6.46–6.48 ppm assigned to the
resonances of H-3 and H-6, respectively, and ii) two dou-
blets at δ = 7.27–7.30 and 7.40–7.45 ppm assigned to the
resonances of H-α and H-β, respectively, with a coupling
constant of J = ca. 16 Hz which indicates a trans configura-
tion of this vinylic system. HMBC correlations between H-α
and C-7 (which correlates also with methoxyl protons) and
C-8a allowed the confirmation of the 8-[2-(4-metoxyphe-
nyl)vinyl] substituent (Figure 1). No correlation between H-
α and C-5 was observed.
In conclusion, a new synthetic route to (E)-8-styrylfla-
vones was developed, based firstly on an efficient one-pot
oxidative cyclization–iodination of (E)-2′-hydroxychalcones
leading to the corresponding 8-iodoflavones in a regioselec-
tive fashion, and secondly on the regio- and stereoselective
Increasing the temperature from 100 °C to 130 °C when
using PdCl2(PPh3)2 in DMF slightly enhanced the yield of 8a
(70% → 72%, Table 1, entry 2), although when using PdCl2 in
NMP the increase of temperature to 155 °C led to a lower
yield of (E)-8-styrylflavone 8a (47%, Table 1, entry 9) to-
gether with the presence of more degradation products.
The optimized reaction conditions therefore consists in the
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 1379–1384

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Synlett
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H3C
O
R2
4''
3''
5''
6''
2''
(10) For biological activities of 2-styrylchromones, see: (a) Shaw, A.
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R1
β
3'
H
O
4'
2'
α
H
CH3
8
O
O
5'
2
7
H3C
8a
4a
6'
3
4
6
H
5
O
O
H3C
8
Figure 1 Main HMBC connectivities of compounds 8
synthesis of (E)-8-styrylflavones by the Heck cross-cou-
pling reaction of 8-iodoflavones and styrene derivatives
with excellent overall yields.
Acknowledgment
Thanks are due to the University of Aveiro, Portuguese Foundation for
Science and Technology (FCT), European Union, QREN, FEDER and
COMPETE for funding the QOPNA research unit (project
PEstC/QUI/UI0062/2013) and the Portuguese NMR Network. R.S.G.R.
Seixas
also
thanks
FCT
for
her
post-doctoral
grant
(SFRH/BPD/74282/2010).
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Lim, K. M.; Lee, C. H.; Chung, S. Bioorg. Med. Chem. Lett. 2003, 13,
413.
(32) Khanna, R. N.; Seshadri, T. R. Indian J. Chem. 1963, 1, 385.
(33) Optimized Experimental Procedure for the Synthesis of 2′-
Hydroxy-4′,6′-dimethoxyacetophenone
(37) Physical Data of α-Hydroxy-7-iodo-4,4′,6-trimethoxyaurone
(5)
White powder. 1H NMR (300.13 MHz, CDCl3): δ = 3.83 (s, 3 H, 4′-
OCH3), 4.03 and 4.06 (2 s, 2 × 3 H, 5-OCH3 and 7-OCH3), 6.18 (s,
1 H, H-5), 6.84 (d, 2 H, J = 8.9 Hz, H-3′,5′), 7.77 (d, 2 H, J = 8.9 Hz,
H-2′,6′) ppm. 13C NMR (75.47 MHz, CDCl3): δ = 55.6 (4′-OCH3),
56.6 and 57.3 (4- and 6-OCH3), 58.2 (C-7), 90.0 (C-5), 101.3 (C-
2), 103.6 (C-3a), 114.4 (C-3′,5′), 124.3 (C-1′), 132.2 (C-2′,6′),
161.0 (C-4 or C-6), 165.0 (C-4′), 168.2 (C-4 or C-6), 172.2 (C-7a),
188.5 (C-α), 190.5 (C-3) ppm. ESI+-MS: m/z (%) = 493 (100) [M +
K]+.
K2CO3 (7.23 g, 52.32 mmol) and Me2SO4 (2.48 mL, 26.16 mmol)
were added to a solution of 2′,4′,6′-trihydroxyacetophenone (1,
2.00 g, 11.89 mmol) in acetone (50 mL). The reaction mixture
was refluxed for 20 min under nitrogen atmosphere. After that,
K2CO3 was filtered off, the acetone evaporated, and the residue
recrystallized in EtOH affording the 2′-hydroxy-4′,6′-dime-
thoxyacetophenone in good yield (82%, 1.91 g).
(38) Physical Data of 3,8-Di-iodo-4′,5,7-trimethoxyflavone (6)
White powder. 1H NMR (300.13 MHz, CDCl3): δ = 3.90 (s, 3 H, 4′-
OCH3), 4.03 (s, 6 H, 5,7-OCH3), 6.45 (s, 1 H, H-6), 7.03 (d, 2 H, J =
8.8 Hz, H-3′,5′), 8.02 (d, 2 H, J = 8.8 Hz, H-2′,6′) ppm. 13C NMR
(75.47 MHz, CDCl3): δ = 55.5 (4′-OCH3), 56.6 and 56.8 (5- and 7-
OCH3), 63.9 (C-8), 89.2 (C-3), 92.0 (C-6), 106.2 (C-4a), 113.4 (C-
3′,5′), 126.2 (C-1′), 132.0 (C-2′,6′), 157.6 (C-8a), 161.7 (C-2, C-5,
C-7, or C-4′), 161.8 (C-2, C-5, C-7, or C-4′), 161.9 (C-2, C-5, C-7,
or C-4′), 162.9 (C-5 or C-7), 172.7 (C-4) ppm. ESI+-MS: m/z
(%) = 565 (94) [M + H]+, 587 (100) [M + Na]+.
(39) Physical Data of 8-Iodo-3′,4′,5,7-tetramethoxyflavone (4b)
Pale yellow powder; mp 273–275 °C. 1H NMR (300.13 MHz,
CDCl3): δ = 3.97 (s, 3 H, 4′-OCH3), 4.00 (s, 3 H, 3′-OCH3), 4.04 (s,
6 H, 5- and 7-OCH3), 6.44 (s, 1 H, H-6), 6.67 (s, 1 H, H-3), 6.99 (d,
1 H, J = 9.0 Hz, H-5′), 7.63–7.67 (m, 2 H, H-2′,6′) ppm. 13C NMR
(75.47 MHz, CDCl3): δ = 56.08 and 56.14 (3′- and 4′-OCH3), 56.6
and 56.8 (5- and 7-OCH3), 64.9 (C-8), 91.8 (C-6), 107.0 (C-3),
109.2 (C-2′), 109.9 (C-4a), 111.2 (C-5′), 119.9 (C-6′), 123.6 (C-1′),
149.2 (C-3′), 151.8 (C-4′), 157.5 (C-8a), 160.9 (C-2), 162.0 and
162.6 (C-5 and C-7), 177.5 (C-4) ppm. ESI+-MS: m/z (%) = 469
(100) [M + H]+, 491 (11) [M + Na]+, 959 (40) [2M + Na]+. Anal.
Calcd (%) for C19H17IO6: C, 48.74; H, 3.66. Found: C, 48.90; H,
3.64.
(34) Physical Data of (E)-2′-Hydroxy-3,4,4′,6′-tetramethoxychal-
cone (3b)
1
Yellow needles; mp 156–157 °C. H NMR (300.13 MHz, CDCl3):
δ = 3.84 and 3.92 (2 s, 2 × 3 H, 4′- and 6′-OCH3), 3.94 (s, 3 H, 4-
OCH3), 3.95 (s, 3 H, 3-OCH3), 5.98 (d, 1 H, J = 2.3 Hz, H-5′), 6.12
(d, 1 H, J = 2.3 Hz, H-3′), 6.90 (d, 1 H, J = 8.4 Hz, H-5), 7.13 (d, 1 H,
J = 1.8 Hz, H-2), 7.22 (dd, 1 H, J = 1.8, 8.4 Hz, H-6), 7.78 (AB, 1 H,
J = 15.6 Hz, H-β), 7.83 (AB, 1 H, J = 15.6 Hz, H-α), 14.41 (s, 2′-OH,
1 H) ppm. 13C NMR (75.47 MHz, CDCl3): δ = 55.6, 55.8, 55.9, and
56.0 (3-, 4-, 4′-, and 6′-OCH3), 91.3 (C-5′), 93.8 (C-3′), 106.3 (C-
1′), 110.4 (C-2), 111.2 (C-5), 122.6 (C-6), 125.4 (C-α), 128.6 (C-
1), 142.7 (C-β), 149.1 (C-3), 151.1 (C-4), 162.4 and 166.1 (C-4′
and C-6′), 168.4 (C-2′), 192.5 (C=O) ppm. ESI+-MS: m/z (%) = 345
(17) [M + H]+, 367 (100) [M + Na]+, 711 (5) [2M + Na]+. Anal.
Calcd (%) for C19H20O6: C, 66.27; H, 5.85. Found: C, 65.99; H,
5.77.
(35) General Optimized Experimental Procedure for the Synthe-
sis of (E)-2′-Hydroxychalcones 3a,b
NaOH (aq, 60%, 37 mL) was added to a solution of 2′-hydroxy-
4′,6′-dimethoxyacetophenone (1.50 g, 7.645 mmol) in MeOH
(37 mL; in the case of derivative a), or in MeOH–DMSO (v/v,
37:4.5 mL; in the case of derivative b). After that, the appropri-
ate benzaldehyde 2a,b (15.04 mmol) was added, and the reac-
tion mixture was stirred for 3 h (derivative a) and 4 h (deriva-
tive b) at r.t. Then, the mixture was poured into ice (50 g) and
H2O (100 mL) and the pH adjusted to 4 with a solution of HCl
(20%). After filtration, the precipitate was taken in CH2Cl2,
washed repeatedly with a sat. solution of KHCO3 (1 × 300 mL)
and H2O (3 × 300 mL), and the organic layer was dried over
anhydrous Na2SO4. Subsequently, after solvent evaporation, the
residue was recrystallized in EtOH giving the correspondent
(E)-2′-hydroxychalcones 3a,b in good yields [3a (77%, 1.78 g);
3b (61%, 1.61 g)].
(40) Physical Data of (E)-8-[2-(4-Methoxyphenyl)vinyl]-4′,5,7-tri-
methoxyflavone (8a)
Pale yellow powder; mp 224–225 °C. 1H NMR (300.13 MHz,
CDCl3): δ = 3.86 (s, 3 H, 4′′-OCH3), 3.88 (s, 3 H, 4′-OCH3), 4.03 (s,
3 H, 5-OCH3), 4.04 (s, 3 H, 7-OCH3), 6.46 (s, 1 H, H-6), 6.62 (s, 1
H, H-3), 6.93 (d, 2 H, J = 8.7 Hz, H-3′′,5′′), 6.98 (d, 2 H, J = 8.8 Hz,
H-3′,5′), 7.30 (d, 1 H, J = 16.6 Hz, H-α), 7.45 (d, 1 H, J = 16.6 Hz,
H-β), 7.48 (d, 2 H, J = 8.7 Hz, H-2′′,6′′), 7.86 (d, 2 H, J = 8.8 Hz, H-
2′,6′) ppm. 13C NMR (75.47 MHz, CDCl3): δ = 55.4 and 55.5 (4′-
and 4′′-OCH3), 56.0 and 56.4 (5- and 7-OCH3), 91.6 (C-6), 107.4
(C-3), 108.0 (C-8), 109.1 (C-4a), 114.2 (C-3′′,5′′), 114.5 (C-3′,5′),
115.7 (C-α), 124.2 (C-1′), 127.4 (C-2′′,6′′), 127.9 (C-2′,6′), 131.3
(C-1′′), 132.4 (C-β), 156.2 (C-8a), 159.2 (C-4′′), 159.7 (C-5), 161.0
(C-2), 161.2 (C-7), 162.0 (C-4′), 178.2 (C-4) ppm. ESI+-MS: m/z
(%) = 445 (100) [M + H]+, 467 (11) [M + Na]+, 911 (60) [2M +
Na]+. EI+-HRMS: m/z calcd for [C27H24O6]: 444.1573; found:
444.1572.
(36) General Optimized Experimental Procedure for the Synthe-
sis of 8-Iodoflavones 4a,b
I2 (0.100 g; 0.3181 mmol) was added to a solution of the appro-
priate (E)-2′-hydroxychalcone 3a,b (0.3181 mmol) in DMSO (1.0
mL), and the reaction mixture was refluxed for 45 min under N2
atmosphere. After that, the reaction mixture was poured into
ice (25 g), H2O (50 mL), and Na2S2O3·5H2O (1 g). The obtained
solid was filtered, taken in CH2Cl2 (100 mL), and washed with
Na2S2O3 (aq, 20%) (100 mL) and H2O (3 × 100 mL). The organic
layer was dried over anhydrous Na2SO4 concentrated and puri-
(41) General Optimized Experimental Procedure for the Synthe-
sis of (E)-8-Styrylflavones 8a–c
The appropriate styrene 7a,b (0.45 mmol) was added to a
mixture of the appropriate 8-iodoflavone 4a,b (0.09 mmol), KCl
(0.09 mmol), TBAB (0.14 mmol), K2CO3 (0.14 mmol), and PdCl2
(5.4 μmol) in NMP (1.5 mL). Each reaction mixture was heated
to 100 °C for 24 h under N2 atmosphere. After this time, the
mixture was poured into H2O (100 mL) and the pH was adjusted
to 5 by adding dropwise a solution of HCl (50%). Afterwards, the
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 1379–1384

1384
O. D. C. C. De Azevedo et al.
Letter
Synlett
obtained residue was extracted with CH2Cl2 (100 mL), washed
with H2O (4 × 200 mL) and the organic layer dried over anhy-
drous Na2SO4. To remove any traces of NMP, the residue was dis-
solved in toluene and evaporated to dryness. Purification by TLC
[two mixtures were used as eluent: first CH2Cl2–MeOH (9:1)
and then CH2Cl2–acetone (4:1)] with subsequent recrystalliza-
tion in EtOH lead to (E)-8-styrylflavones 8a–c in good yields [8a
(87%, 34.8 mg); 8b (90%, 38.4 mg); 8c (93%, 42.2 mg)].
H-3′′′,5′′′), 7.32 (d, 2 H, J = 8.8 Hz, H-2′′′,6′′′), 7.46 (d, 2 H, J = 8.9
Hz, H-2′,6′) ppm. ESI+-MS: m/z (%) = 445 (100) [M + H]+, 467 (32)
[M + Na]+, 911 (19) [2M + Na]+. ESI+-HRMS: m/z calcd for
[C27H24O6 + H+] 445.1646; found: 445.1639.
(43) Physical Data of 4′,5,7-Trimethoxyflavone (10)
White powder; mp 154–156 °C. 1H NMR (300.13 MHz, CDCl3): δ
= 3.88 (s, 3 H, 4′-OCH3), 3.91 (s, 3 H, 7-OCH3), 3.96 (s, 3 H, 5-
OCH3), 6.37 (d, 1 H, J = 2.2 Hz, H-6), 6.56 (d, 1 H, J = 2.2 Hz, H-8),
6.60 (s, 1 H, H-3), 7.00 (d, 2 H, J = 8.8 Hz, H-3′,5′), 7.83 (d, 2 H, J =
8.8 Hz, H-2′,6′) ppm. 13C NMR (75.47 MHz, CDCl3): δ = 55.5 (4′-
OCH3), 55.8 (7-OCH3), 56.5 (5-OCH3), 92.8 (C-8), 96.1 (C-6),
107.7 (C-3), 109.2 (C-4a), 114.4 (C-3′,5′), 123.9 (C-1′), 127.6 (C-
2′,6′), 159.9 (C-8a), 160.1 (C-2), 160.9 (C-5), 162.0 (C-4′), 163.9
(C-7), 177.7 (C-4) ppm. ESI+-MS: m/z (%) = 313 (43) [M + H]+,
335 (27) [M + Na]+, 647 (100) [2M + Na]+.
(42) Physical Data of 8-[1-(4-Methoxyphenyl)vinyl]-4′,5,7-trime-
thoxyflavone (9a)
Pale yellow powder; mp 151–152 °C. 1H NMR (300.13 MHz,
CDCl3): δ = 3.78, 3.82, 3.88, and 4.05 (4 s, 4 × 3 H, 4′-, 4′′′-, 5-,
and 7-OCH3), 5.25 (d, 1 H, J = 0.7 Hz, H-2′′a), 6.02 (d, 1 H, J = 0.7
Hz, H-2′′b), 6.50 (s, 1 H, H-6), 6.55 (s, 1 H, H-3), 6.83 (d, 2 H,
J = 8.8 Hz, H-3′,5′ or H-3′′′,5′′′), 6.84 (d, 2 H, J = 8.9 Hz, H-3′,5′or
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 1379–1384

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