Convenient synthesis of 3-Cinnamoyl-2-styrylchromones: Reinvestigation of the Baker-Venkataraman rearrangement

Article abstract of DOI:10.1002/ejoc.201000957

An efficient and straightforward, one-pot sequence gives access to highly functionalized 3-cinnamoyl-2-styrylchromones in excellent yields. The low solubility of the target molecules allows convenient isolation. The formation of an α,α-dicinnamoylated acetophenone, as a consequence of a two-fold Baker-Venkataraman sequence, has to be anticipated. Copyright

Full text of DOI:10.1002/ejoc.201000957

FULL PAPER
DOI: 10.1002/ejoc.201000957
Convenient Synthesis of 3-Cinnamoyl-2-styrylchromones: Reinvestigation of the
Baker–Venkataraman Rearrangement
Pia Königs,[a] Olivia Neumann,[a] Olga Kataeva,[b] Gregor Schnakenburg,[c] and
Siegfried R. Waldvogel*[a,d]
Keywords: Heterocycles / Cyclization / Domino reactions / One-pot protocol / Rearrangement
An efficient and straightforward, one-pot sequence gives ac-
cess to highly functionalized 3-cinnamoyl-2-styrylchromones
in excellent yields. The low solubility of the target molecules
allows convenient isolation. The formation of an α,α-dicinn-
amoylated acetophenone, as a consequence of a two-fold
Baker–Venkataraman sequence, has to be anticipated.
nione (2) (Figure 1). Both compounds were isolated from
the blue-green algae, chrysophaeum taylori.[6]
Additionally, many synthetic 2-styrylchromones have
been produced that have revealed striking biological activity
such as anti-inflammatory,[7] antiproliferative,[8] and antiox-
idant properties.[9]
Introduction
In recent years, the number of publications dealing with
chromones, i.e., 4H-1-benzopyran-4-ones, has dramatically
increased and syntheses have also been intensively re-
viewed.[1] This can be attributed to the flavones (2-phenyl-
chromones), the most prominent class of naturally occur-
ring chromones, which are found throughout the plant
kingdom.[2] A wide variety of applications has been found
for chromones, including, for example, anticoagulants,[3]
antitumor agents,[4] and antiasthmatics.[5] In contrast to
flavones, there are only two natural products that are
known to contain the vinylogue 2-styrylchromone architec-
ture: Hormothamnione (1) and desmethoxyhormotham-
Results and Discussion
In the course of a natural product synthesis, we required
efficient access to 3-cinnamoyl-2-styrylchromones with a
specific substitution pattern at the A-ring, i.e., 5-hydroxy-
7-methyl-2-styrylchromone. Among the possible synthetic
routes, the Baker–Venkataraman sequence involving the ap-
propriate acetophenone and cinnamic acid seemed to be the
most convenient.[10]
In this transformation, an ortho-acyloxy ketone is re-
arranged to a β-diketone by the catalytic action of base.
Cyclization to the desired chromone may occur in situ or
could require an extra step, which can either be performed
oxidatively or be accomplished in strongly acidic me-
dia.[11,12] For the synthesis of 3-cinnamoyl-2-styrylchrom-
ones, a three-step procedure has been reported by Silva
et al.;[12] however, because 3-cinnamoyl-2-styrylchromones
were considered to be by-products, the yields were usually
low (Ͻ10%, three steps). A two-step approach elaborated
by the same group employed K2CO3 in anhydrous pyridine
to mediate both the rearrangement and cyclization reaction.
In this protocol, the 3-cinnamoyl-2-styrylchromones are af-
forded in moderate yields (Scheme 1).[13] Some results were,
however, contradictory to earlier reports, wherein a one-pot
synthesis of 2-styrylchromones was claimed.[14] Polyhy-
droxyphenones were treated with cinnamoyl chloride in
K2CO3/acetone to yield the corresponding 2-styrylchrom-
ones. The hydroxy groups of the resulting chromone were
anticipated to be acylated with cinnamoyl moieties and
were subsequently saponified with 5% KOH in methanol.
View this journal online at
Figure 1. Naturally occurring products hormothamnione (1) and
desmethoxyhormothamnione (2).
[a] Kekulé-Institut für Organische Chemie und Biochemie,
Rheinische Friedrich-Wilhelms-Universität Bonn,
Gerhard-Domagk-Str. 1, 53121 Bonn, Germany
[b] A. E. Arbuzov Institute of the Russian Academy of Sciences,
Arbuzov Street 8, Kazan 420088, Russia
[c] Institut für Anorganische Chemie,
Rheinische Friedrich-Wilhelms-Universität Bonn,
Gerhard-Domagk-Str. 1, 53121 Bonn, Germany
[d] Institut für Organische Chemie,
Johannes Gutenberg-Universität Mainz,
Duesbergweg 10-14, 55128 Mainz, Germany
Fax: +49-6131-392-6777
E-mail: waldvogel@uni-mainz.de
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201000957.
wileyonlinelibrary.com
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S. R. Waldvogel et al.
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Several substrates decomposed and did not yield the desired
Here, we present a straightforward approach to the con-
chromones. Interestingly, a one-pot synthesis of 5-hy- version of 2,6-dihydroxyacetophenone derivatives into the
droxyflavones by using K2CO3/acetone has been pub- corresponding 3-cinnamoyl-2-styrylchromones in high
lished.[15] We were thus inspired to apply this protocol to yields (Table 1). The protocol exhibits significant advances,
our substrates.
because it is simple to perform and employs very mild reac-
tion conditions. The crude yields of 3-cinnamoyl-2-styryl-
chromones 6 are quantitative and the microanalyses of
these crude materials showed only slight deviations from
acceptable tolerance (1H NMR spectroscopic analysis re-
vealed only traces of solvent as impurities). The major
reason for the outstanding yield of 6 arises from its poor
solubility in the reaction media. In fact, attempts to purify
the target compounds by column chromatography on silica
resulted in tremendously reduced yields, because these com-
pounds are prone to crystallization on the column during
the chromatography process. Thus, the depressed yield upon
chromatography is a direct consequence of the poor solubil-
ity of the individual derivative 6.
2,6-Dihydroxy-4-methylacetophenone (3a) can be con-
verted with cinnamoyl chloride into the intensely yellow
product 6a (Table 1, Entry 1). Introduction of a tert-butyl
moiety at the 4-position of the cinnamoyl fragment en-
hances the solubility of the target compound 6b (Table 1,
Entry 2). Both chromones 6a and 6b furnished suitable sin-
gle crystals for X-ray crystallographic analysis (Figure 2). 3-
Cinnamoyl-2-styryl-chromone (6a) shows dispersion inter-
actions leading to a herringbone structure. This is due to
the cinnamoyl moiety, which is tilted by 62.14° versus the
chromone plane. The crystal structure of 6b exhibits a tetra-
meric assembly with the bulky tert-butyl groups pointing to
Scheme 1. Two-step synthesis of 3-cinnamoyl-2-styrylchrom-
ones.[13]
Table 1. Substrates subjected to the one-pot Baker–Venkataraman rearrangement.[a]
Entry
Acetophenone
Acroyl chloride (R1)
Product
Yield: crude (after chromatography) [%]
1
2
3
4
5
6
7
8
9
3a
3a
3a
3a
3a
3a
3a
3a
3b
3c
Ph
4-tBuC6H4
4-MeOC6H4
3,4-(MeO)2C6H4
3-FC6H4
3,4-(CH2O2)C6H3
2-thienyl
4a
4b
4c
4d
4e
4f
4g
4h
4b
4a
6a
6b
6c
6d
6e
6f
99 (54)
99 (79)[b]
99 (86)[b]
99 (94)[b]
61 (61)
97 (93)
99 (40)
6g
6h
6i
2-furyl
4-tBuC6H4
SiMe3
92 (45)
[c]
–
[c]
10
6j
–
[a] Reagents and conditions: acyl chloride (2.3 equiv.), K2CO3 (3.0 equiv.), acetone, reflux. [b] Recrystallized from ethanol. [c] Complete
formation of β-diketone, originating from a single cinnamoyl transfer.
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Synthesis of 3-Cinnamoyl-2-styrylchromones
the corners of a four-fold water wheel, which forms inter- Consequently, the thiophene congener 6g follows the oppo-
locked columns. The cinnamoyl moiety is twisted out of site trend leading to lower solubility and higher yields
the chromone plane by 62.59°, which also prevents close π- (Table 1, Entry 7). All substances were stable to air and
stacking. The molecular structure of both derivatives 6a moisture, but were sensitive to good nucleophiles such as
and 6b exhibits similar geometries in the solid state. hydroxide. This is made clear with 3-cinnamoylchromone,
Whereas the 2-styrylchromone forms an almost planar sys- which forms a double Michael acceptor that is prone to 1,4-
tem, the cinnamoyl fragment is tilted out of plane, which addition reactions. As a result of our work, the reported 5-
results in a significantly longer C(sp2)–C(sp2) bond of cinnamoyloxy-2-styrylchromones[14] should be structurally
1.502(1) Å in comparison to 1.44–1.46 Å values for the C– reassigned because they most likely represent 3-cinnamoyl-
C bonds within the conjugated fragments.
2-styrylchromones 6. From these observations, a plausible
mechanism can be deduced (Scheme 2). Concerning the
acetophenone substrate 3, two hydroxy groups in positions
2 and 6 are essential. If a single hydroxy group is protected
or if there is only one group present in the acetophenone
component 3, the reaction with cinnamoyl chloride will al-
ways afford the corresponding β-diketone (Table 1, En-
tries 9 and 10).
Figure 2. Molecular structure of chromones 6a (top) and 6b (bot-
tom) obtained by X-ray crystallographic analysis.
The procedure is applicable to electron-rich cinnamoyl
chlorides (Table 1, Entries 3 and 4). However, the adjacent
methoxy groups on the 3,4-dimethoxyphenyl moiety cause
steric demand and slightly enhances the solubility. Com-
pound 6d was efficiently recrystallized from ethanol, pro-
viding the analytically pure compound in excellent yield.
When using electron-poor cinnamoyl chlorides, for exam-
ple, the 3-fluoro derivative, an extremely low solubility of
6e was observed. This might be attributed to effective π-
stacking in the solid state, which stabilizes the lattice. The
lower yield for 6e might be caused by the high reactivity of
4e.
Heterocyclic analogues of cinnamoyl chloride can also
be subjected to this protocol. However, the electron-rich
thiophene and furan moieties led to better solubility of the
Scheme 2. Proposed mechanism of 3-cinnamoyl-2-styrylchromone
products 6g and 6h, respectively (Table 1, Entries 7 and 8). formation.
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S. R. Waldvogel et al.
FULL PAPER
carbonate (2.49 g, 18.0 mmol, 3.0 equiv.) and α,β-unsaturated acyl
chloride (14.0 mmol, 2.3 equiv.) were added. The reaction mixture
was stirred at reflux temperature overnight (the transformation was
monitored by TLC). When the reaction was complete, the solvent
was evaporated, and the residue was fractionated between water
(80 mL) and dichloromethane (80 mL). The mixture was acidified
to pH = 4 with citric acid, and the aqueous layer was extracted
with dichloromethane (3ϫ 50 mL). The combined organic layers
were washed with saturated aqueous NaHCO3 (80 mL), water
(80 mL), and brine (80 mL), dried with anhydrous calcium chloride
This finding can easily be explained by the involvement
of intermediate 5a, which can arise from rearrangement of
both cinnamoyl groups through a Baker–Venkataraman re-
action from diester 5 into the key derivative 5a. One of the
cinnamoyl ketones will predominantly exist as its enol tau-
tomer. This is supported by previous reports wherein 2-sty-
rylchromones have been isolated in the enol form.[16] Con-
sequently, the second cinnamoyl carbonyl group exists as
ketone moiety, which can be attacked by a phenolate nu-
cleophile. Elimination of water takes place during workup and concentrated under reduced pressure. Purification of the crude
chromone 6 was typically performed by column chromatography
with cyclohexane/ethyl acetate as eluent. Details are mentioned
with the individual procedures.
as a result of rearomatization. Concerning the α,β-unsatu-
rated acyl chloride, the absence of protons in the γ-position
is crucial. In the course of reaction, deprotonation at the
γ-position of ester 5 will proceed faster than the Baker–
Venkataraman rearrangement and lead exclusively to the
formation of 3-alkenyl-5-hydroxycoumarins.[17]
(E,E)-3-Cinnamoyl-5-hydroxy-7-methyl-2-styrylchromone (6a): Ob-
tained after column chromatography on silica (cyclohexane/EtOAc,
9:1) as yellow solid in 54% yield. Rf = 0.39 (cyclohexane/EtOAc,
1
9:1); m.p. 217 °C. H NMR (400 MHz, CDCl3, 25 °C): δ = 2.45 (s,
4
4
3 H), 6.66 (d, JH,H = 0.6 Hz, 1 H), 6.85 (d, JH,H = 0.6 Hz, 1 H),
3
3
7.16 (d, JH,H = 15.9 Hz, 1 H), 7.24 (d, JH,H = 16.0 Hz, 1 H),
7.38–7.40 (m, 6 H), 7.56–7.63 (m, 4 H), 7.69 (d, JH,H = 16.0 Hz,
Conclusions
3
1 H), 7.76 (d, 3JH,H = 15.9 Hz, 1 H), 12.29 (s, 1 H) ppm. 13C NMR
(100 MHz, CDCl3, 25 °C): δ = 22.5, 107.3, 108.4, 112.7, 117.6,
120.7, 127.3, 128.3, 128.8, 128.9, 129.0, 130.5, 130.8, 134.5, 134.7,
140.5, 144.6, 148.0, 155.2, 160.6, 162.3, 181.3, 190.9 ppm. HRMS
(EI): calcd. for C27H20O4 [M]·+ 408.1362; found 408.1360.
A very versatile and reliable protocol for the synthesis
of 3-cinnamoyl-2-styrylchromones has been established that
yields highly functionalized building blocks. The aceto-
phenone component requires two hydroxy moieties in both
the 2 and 6 positions. The study indicated that an α,α-
dicinnamoylated acetophenone (5a) is most likely the key
intermediate. Synthetic operations such as olefin metathesis
or stereoselective transformations should readily enhance
product diversity and enable natural product synthesis.[18]
The class of compound is closely related to the 2-styryl-
chromones; however, in contrast to the latter, the biological
properties are as yet unexplored.
X-ray Crystal Data for 6a: Formula C27H20O4; M = 408.43; a =
13.797(1), b = 4.045(1), c = 17.765(1) Å, β = 92.38(1)°; V =
990.6(3) Å3; ρcalcd. = 1.369 gcm–3; µ = 0.738 mm–1; empirical ab-
sorption correction (0.757 Յ T Յ 0.978); Z = 2; monoclinic; space
group Pn (No. 7); T = 223 K; ω and φ scans, 6527 reflections col-
lected (Ϯh, Ϯk, Ϯl), [(sinθ)/λ] = 0.60 Å–1, 2456 independent (Rint
= 0.035) and 2393 observed reflections [I Ն 2σ(I)], 285 refined pa-
rameters, R = 0.035, wR2 = 0.097, max./min. residual electron den-
sity 0.14/–0.17 eÅ–3. Hydrogen atoms were calculated and refined
as riding atoms, except for the hydroxy hydrogen atom, which was
revealed from the difference Fourier map and refined isotropically.
The data set for 6a was collected with a Nonius KappaCCD dif-
fractometer. Programs used: data collection COLLECT (Nonius
B.V., 1998), data reduction Denzo-SMN,[19] absorption correction
Denzo,[20] structure solution SHELXS-97;[21] structure refinement
by full-matrix least-squares against F2 using SHELXL-97 (G. M.
Sheldrick, University of Göttingen, 1997). CCDC-781934 contains
the supplementary crystallographic data for this paper. These data
can be obtained free of charge from The Cambridge Crystallo-
graphic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
Experimental Section
General Comments: All reagents were analytical grade. Solvents
were dried, if necessary, by standard methods. Melting points were
determined with a B-545 Melting Point Apparatus (Büchi Labor-
technik AG, 9320 Flawil 1, Schweiz). Microanalyses were per-
formed with a Vario EL cube (Elementar-Analysensysteme, Hanau,
Germany) instrument. NMR spectra were recorded with a Bruker
ARX 300, DPX 300 and DPX 400 (Analytische Messtechnik,
Karlsruhe, Germany) spectrometer calibrated against CHCl3 [δ =
7.26 ppm (1H) and δ = 77.0 ppm (13C)] or [D6]DMSO [δ =
2.50 ppm (1H) and δ = 39.51 ppm (13C)]; chemical shifts are ex-
pressed in ppm. Full assignments of chemical shifts are reported in
the Supporting Information. Mass spectra were obtained with a
MAT8200 (Finnigan, Bremen, Germany) instrument by employing
EI or with MS50 (Kratos, Manchester, England) or MAT95XL
(Finnigan, Bremen, Germany) instruments for HRMS. All reac-
tions were monitored by thin layer chromatography (TLC); visual-
ization was effected by UV irradiation and by heating with a 1%
aqueous solution of Ce(SO4)2·4H2O containing 2.5% of molybd-
atophosphoric acid and 6% sulfuric acid. Column chromatography
was performed on silica gel (particle size 63–200 µm, Merck,
Darmstadt, Germany) by using mixtures of cyclohexane with ethyl
acetate as eluents.
(E,E)-3-[4-(1,1-Dimethylethyl)cinnamoyl]-2-{2-[4-(1,1-dimethyl-
ethyl)phenyl]ethenyl}-5-hydroxy-7-methylchromone (6b): For the
synthesis of 6b the general procedure was altered: The crude prod-
uct, containing 20 % 5-cinnamoyloxychromone was liberated by
stirring at r.t. with potassium carbonate (10.0 equiv.) in methanol/
dichloromethane (1:2) for 1 h. Workup was performed according
to the general procedure. The crude product was recrystallized from
ethanol at r.t. to afford 6b as a yellow solid in 79% yield. Rf =
0.45 (cyclohexane/EtOAc, 9:1); m.p. 196.3 °C. 1H NMR (400 MHz,
CDCl3, 25 °C): δ = 1.33 (s, 9 H), 1.33 (s, 9 H), 2.45 (s, 3 H), 6.66
(s, 1 H), 6.86 (s, 1 H), 7.09 (d, 3JH,H = 15.9 Hz, 1 H), 7.19 (d, 3JH,H
3
3
= 16.0 Hz, 1 H), 7.41 (d, JH,H = 8.4 Hz, 4 H), 7.51 (d, JH,H
=
=
3
3
8.4 Hz, 2 H), 7.54 (d, JH,H = 8.4 Hz, 2 H), 7.65 (d, JH,H
3
16.0 Hz, 1 H), 7.74 (d, JH,H = 15.9 Hz, 1 H), 12.34 (s, 1 H) ppm.
13C NMR (100 MHz, CDCl3, 25 °C): δ = 22.5, 29.7, 31.1, 34.9,
107.3, 108.5, 112.6, 116.8, 120.5, 125.9, 126.0, 126.68, 128.1, 128.7,
General Procedure: Acetophenone derivative
3
(6.0 mmol,
1.0 equiv.) was dissolved at r.t. in acetone (80 mL), and potassium
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Synthesis of 3-Cinnamoyl-2-styrylchromones
131.7, 132.1, 140.2, 144.9, 147.9, 154.2, 154.5, 155.3, 160.7, 162.2,
181.2, 191.1 ppm. HRMS (EI): calcd. for C35H36O4 [M]·+ 520.2614;
found 520.2612. C35H36O4 (520.66): calcd. C 80.74, H 6.97; found
C 80.48, H 7.39.
uum (10–3 mbar), and the crude product was stirred at 100 °C in
1,4-dioxane (25 mL) for 1 h, cooled to r.t. and filtered off to afford
6e as a bright-yellow solid, which was dried in high vacuum. Yield:
1.123 g, 61%. Rf = 0.46 (cyclohexane/EtOAc, 8:2); m.p. 237.6 °C.
1H NMR (500 MHz, [D6]DMSO, 25 °C): δ = 2.44 (s, 1 H), 6.73 (s,
X-ray Crystal Data for 6b: Formula C35H36O4; M = 520.64; a = b
3
1 H), 7.01 (d, JH,H = 15.9 Hz, 1 H), 7.08 (s, 1 H), 7.24–7.31 (m, 2
= 29.5935(4), c = 13.7585(3) Å; V = 12049.4(3) Å3; ρcalcd.
=
3
H), 7.28 (d, JH,H = 16.4 Hz, 1 H), 7.45–7.52 (m, 2 H), 7.54 (d,
1.148 g cm–3; µ = 0.074 mm–1; no absorption correction; Z = 16;
tetragonal; space group I41/a (No. 88); T = 123 K; ω and φ scans,
75707 reflections collected, 7267 unique (Rint = 0.0696), 418 param-
eters, 67 restraints, R = 0.0617, wR2 = 0.1258 (both for all data),
max./min. residual electron density 0.255/–0.218 e·Å–3. The hydro-
gen atoms were calculated and refined as riding atoms, except for
the hydroxy hydrogen atom, which was revealed from the difference
Fourier map and refined isotropically. The data set for 6b was col-
lected with a Nonius KappaCCD diffractometer. Programs used:
data collection COLLECT (Nonius B. V., 1998), data reduction
Denzo-SMN,[19] absorption correction Denzo,[20] structure solution
SHELXS-97;[21] structure refinement by full-matrix least-squares
against F2 using SHELXL-97 (G. M. Sheldrick, University of
Göttingen, 1997). CCDC-779410 contains the supplementary crys-
tallographic data for this paper. These data can be obtained free
of charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
3
3JH,H = 8.0 Hz, 1 H), 7.60 (d, JH,H = 8.0 Hz, 1 H), 7.63–7.83 (m,
3
3
2 H), 7.72 (d, JH,H = 16.4 Hz, 1 H), 7.89 (d, JH,H = 15.9 Hz, 1
H), 12.1 (s, 1 H) ppm. 13C NMR (126 MHz, [D6]DMSO, 25 °C): δ
= 22.1, 107.2, 107.8, 112.1, 114.5 (2JC,F = 22.2 Hz), 115.0 (2JC,F
=
22.2 Hz), 117.3 (2JC,F = 21.4 Hz), 117.7 (2JC,F = 21.4 Hz), 118.75,
121.0, 124.8 (4JC,F = 2.3 Hz), 125.3 (4JC,F = 2.3 Hz), 129.3, 131.0
(3JC,F = 8.4 Hz), 131.1 (3JC,F = 8.4 Hz), 136.9 (3JC,F = 8.0 Hz),
137.0 (3JC,F = 8.0 Hz), 138.7, 144.4, 148.3, 155.1, 159.6, 160.2,
162.4 (1JC,F = 244.4 Hz), 162.5 (1JC,F = 244.4 Hz), 180.8,
191.3 ppm. 19F NMR (75.5 MHz, [D6]DMSO): δ = –112.4,
–112.5 ppm. HRMS (EI): calcd. for C27H18F2O4 [M – H]·+
443.1089; found 443.1097.
(E,E)-3-[3-(Benzo[1,3]dioxol-5-yl)acroyl]-2-[2-(benzo[1,3]dioxol-5-
yl)ethenyl]-5-hydroxy-7-methylchromone (6f): Prepared according to
the general procedure by using 2,6-dihydroxy-4-methylaceto-
phenone (593 mg, 3.58 mmol, 1.0 equiv.), 3-(benzo[1,3]dioxol-5-yl)-
(E,E)-5-Hydroxy-3-(4-methoxycinnamoyl)-2-[2-(4-methoxyphenyl)- acroyl chloride (1.75 g, 8.33 mmol, 2.33 equiv.) and potassium car-
ethenyl]-7-methylchromone (6c): For purification, the crude product
bonate (1.48 g, 10.74 mmol, 3.0 equiv.) in acetone (45 mL). When
the reaction was complete, the solvent was evaporated, and the resi-
was stirred at 78 °C in ethanol for 1 h. Filtration at r.t. afforded 6c
1
as a yellow solid in 86% yield; m.p. 186 °C. H NMR (400 MHz, due was suspended in distilled water (50 mL). The mixture was
CDCl3, 25 °C): δ = 2.44 (s, 3 H), 3.84 (s, 6 H), 6.64 (s, 1 H), 6.82 acidified with citric acid (pH = 3) and filtered. The residue was
3
3
(s, 1 H), 6.90 (d, JH,H = 8.8 Hz, 4 H), 6.91 (d, JH,H = 8.7 Hz, 2 treated with saturated NaHCO3 (30 mL) at 50 °C for 1 h to remove
3
3
H), 7.00 (d, JH,H = 15.8 Hz, 1 H), 7.11 (d, JH,H = 15.9 Hz, 1 H), the remaining 3,4-methylenedioxycinnamic acid, cooled to r.t. and
7.51 (d, JH,H = 8.7 Hz, 2 H), 7.56 (d, JH,H = 8.8 Hz, 2 H), 7.63
3
3
filtered. After drying under vacuum (10–3 mbar), the crude product
was stirred at 100 °C in 1,4-dioxane (30 mL) for 1 h, cooled to r.t.
3
3
(d, JH,H = 15.9 Hz, 1 H), 7.70 (d, JH,H = 15.8 Hz, 1 H), 12.38 (s,
1 H) ppm. 13C NMR (100 MHz, CDCl3, 25 °C): δ = 22.5, 55.4, and filtered to afford 6f as a yellow solid. Yield: 1.651 g, 93%. Rf
55.4, 107.2, 108.4, 112.5, 114.4, 114.4, 115.2, 120.2, 125.3, 127.2,
127.6, 130.0, 130.6, 140.0, 144.7, 147.7, 155.3, 160.6, 161.6, 161.9,
162.4, 181.2, 191.0 ppm. HRMS (EI): calcd. for C29H24O6 [M]·+
468.1573; found 468.1572.
= 0.24 (cyclohexane/EtOAc, 8:0); m.p. 234.2 °C. 1H NMR
(500 MHz, [D6]DMSO, 25 °C): δ = 2.42 (s, 3 H), 6.08 (s, 4 H), 6.70
3
3
(s, 1 H), 6.75 (d, JH,H = 15.7 Hz, 1 H), 6.96 (d, JH,H = 8.1 Hz, 1
3
3
H), 6.99 (d, JH,H = 8.1 Hz, 1 H), 7.05 (s, 1 H), 7.06 (d, JH,H
=
3
4
16.1 Hz, 1 H), 7.20 (dd, JH,H = 8.1, JH,H = 1.6 Hz, 1 H), 7.24
(E,E)-3-(3,4-Dimethoxycinnamoyl)-2-[2-(3,4-dimethoxyphenyl)-
ethenyl]-5-hydroxy-7-methylchromone (6d): Obtained as a yellow so-
lid after recrystallization from ethanol (10 mL) at r.t. in 94% yield.
Rf = 0.41 (cyclohexane/EtOAc, 6:4); m.p. 211.5 °C. 1H NMR
(400 MHz, CDCl3, 25 °C): δ = 2.43 (s, 3 H), 3.91 (s, 12 H), 6.63
3
4
4
(dd, JH,H = 8.1, JH,H = 1.6 Hz, 1 H), 7.33 (d, JH,H = 1.6 Hz, 1
4
3
H), 7.42 (d, JH,H = 1.6 Hz, 1 H), 7.60 (d, JH,H = 16.1 Hz, 1 H),
7.77 (d, JH,H = 15.7 Hz, 1 H), 12.26 (s, 1 H) ppm. 13C NMR
3
(126 MHz, [D6]DMSO, 25 °C): δ = 21.9, 101.7, 101.8, 106.6, 107.0,
107.6, 107.9, 108.6, 108.8, 111.9, 115.1, 120.2, 125.1, 125.9, 126.3,
128.8, 129.0, 139.8, 146.1, 147.9, 148.1, 148.3, 149.6, 149.9, 155.1,
159.6, 160.6, 180.6, 191.2 ppm. HRMS (EI): calcd. for C29H20O8
[M]+ 496.1158; found 496.1160.
4
4
(d, JH,H = 0.5 Hz, 1 H), 6.82 (d, JH,H = 0.5 Hz, 1 H), 6.86 (d,
3JH,H = 8.4 Hz, 2 H), 6.97 (d, 3JH,H = 15.9 Hz, 1 H), 7.04 (d, 4JH,H
3
4
= 1.9 Hz, 1 H), 7.09 (d, JH,H = 15.8 Hz, 1 H), 7.12 (d, JH,H
=
1.9 Hz, 1 H), 7.15 (dd, 3JH,H = 8.4, 4JH,H = 1.9 Hz, 1 H), 7.18 (dd,
3JH,H = 8.4, JH,H = 1.9 Hz, 1 H), 7.61 (d, JH,H = 15.9 Hz, 1 H),
4
3
(E,E)-5-Hydroxy-7-methyl-3-[3-(2-thienyl)acroyl]-2-[2-(2-thienyl)-
ethenyl]chromone (6g): Obtained after column chromatography on
silica (cyclohexane/EtOAc, 9:1) as an orange solid in 40% yield. Rf
= 0.23 (cyclohexane/EtOAc, 9:1); m.p. 177.2 °C. 1H NMR
(400 MHz, CDCl3, 25 °C): δ = 2.44 (s, 3 H), 6.65 (d, 4JH,H = 0.6 Hz,
1 H), 6.81 (d, 4JH,H = 0.6 Hz, 1 H), 6.95 (d, 3JH,H = 15.6 Hz, 1 H),
7.69 (d, JH,H = 15.8 Hz, 1 H), 12.37 (s, 1 H) ppm. 13C NMR
3
(100 MHz, CDCl3, 25 °C): δ = 22.4, 55.9, 56.0, 56.0, 56.0, 107.2,
108.4, 109.4, 110.13, 111.0, 111.1, 112.5, 115.2, 120.2, 122.9, 123.7,
125.47, 127.4, 127.8, 140.3, 145.0, 147.8, 149.2, 149.3, 151.4, 151.7,
155.2, 160.6, 162.3, 181.1, 191.0 ppm. HRMS (EI): calcd. for
C31H28O8 [M]·+ 528.1784; found 528.1785.
3
3
3
7.03 (d, JH,H = 15.6 Hz, 1 H), 7.07 (dd, JH,H = 5.2, JH,H
=
3
3
(E,E)-3-(3-Fluorocinnamoyl)-2-[2-(3-fluorophenyl)ethenyl]-5-hy- 3.2 Hz, 1 H), 7.08 (dd, JH,H = 5.2, JH,H = 3.2 Hz, 1 H), 7.33 (d,
3
3
droxy-7-methylchromone (6e): Prepared according to the general
procedure by using 2,6-dihydroxy-4-methylacetophenone (685 mg,
4.13 mmol, 1.0 equiv.), 3-fluorocinnamoyl chloride (1.93 g,
9.62 mmol, 2.33 equiv.) and potassium carbonate (1.71 g,
14.2 mmol, 3.0 equiv.) in acetone (55 mL). When the reaction was
complete, the solvent was evaporated, and the residue was sus-
pended in distilled water (50 mL). The mixture was acidified with
citric acid (pH = 3) and filtered. The residue was dried under vac-
3JH,H = 3.2 Hz, 1 H), 7.35 (d, JH,H = 3.2 Hz, 1 H), 7.43 (d, JH,H
3
3
= 5.2 Hz, 2 H), 7.80 (d, JH,H = 15.6 Hz, 1 H), 7.86 (d, JH,H
=
15.6 Hz, 1 H), 12.32 (s, 1 H) ppm. 13C NMR (100 MHz, CDCl3,
25 °C): δ = 22.5, 107.2, 108.4, 112.6, 116.4, 120.6, 126.2, 128.4,
129.4, 129.6, 131.0, 132.3, 133.0, 136.9, 140.0, 140.4, 148.0, 155.2,
160.7, 162.1, 181.1, 190.1 ppm. HRMS (ESI): calcd. for
C23H16O4S2 [M + H]+ 421.0568; found 421.0564. C23H16O4S2
(420.50): calcd. C 65.69, H 3.84; found C 65.13, H 4.28.
Eur. J. Org. Chem. 2010, 6417–6422
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6421

S. R. Waldvogel et al.
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Received: July 7, 2010
Published Online: October 18, 2010
6422
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© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 6417–6422