Darzens reaction of 2-bromo-4,6-dimethoxy-3(2H)-benzofuranone with aromatic aldehydes to form flavonoids

Article abstract of DOI:10.1002/jhet.5570450432

(Chemical Equation Presented) The applicability of 2-bromo-4,6-dimethoxy- 3(2H)-benzofuranone (1) to produce flavonoid-derived epoxides in the course of the Darzens reaction with aldehydes was investigated. However, instead of the epoxides, flavonols 3 and, in certain cases, benzofuranyl-substituted flavonols 4 were isolated. The generation of 3 is assumed due to a ring expansion of the initially formed epoxides. These flavonols can react with 1 to produce the unexpected 1:2 adducts 4 as minor products. The structure of the hexamethoxy derivative 4b (R¹ = H, R² = R³ = OMe) was confirmed by X-ray crystallographic analysis.

Full text of DOI:10.1002/jhet.5570450432

Jul-Aug 2008
1149
Darzens Reaction of 2-Bromo-4,6-dimethoxy-3(2H)-benzofuranone
with Aromatic Aldehydes to Form Flavonoids
Philipp A. Ottersbach,a David Bolek,a Eva Lepiꢀová,a Martin Nieger,b
and Michael Gütschow a,*
aPharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn,
An der Immenburg 4, D-53121 Bonn, Germany
bLaboratory of Inorganic Chemistry, Department of Chemistry, University of Helsinki,
PO Box 55, FIN-00014 University of Helsinki, Finland
E-mail: guetschow@uni-bonn.de
Received December 6, 2007
R2
R2
R1
R3
R1
R3
MeO
O
O
MeO
O
O
OMe
O
O
OH
MeO
MeO
H
O
OMe
3
4
The applicability of 2-bromo-4,6-dimethoxy-3(2H)-benzofuranone (1) to produce flavonoid-derived
epoxides in the course of the Darzens reaction with aldehydes was investigated. However, instead of the
epoxides, flavonols 3 and, in certain cases, benzofuranyl-substituted flavonols 4 were isolated. The
generation of 3 is assumed due to a ring expansion of the initially formed epoxides. These flavonols can
react with 1 to produce the unexpected 1:2 adducts 4 as minor products. The structure of the hexamethoxy
derivative 4b (R1 = H, R2 = R3 = OMe) was confirmed by X-ray crystallographic analysis.
J. Heterocyclic Chem., 45, 1149 (2008).
of the tetramethoxy substituted epoxide III (R = R' =
OMe, R'' = 3,4-(OMe)2) turned out to be difficult.
The corresponding 4,6-dimethoxy-2-(3,4-dimethoxy-
benzylidene)benzofuran-3(2H)-one [12] failed to react
with H2O2 and Triton B in dioxane at room temperature.
Treatment with meta-chloroperbenzoic acid in boiling
toluene resulted in a product mixture that still contained
starting material. Even the reaction of 4,6-dimethoxy-2-
(3,4-dimethoxybenzylidene)benzofuran-3(2H)-one with
dimethyldioxirane [13] in methylene chloride/acetone
under argon atmosphere at room temperature led to an
incomplete conversion, and the desired III (R = R' =
OMe, R'' = 3,4-(OMe)2) was not obtained.
INTRODUCTION
Flavonoids are polyphenolic plant constituents that are
widely distributed in the plant kingdom and possess a
variety of biological activities [1]. The antimicrobial [2],
antiprotozoal [3], antiviral [4], antiinflammatory [5], and
antitumor activity [6] of several flavonoids has been
described. Flavonoids are known to act as vascular
antioxidants [7] and modulators of P-glycoprotein-
mediated multidrug resistance [8].
Alphitonin (IV) and taxifolin (II) share the substitution
pattern (R = R' = OH, R'' = 3,4-(OH)2) with quercetin (I),
a flavonol whose glycosides are highly abundant dietary
flavonoids. The auronol alphitonin has been identified as
a metabolite of the quercetin degradation by the anaerobic
human intestinal bacterium Eubacterium ramulus [9]. To
prepare auronols of type IV, the epoxide III (R = R' = R''
= H) was successfully transformed with H2 in the
presence of Pd/C in toluene at –25 to –20° to obtain IV (R
= R' = R'' = H), the prototype of naturally occurring
auronols [10]. In a further attempt, we planned to prepare
the tetramethoxy substituted epoxide III (R = R' = OMe,
R'' = 3,4-(OMe)2). It was intended to reduce this
compound to the protected auronol IV (R = R' = OMe, R''
= 3,4-(OMe)2), which should then be deprotected to
alphitonin IV (R = R' = OH, R'' = 3,4-(OH)2).
Herein we report a further approach to synthesize
flavonoid-derived epoxides III by means of the Darzens
condensation.
R''
R''
R
R
O
O
R
R
O
O
OH
OH
R'
R'
R'
R'
II
I
R''
O
O
O
R''
OH
H
In contrast to the oxidation of 2-benzylidenebenzo-
furan-3(2H)-one, which easily afforded the unsubstituted
III upon treatment with H2O2 and Triton B (benzyl
trimethylammonium hydroxide) [10,11], the preparation
O
O
III
IV
Figure 1

1150
P. Ottersbach, D. Bolek, E. Lepiꢀová, M. Nieger, M. Gütschow
Vol 45
RESULTS AND DISCUSSION
was unambiguously assigned as 4b on the basis of X-ray
crystallographic analysis.
The Darzens reaction of aldehydes or ketones with
ꢀ-halo carbonyl compounds furnishes ꢀ,ꢁ-epoxy carbonyl
compounds in the course of an intramolecular SN2
mechanism [14]. This powerful C-C bond forming
process was also applied to the preparation of two
flavonoid-derived epoxides. Brady et al. [11] have reacted
2-bromo-6-methoxy-3(2H)-benzofuranone with 2-nitro-
benzaldehyde to obtain an epoxide III (R = OMe, R' = H,
R'' = 2-NO2) in 89% yield of the crude product. By using
benzaldehyde, the corresponding epoxide III (R = OMe,
R' = R'' = H) was isolated in traces.
In order to find a synthetic access to tetramethoxy
substituted epoxides III (R = R' = OMe, R'' = 3,4-(OMe)2)
as potential precursors to alphitonin, we have performed
the Darzens reaction of 2-bromo-4,6-dimethoxy-3(2H)-
benzofuranone (1) with 3,4-dimethoxybenzaldehyde (2b)
(Scheme 1).
Similarly, the analogous adduct 4a was obtained in the
reaction of 1 with benzaldehyde 2a. Compounds 4,
however, were not the main products of these Darzens
reactions. After the separation of the 2:1 adducts 4, other
products were achieved from the reaction solutions and
their structures were elucidated as flavonols 3a and 3b,
respectively. The corresponding flavonols 3c and 3d were
isolated as the only organic products when 1 was reacted
with the 2-halobenzaldehydes 2c and 2d, respectively.
It is known, that the epoxide oxygen of ꢀ,ꢁ-epoxy
ketones can be displaced by nucleophilic attack either the
ꢀ-position or, more frequently, at the ꢁ-position [11].
Thus, the generation of flavonols 3 could be envisaged by
a possible mechanism shown in Scheme 1.
It involves the initial epoxide ring closure, attack of
methoxide at the ꢁ-carbon prior to the opening of the
Scheme 1
R1
R2
MeO
O
NaOMe, MeOH, toluene, r.t.
- NaBr
Br
+
OHC
R3
O
MeO
1
2a-d
R2
R3
R2
R2
R1
R1
R3
R1
R3
MeO
-
MeO
MeO
-
O
O
O
O
O
+ MeO
- MeO
OMe
H
H
H
OMe
O
O
O
O
MeO
MeO
MeO
R2
R2
R1 2'
R3
R1 2'
R3
MeO
O
MeO
O
2
+ 1 (3a, b)
2
R1 = R2 = R3 = H
OMe
O
a
2''
4
O
OH
4
b
c
d
R1 = H, R2 = R3 = OMe
R1 = Cl, R2 = R3 = H
R1 = Br, R2 = R3 = H
MeO
O
MeO
O
H
3''
O
OMe
3a-d
4a, b
Compound 1 [15] was prepared by bromination of 4,6-
dimethoxy-3(2H)-benzofuranone [12,16] with phenyl-
trimethyl ammoniumbromide dibromide [17] in tetra-
hydrofuran.
furanone ring and subsequent recyclization to the 6-
membered pyranone ring. Flavonol formation from
aurone epoxides in the presence of hydroxide ions has
already been observed by Brady et al. [11]. The authors
have considered an alternative mechanism of an ꢀ-attack
with the opening of the furanone ring prior the epoxide
cleavage.
Once generated, flavonols 3 could be converted in the
course of a nucleophilic substitution with a second
bromobenzofuranone 1 to produce the 1:2 adducts 4.
Their isolation, however, was impaired since partial
decomposition was observed after the treatment with
water to remove sodium bromide, and they were therefore
purified by recrystallization.
When performing the reaction of equimolar amounts of
1 and 2b in toluene/methanol in the presence of one
equivalent sodium methoxide at room temperature, a
precipitate was formed after addition of the sodium
methoxide solution. The insoluble material was isolated
and contained an organic compound besides sodium
bromide. Unexpectedly, this organic product was
composed of two units derived from 1 and one unit
derived from 2b, as it could be concluded from NMR and
mass spectroscopic data. The structure for the 2:1 adduct

Jul-Aug 2008
Darzens Reaction to Form Flavonoids
1151
Table 2
MS fragmentation data showed a cleavage at the
C(3)-O bond of 4a and 4b to form the characteristic
fragment (M+ - C10H8O4). Key signals in the nmr spectra
of 4 were the resonances of the 2´´-protons at 6.23, 6.28
ppm, respectively. The corresponding 13C nmr signals for
C-2´´ were found at 98.65, 98.45 ppm, respectively. The
13C chemical shifts of the carbonyl groups were also in
agreement with the structures 4. Whereas the signals of
C-3´´ appeared at 188.20, 188.41 ppm, respectively, those
of the ꢀ,ß-unsaturated, ꢀ-hydroxy ketone carbon C-4
were shifted upfield to 171.45, 171.28 ppm, respectively.
As expected, the C-4 signals of the flavonols 3a-d were in
the same range of 171-172 ppm. 13C nmr data of 3a were
in agreement with those reported from Pelter et al. [18].
Weak hydrogen bonds for 4b [Å] and [°]
D-H...A
D-H
H...A
D...A
<(DHA)
C(351)-H(35C)...O(4)#1
C(231)-H(23B)...O(4)#2
C(371)-H(37B)...O(7)#2
C(371)-H(37C)...O(23)#3
C(371)-H(37C)...O(24)#3
C(351)-H(35B)...O(35)#4
C(51)-H(51C)...O(39)#5
C(351)-H(35A)...O(39)#6
0.98
0.98
0.98
0.98
0.98
0.98
0.98
0.98
2.36
2.58
2.51
2.64
2.53
2. 59
2.44
2.60
3.055(4)
3.550(3)
3.437(3)
3.561(3)
3.335(3)
3.454(4)
3.227(4)
3.190(4)
127.2
169.7
157.9
157.0
138.8
146.4
137.1
118.9
Symmetry transformations used to generate equivalent atoms:
#1: x-1, y, z; #2: x-1/2, -y+1/2, z-1/2; #3: -x+1/2, y-1/2, -z+1/2;
#4: -x, -y, -z+1; #5: x+1/2, -y+1/2, z+1/2; #6: -x+1, -y, -z+1
The structure of 4b was confirmed by X-ray analysis
(Figure 2). All three units of the molecule are planar. The
mean deviations are 0.009 Å (benzopyranone), 0.004 Å
(phenyl), and 0.032 Å (benzofuranone). The latter ring
adopts a slight envelope conformation with C31 being
0.065 Å above the plane. In all substructures, oxygen and
carbon atoms of the methoxy groups are in plane.
Dihedral angles between the planes are as follows,
benzopyran and benzofuran 69°, benzopyran and phenyl
26°, benzofuran and phenyl 60°. Hydrogen bond
parameters are listed in Table 2. Only weak hydrogen
bonds were observed, all of them are intermolecular. Two
carbonyl oxygen atoms (O4, O39) are acceptors of
bifurcated hydrogen bonds, connecting three independent
molecules. C371 acts as a bifurcated donor to the oxygens
of the dimethoxyphenyl group (O23, O24) of one
molecule.
Figure 2. Molecular structure of 4b as determined by X-ray
crystallographic analysis and the numbering.
Table 1
EXPERIMENTAL
Crystal data and structure refinement for 4b
Empirical formula
Formula weight
Temperature
Wavelength
Crystal system, space group
Unit cell dimensions
C29H26O11
550.50
123(2) K
0.71073 Å
Melting points were obtained on a Rapido Boetius apparatus
1
and are uncorrected. H nmr spectra were recorded on a Bruker
Avance spectrometer at 500 MHz. 13C nmr spectra were
recorded on a Bruker Avance spectrometer at 125 MHz. Mass
spectra (EI, 70 eV) were measured on a MS-50 A.E.I.
spectrometer. Thin-layer chromatography was carried out using
aluminum sheets coated with silica gel 60 F254 (Merck). 4,6-
Dimethoxy-3(2H)-benzofuranone was prepared as reported [8b,
12].
2-Bromo-4,6-dimethoxy-3(2H)-benzofuranone (1). A
mixture of 4.85 g (0.025 mole) of 4,6-dimethoxy-3(2H)-benzo-
furanone and 175 mL of dry tetrahydrofuran was heated 40°. A
solution of 9.40 g (0.025 mol) phenyltrimethyl ammonium-
bromide dibromide in 65 mL of dry tetrahydrofuran was added
dropwise over 30 minutes and the mixture was stirred for
additional 75 minutes at 40° and kept at room temperature for 20
minutes. The insoluble material was removed by suction
filtration und the filtrate was evaporated. The residue was
recrystallized from toluene and the precipitate was dissolved in
acetone. After addition of 150 mg of charcoal, the mixture was
stirred at room temperature for 30 minutes and filtrated. The
filtrate was evaporated to dryness to obtain a light brown solid.
4.52 g (66%). mp 139-142°, ref [15] 143-145°; 1H nmr (DMSO-
Monoclinic, P21/n (No.14)
a = 9.9913(2) Å
b = 13.4375(3) Å
c = 19.4220(5) Å
2576.89(10) Å3
4, 1.419 Mg/m3
0.110 mm-1
ꢀ = 90°
ꢁ = 98.797(1)°
ꢂ = 90°
Volume
Z, Calculated density
Absorption coefficient
F(000)
Crystal size
Diffractometer
1152
0.20 ꢃ 0.08 ꢃ 0.04 mm
Nonius KappaCCD
3.03° - 25.03°
-10 ꢅ h ꢅ 11, -15 ꢅ k ꢅ15, -23 ꢅ l ꢅ 19
16437 / 4522 [R(int) = 0.0383]
2880
ꢄ range for data collection
Limiting indices
Reflections collected / unique
Reflections with I > 2ꢆ(ꢀ)
Completeness to ꢄ = 25.03
Absorption correction
Refinement method
Data / restraints / parameters
Goodness-of-fit on F2
Final R indices [I > 2ꢆ(I)]
R indices (all data)
99.6%
none
Full-matrix least-squares on F2
4522 / 0 / 367
0.952
R1 = 0.0480, wR2 = 0.1223
R1 = 0.0827, wR2 = 0.1343
0.455 and -0.238 e Å-3
Largest diff. peak and hole

1152
P. Ottersbach, D. Bolek, E. Lepiꢀová, M. Nieger, M. Gütschow
Vol 45
d6): ꢀ 3.82, 3.84 (each s, 3H, CH3), 5.43 (s, 1H, 2-H), 6.14, 6.25
ppm (each d, 1H, 5-H, 7-H, J = 1.7 Hz); 13C nmr (DMSO-d6) ꢀ
56.06, 56.41 (CH3), 89.48 (C-2), 92.76, 98.48 (C-5, C-7), 102.51
(C-3a), 159.04, 170.13, 173.34 (C-4, C-6, C-7a), 192.48 ppm
(C-3).
2-(3,4-Dimethoxyphenyl)-3-hydroxy-5,7-dimethoxy-4H-1-
1
benzopyran-4-one (3b). mp 189-193°, ref [20] 184-186°; H
nmr (DMSO-d6): ꢀ 3.83, 3.84, 3.85, 3.90 (each s, 3H, CH3), 6.47
(d, 1H, 6-H or 8-H, J = 0.9 Hz), 6.83 (bs, 1H, 6-H or 8-H), 7.12
(d, 1H, 5´-H, J = 8.5 Hz), 7.75 (bs, 1H, 2´-H), 7.79 (dd, 1H, 6´-
H, J = 1.3, 8.5 Hz), 8.84 ppm (s, 1H, OH); 13C nmr (DMSO-d6)
ꢀ 55.74, 55.86, 56.13, 56.32 (CH3), 93.05, 95.83 (C-6, C-8),
106.40 (C-4a), 110.73, 111.75 (C-5´,C-2´), 120.86 (C-6´),
123.75 (C-1´), 138.02 (C-3), 141.81 (C-2), 148.63, 150.10 (C-3´,
C-4´), 158.20 (C-8a), 160.26, 163.87 (C-5, C-7), 171.14 ppm
(C-4).
Reaction of 2-Bromo-4,6-dimethoxy-3(2H)-benzofuranone
(1) with benzaldehyde (2a). Compound 1 (983 mg, 3.60 mmol)
was dissolved upon heating in dry toluene (35 mL) and
subsequently cooled to room temperature. Benzaldehyde (382
mg, 3.60 mmol) was added, followed by an equimolar amount of
sodium methoxide in methanolic solution, prepared from dry
methanol (3.0 mL) and sodium (83 mg). The reaction mixture
was stirred for 45 minutes at room temperature and a precipitate
was isolated by suction filtration and dried (110 mg). The
precipitate was suspended in water (20 mL), filtered off and
dried (71 mg). The material was recrystallized from
toluene/DMF (3:1) to obtain pure 4a (35 mg, 2%) as pale yellow
crystals. The filtrate that was obtained by the suction filtration
after 45 minutes was stirred for further 135 minutes. It was
filtrated and the filtrate was cooled (8°) for 7 days. The
precipitate formed was isolated by suction filtration to furnish
pure 3a (412 mg, 38%) as brown crystals.
3-(4,6-Dimethoxy-3-oxo-2,3-dihydrobenzofuran-2-yloxy)-
2-(3,4-dimethoxyphenyl)-5,7-dimethoxy-4H-1-benzopyran-4-
1
one (4b). mp 214-219°; H nmr (DMSO-d6): ꢀ 3.50, 3.77, 3.78,
3.85, 3.86, 3.91 (each s, 3H, CH3), 6.10, 6.19 (each d, 1H, 5´´-H,
7´´-H, J = 1.6 Hz), 6.28 (s, 1H, 2´´-H), 6.53, 6.84 (each d, 1H, 6-
H, 8-H, J = 2.1 Hz), 6.98 (d, 1H, 5´-H, J = 8.5 Hz), 7.44 (d, 1H,
2´-H, J = 2.2 Hz), 7.53 ppm (dd, 1H, 6´-H, J = 2.2, 8.5 Hz); 13C
nmr (DMSO-d6) ꢀ 55.01, 55.70, 56.23, 56.29, 56.35, 56.50
(CH3), 89.88, 93.31 (C-5´´, C-7´´), 93.65, 96.38 (C-6, C-8),
98.45 (C-2´´), 101.91 (C-3a´´), 108.38 (C-4a), 111.37, 111.69
(C-2´, C-5´), 121.64 (C-6´), 122.19 (C-1´), 135.39 (C-3), 148.13,
150.91 (C-3´, C-4´), 153.26 (C-2), 158.35 (C-8a), 159.30,
170.31, 173.60 (C-4´´, C-6´´ ,C-7a´´), 160.54, 164.18 (C-5, C-7),
171.28 (C-4), 188.41 ppm (C-3´´); ms: m/z 550 (29%, M+), 358
(77%, M+-C10H8O4), 329 (100%, M+-C11H9O5).
3-Hydroxy-5,7-dimethoxy-2-phenyl-4H-1-benzopyran-4-
1
one (3a). mp 170-173°, ref [19] 172-174°; H nmr (DMSO-d6):
ꢀ 3.86, 3.89 (each s, 3H, CH3,), 6.47, 6.82 (each d, 1H, 6-H, 8-H,
J = 2.3 Hz), 7.45 (tt, 1H, 4´-H, J = 1.3, 7.6 Hz), 7.51-7.56 (m,
2H, 3´-H, 5´-H), 8.16-8.19 (m, 2H, 2´-H, 6´-H), 9.02 ppm (s,
1H, OH); 13C nmr (DMSO-d6) ꢀ 56.12, 56.35 (CH3), 92.96,
95.87 (C-6, C-8), 106.49 (C-4a), 127.10 (C-2´, C-6´), 128.63 (C-
3´, C-5´), 129.49 (C-4´), 131.35 (C-1´), 138.94 (C-3), 141.44 (C-
2), 158.37 (C-8a), 160.35, 164.04 (C-5, C-7), 171.38 ppm (C-4).
3-(4,6-Dimethoxy-3-oxo-2,3-dihydrobenzofuran-2-yloxy)-
5,7-dimethoxy-2-phenyl-4H-1-benzopyran-4-one (4a). mp
2-(2-Chlorophenyl)-3-hydroxy-5,7-dimethoxy-4H-1-benzo-
pyran-4-one (3c). Upon heating, 2-bromo-4,6-dimethoxy-
3(2H)-benzofuranone (1) (492 mg, 1.80 mmol) was dissolved in
dry toluene (20 mL) and subsequently cooled to room
temperature. 2-Chlorobenzaldehyde (2c) (253 mg, 1.80 mmol)
was added, followed by an equimolar amount sodium methoxide
in a methanolic solution, prepared from dry methanol (3.0 mL)
and sodium (41 mg). The orange-green suspension was stirred
for 100 minutes and a colorless precipitate was removed by
filtration (143 mg). The filtrate was evaporated to dryness and
the residue was recrystallized from toluene to obtain 3c as
brown crystals (267 mg, 45%), mp 190-194°C; 1H nmr (DMSO-
d6): ꢀ 3.85, 3.87 (each s, 3H, CH3), 6.49, 6.64 (each d, 3H, 6-H,
8-H, J = 2.2 Hz), 7.48, 7.54 (each dt, 1H, 4´-H, 5´-H, J = 1.6, 7.4
Hz), 7.62 (dd, 1H, 3´-H or 6´-H, J = 1.3, 8.0 Hz), 7.64 (dd, 1H,
3´-H or 6´-H, J = 1.9, 7.6 Hz), 8.69 ppm (s, 1H, OH); 13C nmr
(DMSO-d6) ꢀ 56.11, 56.42 (CH3), 92.88, 95.96 (C-6, C-8),
107.27 (C-4a), 127.30 (C-5´), 129.85, 131.75, 132.09 (C-3´, C-
4´, C-6´), 130.06 (C-1´), 132.92 (C-2´), 139.26 (C-3), 142.25 (C-
2), 158.81 (C-8a), 160.35, 164.04 (C-5, C-7), 171.35 ppm (C-4).
Anal. Calcd. for C17H13ClO5: C, 61.37; H, 3.94. Found: C, 61.22;
H, 4.01.
1
213-217°; H nmr (DMSO-d6): ꢀ 3.79, 3.84, 3.87, 3.90 (each s,
3H, CH3,), 6.09, 6.18 (each d, 1H, 5´´-H, 7´´-H, J = 1.9 Hz), 6.23
(s, 1H, 2´´-H), 6.55, 6.84 (each d, 1H, 6-H, 8-H, J = 2.2 Hz),
7.36-7.41 (m, 3H, phenyl protons), 7.85-7.87 ppm (m, 2H,
phenyl protons); 13C nmr (DMSO-d6) ꢀ 56.24, 56.40, 56.53
(CH3), 89.77, 93.30 (C-5´´, C-7´´), 93.60, 96.49 (C-6, C-8),
98.65 (C-2´´), 102.12 (C-3a´´), 108.73 (C-4a), 128.34 (C-2´, C-
6´), 128.42 (C-3´,C-5´), 130.05 (C-4´), 130.69 (C-1´), 136.18
(C-3), 153.63 (C-2), 158.53 (C-8a), 159.24, 170.27, 173.60 (C-
4´´, C-6´´, C-7a´´), 160.63, 164.32 (C-5, C-7), 171.45 (C-4),
188.20 ppm (C-3´´); ms: m/z 490 (95%, M+), 298 (79%, M+-
C10H8O4), 282 (100%, M+-C10H8O5), 269 (48%, M+-C11H9O5).
Reaction of 2-Bromo-4,6-dimethoxy-3(2H)-benzofuranone
(1) with 3,4-dimethoxybenzaldehyde (2b). Compound 1 (983
mg, 3.60 mmol) was dissolved upon heating in dry toluene (35
mL) and subsequently cooled to room temperature. 3,4-Di-
methoxybenzaldehyde (598 mg, 3.60 mmol) was added,
followed by an equimolar amount of sodium methoxide in
methanolic solution, prepared from dry methanol (3.0 mL) and
sodium (83 mg). A bright precipitate was formed in the orange
reaction mixture. The suspension was stirred for 45 minutes at
room temperature and the precipitate was collected by filtration,
dried and washed with water (20 mL) and dried. The material
(94 mg) was recrystallized from toluene/DMF (3:1) to obtain a
pure product 4b (44 mg, 2%) as a yellow solid. The filtrate that
was obtained from the suction filtration after 45 minutes was
stirred for further 19 hours and evaporated to dryness. The
residue was recrystallized from toluene to furnish 3b (99 mg,
8%) as a brown solid.
2-(2-Bromophenyl)-3-hydroxy-5,7-dimethoxy-4H-1-benzo-
pyran-4-one (3d). Following the aforementioned procedure,
2-bromo-4,6-dimethoxy-3(2H)-benzofuranone (1) (492 mg,
1.80 mmol) was reacted with 2-bromobenzaldehyde (2d)
(333 mg, 1.80 mmol) to obtain 3d as brown crystals (260 mg,
38%), mp 187-190° (toluene); 1H nmr (DMSO-d6): ꢀ 3.85,
3.87 (each s, 3H, CH3), 6.49, 6.64 (each d, 1H, 6-H, 8-H, J =
2.4 Hz), 7.45, 7.52 (each dt, 1H, 4´-H, 5´-H, J = 1.6, 7.6 Hz),
7.62 (dd, 1H, 6´-H, J = 1.6, 7.6 Hz), 7.79 (dd, 1H, 3´-H, J =
1.0, 8.2 Hz), 8.69 ppm (s, 1H, OH); 13C nmr (DMSO-d6): ꢀ
56.11, 56.42 (CH3), 92.89, 95.95 (C-6, C-8), 107.31 (C-4a),
122.85 (C-2´), 127.81 (C-5´), 131.88, 132.23, 132.95 (C-3´,
C-4´, C-6´), 132.11 (C-1´), 138.99 (C-3), 143.58 (C-2),
158.76 (C-8a), 160.57, 163.94 (C-5, C-7), 171.43 ppm (C-4).

Jul-Aug 2008
Darzens Reaction to Form Flavonoids
1153
Res., 2000, 33, 79; [b] Westenburg, H. E.; Lee, K. J.; Lee, S. K.;
Fong, H. S.; van Breemen, R. B.; Pezzuto, J. M., Kinghorn, A. D. J.
Nat. Prod., 2000, 63, 1696.
[8a] Hadjeri, M.; Barbier, M.; Ronot, X.; Mariotte, A. M.;
Boumendjel, A.; Boutonnat, J. J. Med. Chem., 2003, 46, 2125. [b]
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A.; Trompier, D.; Baubichon-Cortay, H.; Di Pietro, A. Chem.
Pharm. Bull., 2002, 50, 854.
Anal. Calcd. for C17H13BrO5: C, 54.13; H, 3.47. Found: C,
54.33; H, 3.66.
X-ray crystal structure analysis. Appropriate crystals of 4b
were obtained by recrystallization from toluene/DMF (3:1).
Crystal data, the data collection procedure and structure
determination for compound 4b are given in Table 1. The
following programs were used to solve and refine the structure,
SHELXS97 [21], SHELXL97 [22]. SHELXTL [23] was used
for molecular graphics, and DIAMOND [24] and SHELXL97
for preparing material for publication. The details of the
structure analysis have been deposited at the Cambridge
Crystallographic Data Centre with the number CCDC-
665667. These data can be obtained, free of charge, from
CCDC, 12 Union Road, Cambridge, CB2 1EZ, UK (fax: +44-
1233-336033; e-mail: deposit@ccdc.cam.ac.uk; internet:
http://www.ccdc.cam.ac.uk).
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Acknowledgement. P.A.O. and M.G. are grateful to the
Graduate Colleges 677 and 804 for financial support.
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