Synthesis of novel 3-alkyl-3′,4′,5,7-tetrahydroxyflavones

Article abstract of DOI:10.1071/CH08162

Novel 3-alkyl-3′,4′,5,7-tetrahydroxyflavones have been prepared. The synthetic strategy involves the preparation of 1-(2-hydroxy-4,6-dimethoxyphenyl)alkan-1-ones from the FriedelCrafts acylation of phloroglucinol followed by methylation. These key compounds were submitted to the three-step BakerVenkataraman method, giving the 3-alkyl-3′,4′, 5,7-tetramethoxyflavones, which were demethylated with boron tribromide. CSIRO 2008.

Full text of DOI:10.1071/CH08162

Full Paper
CSIRO PUBLISHING
Aust. J. Chem. 2008, 61, 718–724
www.publish.csiro.au/journals/ajc
Synthesis of Novel 3-Alkyl-3ꢀ,4ꢀ,5,7-Tetrahydroxyflavones
Raquel S. G. R. Seixas,A Diana C. G. A. Pinto,A Artur M. S. Silva,A,B
and José A. S. CavaleiroA
ADepartment of Chemistry & QOPNA, University of Aveiro, 3810-193 Aveiro, Portugal.
BCorresponding author. Email: artur.silva@ua.pt
Novel 3-alkyl-3ꢀ,4ꢀ,5,7-tetrahydroxyflavones have been prepared. The synthetic strategy involves the preparation of 1-(2-
hydroxy-4,6-dimethoxyphenyl)alkan-1-ones from the Friedel–Crafts acylation of phloroglucinol followed by methylation.
These key compounds were submitted to the three-step Baker–Venkataraman method, giving the 3-alkyl-3ꢀ,4ꢀ,5,7-
tetramethoxyflavones, which were demethylated with boron tribromide.
Manuscript received: 17 April 2008.
Final version: 14 July 2008.
Introduction
atherosclerosis.[2a,10] The lipophilic character of this antioxidant
agent can also be realized by its higher protection of mitochon-
drial membrane integrity against the effect of primary reactive
oxygen species compared with other hydrophilic compounds.[11]
However, a synergic effect can occur when both hydrophilic and
lipophilic antioxidants are present.[8j,12] For instance, myricetin
(3,3ꢀ,4ꢀ,5,5ꢀ,7-hexahydroxyflavone) reacts faster and with twice
as many oxygen-centred radicals compared with vitamin E 3,
but fails to protect vitamin E-deficient microsomes from lipid
peroxidation. However, compounds whose structures consist of
polyhydroxylated flavones bearing lipophilic chains similar to
that of vitamin E 3 on their C7 carbon circumvent this situation,
being effective protectors of vitamin E-deficient microsomes.[8j]
Taking into consideration these results and pursuing our stud-
ies on chromone-type compounds with potential antioxidant
activity,[13] we decided to devote some attention to the synthe-
sis of luteolin analogues bearing a lipophilic 3-alkyl chain with
variable length for further biological activity. It is expected these
compounds might have better pharmacokinetics in humans than
other types of polyhydroxyflavones (e.g. quercetin),[14] which
are not well absorbed and are extensively metabolized, and could
behave as real antioxidants by scavenging free radicals. 3-Alkyl-
3ꢀ,4ꢀ-dihydroxypolymethoxyflavone derivatives have already
been described as inhibitors of arachidonate 5-lipoxygenase.[15]
Flavonoids are a group of low-molecular weight molecules
widely distributed in the plant kingdom, and represent a sig-
nificant part of the average western daily diet because they are
ubiquitous in fruits, vegetables, and beverages.[1] The interest in
this type of compounds has greatly grown in the past decades,
owing to their antioxidant properties and to the potential health
benefits in the treatment of deadly diseases involving substan-
tial oxidative processes, such as inflammatory and heart disease,
cancer, and HIV.[2–5] Among these phenolic compounds, the
flavones and flavonols are the most common classes, being the
first derivatives responsible for most of the important biological
activities assigned to flavonoids.
Beneficial effects of flavones have been described for
cancer,[3] and against bacteria,[4,5] viral infections[6] and
inflammations,[5,7] but one of the most reported activities is
the antioxidant one.[2,8] Several studies have reported on the
qualitative structure–activity relationships for flavone-mediated
antioxidant activities and have stressed the importance of the
catechol moiety in the B-ring, the 4ꢀ-OH group conjugated
with the 3-OH or 4-keto functions of the C-ring through the
C2=C3 double bond and the additional presence of 3- and 5-
hydroxyl groups in the flavone molecular structure to achieve
efficient antioxidant action.[2,8] In addition, the antioxidant effi-
ciency of hydroxyflavones has been related to the number of
hydroxyl groups in the molecule, and also to their hydrogen
radical-donating abilities.[8] A great number of studies have
demonstrated that quercetin 1,[2] a flavonol-type compound, and
luteolin 2,[9] a flavone-type compound, are powerful antioxidant
agents (Scheme 1).
Results and Discussion
Chemistry
The synthesis of 3-alkyl-3ꢀ,4ꢀ,5,7-tetrahydroxyflavones 9a–d
began with the synthesis of the key compounds 1-(2-hydroxy-
4,6-dimethoxyphenyl)alkan-1-ones 4a–d. Fries rearrangement
of 1-acyloxy-3,5-dihydroxybenzenes was our first approach,
but the treatment of 1-octanoyloxy-3,5-dihydroxybenzene with
aluminium(iii) chloride under different experimental conditions
(using 1,2,4-trichlorobenzene as solvent or solvent-free molten
conditions) did not afford the corresponding and expected
ketone. In the second attempt, the direct acylation of 1,3,5-
Recent studies showed that lipophilic flavones bearing
methyl, isopropyl, benzyl, or isoprenyl groups enhance the bind-
ing affinity towards P-glycoprotein and the modulation of cancer
cell chemoresistance.[3a] VitaminE (α-tocopherol) 3, a lipophilic
antioxidant agent, is thought to be the major non-enzymatic
antioxidant present in the lipid structures of cells and lipo-
proteins that reacts with peroxyl radicals, inhibiting the propaga-
tion cycle of lipid peroxidation and decreasing the modification
of low-density lipoprotein, and preventing the development of
trimethoxybenzene with two molar equiv. of octanoyl chloride
[16]
in the presence of AlCl3
was attempted, but this procedure
was also unproductive as the low-yield formation of a mixture
© CSIRO 2008 10.1071/CH08162 0004-9425/08/090718

Synthesis of Tetrahydroxyflavones
719
OH
OH
OH
OH
HO
O
HO
O
O
OH
HO
OH O
OH O
3
1
2
Scheme 1.
5؅
OH
4؅
O
MeO
6؅ OMe
O
MeO
MeO
ϩ
A
B
1
OH
3؅
Cl
n
2؅
C
n
HO
HO
OH
OH
O
a n ϭ 0
b n ϭ 3
c n ϭ 5
d n ϭ 9
4
5؅
MeO
6؅
OMe
4؅
3؅
1
OH
O
2؅
O
n
5؅
5؆
O
O
MeO
4؅
6؅ OMe
OMe
OMe
6؆
1؆
D
4؆
3؆
nϪ1
6
3؆
4؆
7؆
6؆
3؅
2
1
OH
5
3
2؅
2؆
OH
O
O
OMe
5؆
7
OMe
A BF3·Et2O
6
E
B (CH3)2SO4/K2CO3/acetone
C DCC, 4-ppy, CH2Cl2
or POCl3, Py
D KOH, DMSO
E p-TsOH, DMSO
F BBr3, CH2Cl2
5؅
OMe
OMe
4؅
3؅
OH
OH
6؅
8
MeO
HO
9
2
3
O
O
7
6
2؅
F
4
10
5
nϪ1
nϪ1
MeO
OH
O
O
8
9
Scheme 2.
of mono- and diacylated products was obtained,[17] the mono-
acylated product being the minor one. Changes in reaction time
(from 24 to 12 h) and amount of octanoyl chloride (from 2 to
1 equiv.) did not improve the yield of the monoacylated prod-
uct. Then, we changed the Friedel–Crafts reaction catalyst to
a diethyl ether solution of BF3,[18] and the acylation of phloro-
glucinol with octanoyl chloride in the presence of BF3·Et2O was
attempted (Scheme 1). Attempts to isolate the corresponding 1-
(2,4,6-trihydroxyphenyl)octan-1-one 5 proved to be unsuccess-
ful, because a mixture of compounds was always obtained. To
circumvent this problem, we decided to perform a quick purifi-
cation of the raw material obtained by column chromatography,
to eliminate most of the undesired by-products, and immediately
proceeded with the protection of two hydroxyl groups by treat-
ment of the residue obtained with methyl sulfate under basic
conditions (see Experimental). The desired 1-(2-hydroxy-4,6-
dimethoxyphenyl)octan-1-one 4c was obtained in a moderate
overall yield (34%).A similar procedure was applied to the reac-
tion of phoroglucinol with propanoyl, hexanoyl, or dodecanoyl
chloride, followed by methylation, affording the 1-(2-hydroxy-
4,6-dimethoxyphenyl)alkan-1-ones 4a, b, d in moderate yields
(32–46%; Scheme 1).
The esterification of 1-(2-hydroxy-4,6-dimethoxyphenyl)
alkan-1-ones 4a–d was attempted by reaction with
3,4-dimethoxybenzoyl chloride, prepared in situ from 3,4-
dimethoxybenzoic acid and phosphorous oxychloride in dry
pyridine.[19] However, after an extensive study of this
reaction by changing the amounts of phosphorous oxychlo-
ride (2.5 or 5 equiv.), the reaction temperatures (room tem-
perature, 60, or 100◦C) and times (12, 24, or 48 h), the
expected esters 7a–d were obtained in low to moderate yield
(16–37%). As these results were not satisfactory, we decided
to use N,N-dicyclohexylcarbodiimide (DCC) as coupling
esterification agent in the presence of a catalytic amount of
4-pyrrolidinopyridine (4-ppy).[20] Treatment of 1-(2-hydroxy-4,
6-dimethoxyphenyl)octan-1-one 4c with 3,4-dimethoxybenzoic
acid with an equivalent molar amount of DCC and a catalytic
amount of 4-ppy in CH2Cl2 for 24 h led to the formation of
ester 6c in moderate yield (38%). Increasing the reaction time
to 7 days improved the yield of 6c to 72%, but it was necessary
to add a new batch of DCC and 4-ppy to improve the yield up to
94% (see Experimental). Under similar conditions, esters 6a, b,
d were obtained in excellent yields (89–94%).
Baker–Venkataraman rearrangement of esters 6a–d with
potassium hydroxide in DMSO afforded β-diketones 7a–d in
good yields (60–75%); these were submitted to a cyclodehy-
dration process with a p-toluenesulfonic acid/DMSO mixture,
leadingtothesynthesisof3-alkyl-3ꢀ,4ꢀ,5,7-tetramethoxyflavones
8a–d in very good yields (77–95%).
The final step of our synthetic route consisted of the demethy-
lation of flavones 8a–d, and this was performed by treatment
with boron tribromide (2.5 equiv. per methyl group) in CH2Cl2
for 48 h (Scheme 2). The 7-OMe was the most difficult group
to be cleaved, as 3-hexyl-3ꢀ,4ꢀ,5-trihydroxy-7-methoxyflavones
were obtained when the demethylation of 3-hexyl-3ꢀ,4ꢀ,5,7-
tetramethoxyflavone 8c was complete after 24 h of reaction.[21]
NMR Spectroscopy
The main features of the 1H NMR spectra of each 1-(2-hydroxy-
4,6-dimethoxyphenyl)alkan-1-one 4a–d are the high-frequency
singlet at δH 14.12–14.13, due to hydroxyl protons involved in
intramolecular hydrogen bonds with the carbonyl groups, the
two singlets at δH 3.82–3.86, assigned to the 4- and 6-methoxy

720
R. S. G. R. Seixas et al.
5؅
OMe
OMe
4؅
3؅
OH
OH
H
6؅
5؅
5؆
OMe
R
OMe
6؅
H 6؆
MeO
8
2
O
HO
O
O
MeO
H
4؅
3؅
2؅
R
3
6
2
1
4
3؆ OMe
2؅
΃
΂
C
H2
5
n
O
O
O
H
MeO
O
O
H
H
7
8
9
Fig. 1. Main connectivities found in the heteronuclear multiple bond coherence spectra of compounds 7, 8, and 9.
groups, and the two doublets δH 5.92–5.93 and 6.06–6.07,
attributed to the resonances of H5ꢀ and H3ꢀ, respectively. The
typical carbon resonance at δC 206.1–206.4 in their 13C NMR
spectra also confirms the presence of a ketone carbonyl group.
The formation of esters 6a–d can be inferred from the absence
of the signals due to the hydroxyl proton singlets in their
1H NMR spectra and the presence of an ester carbonyl group
at δC 164.4–164.5 in their 13C NMR spectra.
The appearance of only one hydroxyl resonance at high-
frequency values (δH 13.87) in the 1H NMR spectra of
β-diketones 7a–d suggests the presence of only one tautomer,
as depicted in Scheme 2, and the absence of a keto–enol tauto-
meric equilibrium that is seen for other types of diketones.[22]
These structures were also supported by the carbon resonances
of two ketone carbonyl groups, appearing at δC 195.6–195.8 and
200.6–201.4, in their 13C NMR spectra, and assigned to C3 and
C1, respectively. The unequivocal assignment of these carbon
resonances and those of the always difficult to differentiate C3ꢀ
and C5ꢀ[23] were confirmed by the connectivities found in the
heteronuclear multiple quantum coherence (HMBC) spectra of
diketones 7a–d (Fig. 1).
The connectivities found in the HMBC spectra of poly-
methoxyflavones 8a–d supported their structures and allowed
the assignment of the quaternary carbons, mainly those of
the A and C rings (Fig. 1). From the 1H NMR spectra of
polyhydroxyflavones 9a–d, it is important to notice the high-
frequencyresonances, appearingasfoursingletsatδH 9.39–9.42,
9.64–9.65, 10.81–10.85, and 13.09, due to the proton reso-
nances of 3ꢀ-OH, 4ꢀ-OH, 7-OH, and 5-OH, respectively and
the important connectivities presented by two of these hydroxyl
protons (Fig. 1).
200 µL of 0.1% trifluoroacetic acid/methanol solution. Nitrogen
was used as nebulizer gas and argon as collision gas. The nee-
dle voltage was set at 3000V, with the ion source at 80◦C
and desolvation temperature at 150◦C. Cone voltage was 35V).
The high-resolution mass spectra (electron impact (EI), 70 eV)
were measured on a VG Autospec M mass spectrometer. Ele-
mental analyses were obtained with a LECO 932 CHN anal-
yser (University of Aveiro). 1H and 13C NMR spectra were
recorded on a Bruker Avance 300 spectrometer (at 300.13
and 75.47 MHz, respectively) unless stated otherwise; chemical
shifts are reported in ppm (δ) using TMS as internal reference
and coupling constants (J) are given in Hz. The 13C unequivocal
assignments were made with the aid of two-dimensional gradient
selected heteronuclear single quantum coherence (gHSQC) and
two-dimensional gradient selected heteronuclear multiple quan-
tum coherence (gHMBC) (delays for one-bond and long-range
J C–H couplings were optimized for 145 and 7 Hz, respec-
tively) experiments. Column chromatography was performed
with Merck silica gel 60.
General Procedure for the Synthesis of 1-(2-Hydroxy-
4,6-dimethoxyphenyl)alkan-1-ones 4a–d
BF3·Et2O (11.1 mL, 39.8 mmol) was added dropwise to an
ice-cooled mixture of 1,3,5-trihydroxybenzene (phlorogluci-
nol) (2.00 g, 15.9 mmol) and the appropriate alkanoyl chloride
(15.9 mmol). After the addition, the ice bath was removed and
the reaction mixture was stirred under nitrogen at room tem-
perature for 48 h. Then the solution was poured into ice (50 g)
and water (150 mL) and the mixture obtained was extracted with
ethyl acetate (3 × 150 mL); the organic layer was washed with
water and the solvent was evaporated to dryness. The residue
obtained was submitted to column chromatography to remove
most of the impurities; the major component was collected by
using a mixture of CH2Cl2/acetone (20:1) as eluent.
Anhydrous K2CO3 (8.8 g, 63.6 mmol) and (CH3)2SO4 were
added (6.02 mL, 63.6 mmol) to the crude product obtained taken
up in acetone (150 mL). The reaction mixture was heated to
50–60◦C under nitrogen for 1.5 h. After this period, K2CO3
was filtered off, washed with acetone (100 mL), and the sol-
vent was evaporated to dryness. The residue was purified by
silica gel column chromatography using a 1:1 mixture of light
petroleum/CH2Cl2 as eluent. The solvent was evaporated to dry-
ness and the residue was recrystallized from ethanol in each case
to give 1-(2-hydroxy-4,6-dimethoxyphenyl)alkan-1-ones 4a–d
as white needles.
Conclusions
The Friedel–Crafts acylation of phloroglucinol with appro-
priate long-chain alkanoyl chlorides in the presence of
BF3·Et2O, followed by methylation with methyl sulfate in
alkaline medium gave 1-(2-hydroxy-4,6-dimethoxyphenyl)-
1-alkan-1-ones 4a–d. These compounds 4a–d were ester-
ified with 3,4-dimethoxybenzoic acid, with DCC and
4-ppy as coupling agents. Esters 6a–d were submit-
ted to a Baker–Venkataraman rearrangement, giving the
β-diketones
2-alkyl-1-(2-hydroxy-4,6-dimethoxyphenyl)-3-
(3,4-dimethoxyphenyl)propan-1,3-diones 7a–d; these were con-
verted to the 3-alkyl-3ꢀ,4ꢀ,5,7-tetramethoxyflavones 8a–d by
cyclodehydration with p-toluenesulfonic acid in DMSO. Finally,
the demethylation of 8a–d with boron tribromide afforded the
novel 3-alkyl-3ꢀ,4ꢀ,5,7-tetrahydroxyflavones 9a–d.
1-(2-Hydroxy-4,6-dimethoxyphenyl)propan-1-one 4a
Yield: (1.10 g, 33%), mp 106–107◦C. δH (CDCl3) 1.16 (3H, t, J
7.2, H3), 3.03 (2H, q, J 7.2, H2), 3.82 (3H, s, 4ꢀ-OCH3), 3.86
(3H, s, 6ꢀ-OCH3), 5.93 (1H, d, J 2.4, H5ꢀ), 6.07 (1H, d, J 2.4,
H3ꢀ), 14.12 (1H, s, 2ꢀ-OH). δC (CDCl3) 8.6 (C3), 37.4 (C2), 55.5
(4ꢀ,6ꢀ-OCH3), 90.7 (C5ꢀ), 93.5 (C3ꢀ), 105.7 (C1ꢀ), 162.8 (C6ꢀ),
165.7 (C4ꢀ), 167.5 (C2ꢀ), 206.4 (C1). m/z 211 [M + H]+, 233
[M + Na]+. Found: m/z 210.0895. M+• requires 210.0892.
Experimental
Melting points were measured in a Griffin–Gallenkamp appa-
ratus and are uncorrected. Positive-ion electrospray ionization
(ESI) mass spectra were acquired using a Q-TOF 2 instrument
(diluting 1 µL of the sample chloroform solution (∼10−5 M) in

Synthesis of Tetrahydroxyflavones
721
1-(2-Hydroxy-4,6-dimethoxyphenyl)hexan-1-one 4b
(6H, s, 4ꢀ,6ꢀ-OCH3), 3.95 and 3.96 (6H, s, 4ꢀꢀ,5ꢀꢀ-OCH3), 6.40
(2H, AB, J 2.3, H3ꢀ and H5ꢀ), 6.93 (1H, d, J 8.5, H6ꢀꢀ), 7.60
(1H, d, J 2.0, H3ꢀꢀ), 7.78 (1H, dd, J 2.0 and 8.5, H7ꢀꢀ). δC
(CDCl3) 8.2 (C3), 37.5 (C2), 55.6 and 55.9 (4ꢀ,6ꢀ-OCH3), 56.0
and 56.1 (4ꢀꢀ,5ꢀꢀ-OCH3), 96.5 and 99.9 (C3ꢀ and C5ꢀ), 110.4
(C6ꢀꢀ), 112.3 (C3ꢀꢀ), 117.5 (C1ꢀ), 121.4 (C2ꢀꢀ), 124.6 (C7ꢀꢀ), 148.7
(C4ꢀꢀ), 149.4 (C2ꢀ), 153.6 (C5ꢀꢀ), 158.5 and 161.8 (C4ꢀ and C6ꢀ),
164.6 (C1ꢀꢀ), 203.3 (C1). m/z 397 [M + Na]+, 413 [M + K]+,
771 [2M + Na]+. (Found: C 63.9, H 5.9. C20H22O7 requires
C 64.2, H 5.9%.)
Yield: (1.28 g, 32%), mp 74–75◦C. δH (CDCl3) 0.91 (3H, t, J
6.7, H6), 1.32–1.37 (4H, m, H4 and H5), 1.66 (2H, quint., J 7.2,
H3), 2.95–3.00 (2H, m, H2), 3.82 (3H, s, 4ꢀ-OCH3), 3.85 (3H,
s, 6ꢀ-OCH3), 5.92 (1H, d, J 2.4, H5ꢀ), 6.07 (1H, d, J 2.4, H3ꢀ),
14.13 (1H, s, 2ꢀ-OH). δC (CDCl3) 14.0 (C6), 22.6 (C5), 24.5
(C3), 31.7 (C4), 44.2 (C2), 55.5 (4ꢀ,6ꢀ-OCH3), 90.8 (C5ꢀ), 93.6
(C3ꢀ), 105.7 (C1ꢀ), 162.7 (C6ꢀ), 165.7 (C4ꢀ), 167.7 (C2ꢀ), 206.1
(C1). m/z (ESI-MS) 253 [M + H]+, 275 [M + Na]+. (Found:
C 66.7, H 7.7. C14H20O4 requires C 66.7, H 8.0%.)
1-(2-Hydroxy-4,6-dimethoxyphenyl)octan-1-one 4c
1-[2-(3,4-Dimethoxybenzoyloxy)-4,6-
Yield: (1.52 g, 34%), mp 73–74◦C. δH (CDCl3) 0.86–0.91 (3H,
m, H8), 1.29–1.34 (8H, m, H4 to H7), 1.65 (2H, quint., J 7.2,
H3), 2.95–3.00 (2H, m, H2), 3.82 (3H, s, 4ꢀ-OCH3), 3.85 (3H,
s, 6ꢀ-OCH3), 5.92 (1H, d, J 2.4, H5ꢀ), 6.06 (1H, d, J 2.4, H3ꢀ),
14.13 (1H, s, 2ꢀ-OH). δC (CDCl3) 14.1 (C8), 22.6 (C7), 24.8
(C3), 29.2 and 29.5 (C4 and C5), 31.7 (C6), 44.3 (C2), 55.5
(4ꢀ,6ꢀ-OCH3), 90.7 (C5ꢀ), 93.5 (C3ꢀ), 105.7 (C1ꢀ), 162.7 (C6ꢀ),
165.7 (C4ꢀ), 167.6 (C2ꢀ), 206.1 (C1). m/z 281 [M + H]+, 303
[M + Na]+, 583 [2M + Na]+. (Found: C 68.7, H 8.4. C16H24O4
requires C 68.5, H 8.6%.)
dimethoxyphenyl]hexan-1-one 6b
Yield: (1.93 g, 89%), mp 93–95◦C. δH (CDCl3) 0.81 (3H, t, J
6.8, H6), 1.18–1.26 (4H, m, H4 and H5), 1.59 (2H, quint., J
7.3, H3), 2.78 (2H, t, J 7.3, H2), 3.81 and 3.83 (6H, s, 4ꢀ,6ꢀ-
OCH3), 3.95 (6H, s, 4ꢀꢀ,5ꢀꢀ-OCH3), 6.40 (2H, AB, J 2.4, H3ꢀ and
H5ꢀ), 6.93 (1H, d, J 8.5, H6ꢀꢀ), 7.60 (1H, d, J 1.9, H3ꢀꢀ), 7.79
(1H, dd, J 1.9 and 8.5, H7ꢀꢀ). δC (CDCl3) 13.8 (C6), 22.3 and
31.2 (C4 and C5), 23.5 (C3), 44.1 (C2), 55.4 and 55.7 (4ꢀ,6ꢀ-
OCH3), 55.8 and 55.9 (4ꢀꢀ,5ꢀꢀ-OCH3), 96.3 and 99.9 (C3ꢀ and
C5ꢀ), 110.2 (C6ꢀꢀ), 112.1 (C3ꢀꢀ), 117.4 (C1ꢀ), 121.3 (C2ꢀꢀ), 124.4
(C7ꢀꢀ), 148.5 (C4ꢀꢀ), 149.3 (C2ꢀ), 153.4 (C5ꢀꢀ), 158.4 and 161.6
(C4ꢀ and C6ꢀ), 164.4 (C1ꢀꢀ), 202.5 (C1). m/z 439 [M + Na]+,
455 [M + K]+, 855 [2M + Na]+, 871 [2M + K]+. (Found: 66.4,
H 6.9. C23H28O7 requires C 66.3, H 6.8%.)
1-(2-Hydroxy-4,6-dimethoxyphenyl)dodecan-1-one 4d
Yield: (2.46 g, 46%), mp 80–83◦C. δH (CDCl3) 0.88 (3H, t, J
6.7, H12), 1.26–1.32 (16H, m, H4 to H11), 1.60–1.70 (2H, m,
H3), 2.96–2.99 (2H, m, H2), 3.82 (3H, s, 4ꢀ-OCH3), 3.85 (3H, s,
6ꢀ-OCH3), 5.92 (1H, d, J 2.4, H5ꢀ), 6.06 (1H, d, J 2.4, H3ꢀ), 14.13
(1H, s, 2ꢀ-OH). δC (CDCl3) 14.1 (C12), 22.7, 29.3, 29.53, 29.54,
29.6 and 31.9 (C4 to C11), 24.8 (C3), 44.3 (C2), 55.5 (4ꢀ,6ꢀ-
OCH3), 90.7 (C5ꢀ), 93.6 (C3ꢀ), 105.7 (C1ꢀ), 162.7 (C6ꢀ), 165.7
(C4ꢀ), 167.6 (C2ꢀ), 206.1 (C1). m/z (ESI-MS) 337 [M + H]+, 359
[M + Na]+, 695 [2M + Na]+. (Found: C 71.4, H 9.6. C20H32O4
requires C 71.4, H 9.6%.)
1-[2-(3,4-Dimethoxybenzoyloxy)-4,6-
dimethoxyphenyl]octan-1-one 6c
Yield: (2.17 g, 94%), mp 80–82◦C. δH (CDCl3) 0.84 (3H, t, J
6.8, H8), 1.18–1.24 (8H, m, H4 to H7), 1.57 (2H, quint., J 7.3,
H3), 2.77 (2H, t, J 7.3, H2), 3.82 and 3.84 (6H, s, 4ꢀ,6ꢀ-OCH3),
3.95 and 3.96 (6H, s, 4ꢀꢀ,5ꢀꢀ-OCH3), 6.39–6.40 (2H, m, H3ꢀ and
H5ꢀ), 6.93 (1H, d, J 8.5, H6ꢀꢀ), 7.60 (1H, d, J 2.0, H3ꢀꢀ), 7.78
(1H, dd, J 2.0 and 8.5, H7ꢀꢀ). δC (CDCl3) 14.1 (C8), 22.6 (C7),
31.7 (C6), 24.0 (C3), 29.1 (C4 and C5), 44.3 (C2), 55.6 and 55.8
(4ꢀ,6ꢀ-OCH3), 56.0 and 56.1 (4ꢀꢀ,5ꢀꢀ-OCH3), 96.6 and 100.0 (C3ꢀ
and C5ꢀ), 110.3 (C6ꢀꢀ), 112.3 (C3ꢀꢀ), 117.6 (C1ꢀ), 121.4 (C2ꢀꢀ),
124.6 (C7ꢀꢀ), 148.7 (C4ꢀꢀ), 149.4 (C2ꢀ), 153.6 (C5ꢀꢀ), 158.5 and
161.7 (C4ꢀ and C6ꢀ), 164.6 (C1ꢀꢀ), 202.8 (C1). m/z 445 [M + H]+,
467 [M + Na]+, 483 [M + K]+, 911 [2M + Na]+, 927
[2M + K]+. (Found: C 67.5, H 7.2. C25H32O7 requires C 67.6,
H 7.3%.)
General Procedure for the Synthesis
of 1-[2-(3,4-Dimethoxybenzoyloxy)-4,6-
dimethoxyphenyl]alkan-1-ones 6a–d
3,4-Dimethoxybenzoic acid (0.95 g, 5.2 mmol), N,N-dicyclo-
hexylcarbodiimide (1.07 g, 5.2 mmol) and 4-pyrrolidinopyridine
(77.1 mg, 0.52 mmol) were added to a solution of the appro-
priate 1-(2-hydroxy-4,6-dimethoxyphenyl)alkan-1-ones 4a–d
(5.2 mmol) in CH2Cl2 (100 mL). The mixture was stirred
under nitrogen at room temperature for 7 days, then a
new portion of 3,4-dimethoxybenzoic acid (0.95 g, 5.2 mmol),
N,N-dicyclohexylcarbodiimide (1.07 g, 5.2 mmol), and
4-pyrrolidinopyridine (77.1 mg, 0.52 mmol) were added and the
reaction continued for another 7 days. After that period, the
urea formed was filtered off and washed with CH2Cl2 (50 mL).
The solution was concentrated under reduced pressure and puri-
fied by silica gel column chromatography using a mixture of
light petroleum/ethyl acetate (5:2) as eluent. The solvent was
evaporated to dryness and the residue was crystallized in each
case from a mixture of light petroleum/CH2Cl2 to give 1-[2-
(3,4-dimethoxybenzoyloxy)-4,6-dimethoxyphenyl]alkan-1-ones
6a–d as white powders.
1-[2-(3,4-Dimethoxybenzoyloxy)-4,6-
dimethoxyphenyl]dodecan-1-one 6d
Yield: (2.45 g, 94%), mp 45–46◦C. δH (CDCl3) 0.87 (3H, t, J 6.7,
H12), 1.21–1.29 (16H, m, H4 to H11), 1.58 (2H, quint., J 7.2,
H3), 2.78 (2H, t, J 7.2, H2), 3.82 and 3.83 (6H, s, 4ꢀ,6ꢀ-OCH3),
3.95 and 3.96 (6H, s, 4ꢀꢀ,5ꢀꢀ-OCH3), 6.39 (2H, AB, J 2.4, H3ꢀ
and H5ꢀ), 6.92 (1H, d, J 8.5, H6ꢀꢀ), 7.60 (1H, d, J 2.0, H3ꢀꢀ),
7.78 (1H, dd, J 2.0 and 8.5, H7ꢀꢀ). δC (CDCl3) 14.0 (C12), 22.6
and 31.8 (C10 and C11), 23.9 (C3), 29.1, 29.2, 29.36, 29.42,
29.5 (C4 to C9), 44.2 (C2), 55.5 and 55.7 (4ꢀ,6ꢀ-OCH3), 55.9
and 56.0 (4ꢀꢀ,5ꢀꢀ-OCH3), 96.5 and 99.9 (C3ꢀ and C5ꢀ), 110.3
(C6ꢀꢀ), 112.2 (C3ꢀꢀ), 117.6 (C1ꢀ), 121.4 (C2ꢀꢀ), 124.5 (C7ꢀꢀ), 148.6
(C4ꢀꢀ), 149.4 (C2ꢀ), 153.5 (C5ꢀꢀ), 158.4 and 161.7 (C4ꢀ and C6ꢀ),
164.5 (C1ꢀꢀ), 202.7 (C1). m/z 501 [M + H]+, 523 [M + Na]+,
539[M + K]+. (Found:C69.7, H7.9. C29H40O7 requiresC69.6,
H 8.1%.)
1-[2-(3,4-Dimethoxybenzoyloxy)-4,6-
dimethoxyphenyl]propan-1-one 6a
Yield: (1.75 g, 90%), mp 136–138◦C. δH (CDCl3) 1.07 (3H,
t, J 7.3, H3), 2.81 (2H, q, J 7.3, H2), 3.82 and 3.84

722
R. S. G. R. Seixas et al.
General Procedure for the Synthesis of
2-Alkyl-1-(2-hydroxy-4,6-dimethoxyphenyl)-3-
(3,4-dimethoxyphenyl)propan-1,3-diones 7a–d
1.9, H2ꢀꢀ), 7.60 (1H, dd, J 1.9 and 8.3, H6ꢀꢀ), 13.87 (1H, s, 2ꢀ-
OH). δC (CDCl3) 14.1 (C6ꢀꢀꢀ), 22.6 and 31.6 (C4ꢀꢀꢀ and C5ꢀꢀꢀ),
28.7, 29.0 and 29.5 (C1ꢀꢀꢀ to C3ꢀꢀꢀ), 55.3 and 55.6 (4ꢀ,6ꢀ-OCH3),
55.9 (3ꢀꢀ-OCH3), 56.1 (4ꢀꢀ-OCH3), 60.0 (C2), 90.9 (C5ꢀ), 94.0
(C3ꢀ), 105.4 (C1ꢀ), 110.1 (C5ꢀꢀ), 110.6 (C2ꢀꢀ), 122.7 (C6ꢀꢀ), 129.3
(C1ꢀꢀ), 149.1 (C3ꢀꢀ), 153.0 (C4ꢀꢀ), 161.7 and 166.1 (C4ꢀ and C6ꢀ),
168.1 (C2ꢀ), 195.6 (C3), 200.7 (C1). m/z 445 [M + H]+, 467
[M + Na]+, 483 [M + K]+, 911 [2M + Na]+, 927 [2M + K]+,
1356 [3M + Na]+. (Found: C 67.5, H 7.1. C25H32O7 requires C
67.6, H 7.3%.)
Potassium hydroxide (powder, 0.98 g, 17.5 mmol) was added to
a solution of the appropriate 1-[2-(3,4-dimethoxybenzoyloxy)-
4,6-dimethoxyphenyl]alkan-1-ones 6a–d (3.5 mmol) in DMSO
(30 mL). The solution was stirred under nitrogen at room tem-
perature for 1 h. After that period, the solution was poured
into ice (50 g) and water (150 mL), and the pH adjusted to 4
with dilute HCl. The solid obtained was removed by filtration,
taken up in CHCl3 (150 mL), and the organic layer was washed
with water (3 × 150 mL). The mixture was purified by silica
gel column chromatography using 5:2 light petroleum/ethyl
acetate as eluent. The solvent was evaporated to dryness and
the residue in each case was recrystallized from a mixture
of light petroleum/CH2Cl2 to give 2-alkyl-1-(2-hydroxy-4,6-
dimethoxyphenyl)-3-(3,4-dimethoxyphenyl)propan-1,3-diones
7a–d as white powders.
2-Decyl-1-(2-hydroxy-4,6-dimethoxyphenyl)-3-
(3,4-dimethoxyphenyl)propan-1,3-dione 7d
Yield: (1.31 g, 75%), mp 114–116◦C. δH (CDCl3) 0.87 (3H, t, J
6.7, H10ꢀꢀꢀ), 1.25–1.42 (16H, m, H2ꢀꢀꢀ to H9ꢀꢀꢀ), 1.78–1.90 (1H,
m, H1ꢀꢀꢀ), 2.08–2.18 (1H, m, H1ꢀꢀꢀ), 3.43 and 3.80 (6H, s, 4ꢀ,6ꢀ-
OCH3), 3.92 (3H, s, 3ꢀꢀ-OCH3), 3.97 (3H, s, 4ꢀꢀ-OCH3), 5.31
(1H, dd, J 4.2 and 8.5, H2), 5.84 (1H, d, J 2.3, H5ꢀ), 6.09 (1H, d,
J 2.3, H3ꢀ), 6.94 (1H, d, J 8.3, H5ꢀꢀ), 7.57 (1H, d, J 2.0, H2ꢀꢀ), 7.60
(1H, dd, J 2.0 and 8.3, H6ꢀꢀ), 13.87 (1H, s, 2ꢀ-OH). δC (CDCl3)
14.1 (C10ꢀꢀꢀ), 22.6 and 31.8 (C8ꢀꢀꢀ and C9ꢀꢀꢀ), 28.7 (C2ꢀꢀꢀ), 29.0
(C1ꢀꢀꢀ), 29.3, 29.4, 29.5 and 29.8 (C3ꢀꢀꢀ to C7ꢀꢀꢀ), 55.2 and 55.5
(4ꢀ,6ꢀ-OCH3), 55.9 (3ꢀꢀ-OCH3), 56.0 (4ꢀꢀ-OCH3), 59.9 (C2), 90.8
(C5ꢀ), 93.9 (C3ꢀ), 105.3 (C1ꢀ), 110.0 (C5ꢀꢀ), 110.5 (C2ꢀꢀ), 122.6
(C6ꢀꢀ), 129.2 (C1ꢀꢀ), 149.0 (C3ꢀꢀ), 153.0 (C4ꢀꢀ), 161.6 and 166.1
(C4ꢀ and C6ꢀ), 168.0 (C2ꢀ), 195.6 (C3), 200.6 (C1). m/z 501
[M + H]+, 523 [M + Na]+, 539 [M + K]+, 1024 [2M + Na]+.
(Found: C 69.3, H 8.1. C29H40O7 requires C 69.6, H 8.1%.)
1-(2-Hydroxy-4,6-dimethoxyphenyl)-2-methyl-3-
(3,4-dimethoxyphenyl)propan-1,3-dione 7a
Yield: (786 mg, 60%), mp 200–202◦C. δH (500.13 MHz, CDCl3)
1.50 (3H, d, J 7.1, H3), 3.36 (3H, s, 6ꢀ-OCH3) 3.80 (3H, s, 4ꢀ-
OCH3), 3.92 (3H, s, 3ꢀꢀ-OCH3), 3.97 (3H, s, 4ꢀꢀ-OCH3), 5.34
(1H, q, J 7.1, H2), 5.82 (1H, d, J 2.4, H5ꢀ), 6.09 (1H, d, J
2.4, H3ꢀ), 6.94 (1H, d, J 8.4, H5ꢀꢀ), 7.57 (1H, d, J 2.0, H2ꢀꢀ),
7.63 (1H, dd, J 2.0 and 8.4, H6ꢀꢀ), 13.87 (1H, s, 2ꢀ-OH). δC
(125.77 MHz, CDCl3) 14.2 (C3), 54.3 (C2), 55.2 (6ꢀ-OCH3),
55.6 (4ꢀ-OCH3), 56.0 (3ꢀꢀ-OCH3), 56.1 (4ꢀꢀ-OCH3), 90.8 (C5ꢀ),
94.0 (C3ꢀ), 105.0 (C1ꢀ), 110.0 (C5ꢀꢀ), 110.6 (C2ꢀꢀ), 122.8 (C6ꢀꢀ),
128.9 (C1ꢀꢀ), 149.1 (C3ꢀꢀ), 153.1 (C4ꢀꢀ), 161.6 (C6ꢀ), 166.2 (C4ꢀ),
168.0 (C2ꢀ), 196.8 (C3), 201.4 (C1). m/z 375 [M + H]+, 397
[M + Na]+, 413 [M + K]+, 771 [2M + Na]+, 787 [2M + K]+.
Found: m/z 374.1367. M+• requires 374.1366.
General Procedure for the Synthesis of 3-Alkyl-
3ꢀ,4ꢀ,5,7-tetramethoxyflavones 8a–d
p-Toluenesulfonicacidmonohydrate(199.7 mg, 1.05 mmol)was
added to a solution of the appropriate 2-alkyl-1-(2-hydroxy-4,6-
dimethoxyphenyl)-3-(3,4-dimethoxyphenyl)propan-1,3-dione
7a–d (2.1 mmol) in DMSO (30 mL). The solution obtained was
heated under nitrogen at 90◦C for 15 h. After that period, the
solution was poured into ice (50 g) and water (150 mL), and
the solid obtained was removed by filtration. The solid was
taken up in CHCl3 (150 mL) and the organic layer washed with
water (3 × 150 mL). After solvent evaporation, the residue was
purified by silica gel column chromatography using a 5:3 mix-
ture of light petroleum/ethyl acetate as eluent. The solvent was
evaporated to dryness and the residue was in each case recrys-
tallized from a mixture of light petroleum/CH2Cl2 to give the
3-alkyl-3ꢀ,4ꢀ,5,7-tetramethoxyflavones 8a–d as white solids.
2-Butyl-1-(2-hydroxy-4,6-dimethoxyphenyl)-3-
(3,4-dimethoxyphenyl)propan-1,3-dione 7b
Yield: (1.05 g, 72%), mp 141–143◦C. δH (CDCl3) 0.90 (3H, t,
J 7.0, H4ꢀꢀꢀ), 1.35–1.42 (4H, m, H2ꢀꢀꢀ and H3ꢀꢀꢀ), 1.79–1.90 (1H,
m, H1ꢀꢀꢀ), 2.09–2.21 (1H, m, H1ꢀꢀꢀ), 3.43 and 3.80 (6H, s, 4ꢀ,6ꢀ-
OCH3), 3.91 (3H, s, 3ꢀꢀ-OCH3), 3.96 (3H, s, 4ꢀꢀ-OCH3), 5.31
(1H, dd, J 4.1 and 8.6, H2), 5.84 (1H, d, J 2.4, H5ꢀ), 6.08 (1H, d,
J 2.4, H3ꢀ), 6.93 (1H, d, J 8.3, H5ꢀꢀ), 7.57 (1H, d, J 1.9, H2ꢀꢀ), 7.60
(1H, dd, J 1.9 and 8.3, H6ꢀꢀ), 13.87 (1H, s, 2ꢀ-OH). δC (CDCl3)
13.9 (C4ꢀꢀꢀ), 22.8 and 30.8 (C2ꢀꢀꢀ and C3ꢀꢀꢀ), 28.7 (C1ꢀꢀꢀ), 55.2
and 55.5 (4ꢀ,6ꢀ-OCH3), 55.9 (3ꢀꢀ-OCH3), 56.0 (4ꢀꢀ-OCH3), 59.8
(C2), 90.8 (C5ꢀ), 93.9 (C3ꢀ), 105.3 (C1ꢀ), 110.0 (C5ꢀꢀ), 110.5
(C2ꢀꢀ), 122.6 (C6ꢀꢀ), 129.2 (C1ꢀꢀ), 149.0 (C3ꢀꢀ), 153.0 (C4ꢀꢀ),
161.7 and 166.1 (C4ꢀ and C6ꢀ), 168.0 (C2ꢀ), 195.6 (C3), 201.0
(C1). m/z 417 [M + H]+, 439 [M + Na]+, 455 [M + K]+, 855
[2M + Na]+, 871 [2M + K]+. (Found: C 66.2, H 6.8. C23H28O7
requires C 66.3, H 6.8%.)
3ꢀ,4ꢀ,5,7-Tetramethoxy-3-methylflavone 8a
Yield: (711 mg, 95%), mp 172–173◦C. δH (500.13 MHz, CDCl3)
2.11 (3H, s, 3-CH3), 3.88 (3H, s, 7-OCH3), 3.96 (9H, s, 5,3ꢀ,4ꢀ-
OCH3), 6.36 (1H, d, J 2.3, H6), 6.45 (1H, d, J 2.3, H8), 6.98 (1H,
d, J 8.3, H5ꢀ), 7.14 (1H, d, J 1.9, H2ꢀ), 7.21 (1H, dd, J 1.9 and 8.3,
H6ꢀ). δC (125.77 MHz, CDCl3) 11.7 (3-CH3), 55.7 (7-OCH3),
56.0, 56.1 and 56.3 (5,3ꢀ,4ꢀ-OCH3), 92.2 (C8), 95.8 (C6), 108.0
(C10), 110.6 (C5ꢀ), 111.7 (C2ꢀ), 117.9 (C3), 122.3 (C6ꢀ), 125.9
(C1ꢀ), 148.7 (C3ꢀ), 150.3 (C4ꢀ), 158.2 (C2), 159.6 (C9), 160.9
(C5), 163.7 (C7), 177.7 (C4). m/z 357 [M + H]+. Found: m/z
356.1250. M+• requires 356.1260.
2-Hexyl-1-(2-hydroxy-4,6-dimethoxyphenyl)-3-
(3,4-dimethoxyphenyl)propan-1,3-dione 7c
Yield: (1.17 g, 75%), mp 105–107◦C. δH (CDCl3) 0.87 (3H, t,
J 6.8, H6ꢀꢀꢀ), 1.26–1.29 (8H, m, H2ꢀꢀꢀ to H5ꢀꢀꢀ), 1.79–1.90 (1H,
m, H1ꢀꢀꢀ), 2.08–2.21 (1H, m, H1ꢀꢀꢀ), 3.43 and 3.80 (6H, s, 4ꢀ,6ꢀ-
OCH3), 3.92 (3H, s, 3ꢀꢀ-OCH3), 3.97 (3H, s, 4ꢀꢀ-OCH3), 5.31
(1H, dd, J 4.1 and 8.5, H2), 5.85 (1H, d, J 2.3, H5ꢀ), 6.09
(1H, d, J 2.3, H3ꢀ), 6.94 (1H, d, J 8.3, H5ꢀꢀ), 7.57 (1H, d, J
3-Butyl-3ꢀ,4ꢀ,5,7-tetramethoxyflavone 8b
Yield: (786 mg, 94%), mp 164–166◦C. δH (500.13 MHz, CDCl3)
0.87 (3H, t, J 7.4, H4ꢀꢀ), 1.35 (2H, sext., J 7.4, H3ꢀꢀ), 1.55–1.62
(2H, m, H2ꢀꢀ), 2.48–2.51 (2H, m, H1ꢀꢀ), 3.86 (3H, s, 7-OCH3),

Synthesis of Tetrahydroxyflavones
723
3.949, 3.953 and 3.96 (9H, 3s, 5,3ꢀ,4ꢀ-OCH3), 6.34 (1H, d, J
2.1, H6), 6.43 (1H, d, J 2.1, H8), 6.98 (1H, d, J 8.3, H5ꢀ),
7.11 (1H, d, J 1.8, H2ꢀ), 7.19 (1H, dd, J 1.8 and 8.3, H6ꢀ).
δC (125.77 MHz, CDCl3) 13.8 (C4ꢀꢀ), 23.0 (C3ꢀꢀ), 25.6 (C1ꢀꢀ),
31.4 (C2ꢀꢀ), 55.5 (7-OCH3), 55.9 and 56.1 (5,3ꢀ,4ꢀ-OCH3), 92.1
(C8), 95.5 (C6), 108.2 (C10), 110.5 (C5ꢀ), 111.3 (C2ꢀ), 121.5
(C6ꢀ), 122.6 (C3), 125.9 (C1ꢀ), 148.5 (C3ꢀ), 150.1 (C4ꢀ), 158.6
(C2), 159.5 (C9), 160.8 (C5), 163.5 (C7), 177.3 (C4). m/z 399
[M + H]+, 819 [2M + Na]+, 1218 [3M + Na]+. (Found: C 69.4,
H 6.5. C23H26O6 requires C 69.3, H 6.6%.)
(C7), 181.9 (C4). m/z 301 [M + H]+, 323 [M + Na]+. Found:
m/z 300.0630. M+• requires 300.0634.
3-Butyl-3ꢀ,4ꢀ,5,7-tetrahydroxyflavone 9b
Yield: (201 mg, 98%), mp 188–191◦C. δH ([D6]DMSO) 0.83
(3H, t, J 7.3, H4ꢀꢀ), 1.26 (2H, sext., J 7.3, H3ꢀꢀ), 1.42–1.52 (1H,
m, H2ꢀꢀ), 2.40–2.45 (2H, m, H1ꢀꢀ), 6.19 (1H, d, J 2.1, H6), 6.31
(1H, d, J 2.1, H8), 6.89 (1H, d, J 8.2, H5ꢀ), 6.95 (1H, dd, J 2.0, 8.2,
H6ꢀ), 7.02 (1H, d, J 2.0, H2ꢀ), 9.42 (1H, s, 3ꢀ-OH), 9.65 (1H, s, 4ꢀ-
OH), 10.82 (1H, s, 7-OH), 13.09 (1H, s, 5-OH). δC ([D6]DMSO)
13.6 (C4ꢀꢀ), 22.2 (C3ꢀꢀ), 24.2 (C1ꢀꢀ), 30.6 (C2ꢀꢀ), 93.3 (C8), 98.5
(C6), 103.1 (C10), 115.5 (C5ꢀ), 115.8 (C2ꢀ), 118.4 (C3), 120.4
(C6ꢀ), 123.4 (C1ꢀ), 145.2 (C3ꢀ), 147.8 (C4ꢀ), 157.3 (C9), 161.5
(C5), 162.3 (C2), 164.1 (C7), 181.8 (C4). m/z 343 [M + H]+,
365 [M + Na]+. (Found: C 66.4, H 5.2. C19H18O6 requires
C 66.7, H 5.3%.)
3-Hexyl-3ꢀ,4ꢀ,5,7-tetramethoxyflavone 8c
Yield: (761 mg, 85%), mp 107–109◦C. δH (CDCl3) 0.85 (3H,
t, J 6.7, H6ꢀꢀ), 1.23–1.37 (6H, m, H3ꢀꢀ–H5ꢀꢀ), 1.55–1.65 (2H,
m, H2ꢀꢀ), 2.46–2.51 (2H, m, H1ꢀꢀ), 3.86 (3H, s, 7-OCH3), 3.94,
3.95, 3.96 (9H, 3s, 5,3ꢀ,4ꢀ-OCH3), 6.33 (1H, d, J 2.2, H6), 6.42
(1H, d, J 2.2, H8), 6.98 (1H, d, J 8.3, H5ꢀ), 7.11 (1H, d, J 1.9,
H2ꢀ), 7.19 (1H, dd, J 1.9 and 8.3, H6ꢀ). δC (CDCl3) 13.8 (C6ꢀꢀ),
22.4, 29.4 and 31.3 (C3ꢀꢀ–C5ꢀꢀ), 25.7 (C1ꢀꢀ), 29.0 (C2ꢀꢀ), 55.4 (7-
OCH3), 55.7, 55.9 (5,3ꢀ,4ꢀ-OCH3), 91.9 (C8), 95.3 (C6), 108.0
(C10), 110.4 (C5ꢀ), 111.2 (C2ꢀ), 121.4 (C6ꢀ), 122.4 (C3), 125.7
(C1ꢀ), 148.4 (C3ꢀ), 150.0 (C4ꢀ), 158.5 (C2), 159.3 (C9), 160.6
(C5), 163.4 (C7), 177.1 (C4). m/z 427 [M + H]+. (Found: C 70.4,
H 7.1. C25H30O6 requires C 70.4, H 7.1%.)
3-Hexyl-3ꢀ,4ꢀ,5,7-tetrahydroxyflavone 9c
Yield: (196 mg, 88%), mp 181–183◦C. δH ([D6]DMSO) 0.82
(3H, t, J 6.6, H6ꢀꢀ), 1.20–1.25 (6H, m, H3ꢀꢀ–H5ꢀꢀ), 1.41–1.49
(1H, m, H2ꢀꢀ), 2.39–2.44 (2H, m, H1ꢀꢀ), 6.18 (1H, d, J 2.1, H6),
6.31 (1H, d, J 2.1, H8), 6.88 (1H, d, J 8.2, H5ꢀꢀ), 6.94 (1H, dd, J
1.9 and 8.2, H6ꢀ), 7.01 (1H, d, J 1.9, H2ꢀ), 9.39 (1H, s, 3ꢀ-OH),
9.64 (1H, s, 4ꢀ-OH), 10.81 (1H, s, 7-OH), 13.09 (1H, s, 5-OH).
δC ([D6]DMSO) 14.0 (C6ꢀꢀ), 22.0, 30.8 (C4ꢀꢀ, C5ꢀꢀ), 24.4 (C1ꢀꢀ),
28.3 (C2ꢀꢀ), 28.7 (C3ꢀꢀ), 93.3 (C8), 98.6 (C6), 103.1 (C10), 115.5
(C5ꢀ), 115.8 (C2ꢀ), 118.4 (C3), 120.4 (C6ꢀ), 123.4 (C1ꢀ), 145.3
(C3ꢀ), 147.8 (C4ꢀ), 157.3 (C9), 161.5 (C5), 162.3 (C2), 164.1
(C7), 181.8 (C4). m/z 371 [M + H]+, 393 [M + Na]+. (Found:
C 67.7, H 6.0. C21H22O6 requires C 68.1, H 6.0%.)
3-Decyl-3ꢀ,4ꢀ,5,7-tetramethoxyflavone 8d
Yield: (780 mg, 77%), mp 65–67◦C. δH (CDCl3) 0.87 (3H, t,
J 6.6, H10ꢀꢀ), 1.22–1.29 (14H, m, H3ꢀꢀ–H9ꢀꢀ), 1.54–1.65 (2H,
m, H2ꢀꢀ), 2.45–2.50 (2H, m, H1ꢀꢀ), 3.87 (3H, s, 7-OCH3), 3.94,
3.957, 3.964 (9H, 3s, 5,3ꢀ,4ꢀ-OCH3), 6.34 (1H, d, J 2.2, H6), 6.43
(1H, d, J 2.2, H8), 6.97 (1H, d, J 8.3, H5ꢀ), 7.10 (1H, d, J 1.9, H2ꢀ),
7.18 (1H, dd, J 1.9 and 8.3, H6ꢀ). δC (CDCl3) 14.1 (C10ꢀꢀ), 22.7,
31.9 (C8ꢀꢀ, C9ꢀꢀ), 26.0 (C1ꢀꢀ), 29.3, 29.4, 29.60, 29.64, 30.0 (C2ꢀꢀ–
C7ꢀꢀ), 55.6 (7-OCH3), 56.0, 56.3 (5,3ꢀ,4ꢀ-OCH3), 92.2 (C8), 95.7
(C6), 108.4 (C10), 110.6 (C5ꢀ), 111.4 (C2ꢀ), 121.6 (C6ꢀ), 122.8
(C3), 126.0 (C1ꢀ), 148.6 (C3ꢀ), 150.2 (C4ꢀ), 158.7 (C2), 159.6
(C9), 160.9 (C5), 163.6 (C7), 177.4 (C4). m/z 483 [M + H]+.
(Found: C 72.1, H 7.9. C29H38O6 requires C 72.2, H 7.9%.)
3-Decyl-3ꢀ,4ꢀ,5,7-tetrahydroxyflavone 9d
Yield: (220 mg, 86%), mp 173–175◦C. δH ([D6]DMSO) 0.85
(3H, t, J 6.7, H10ꢀꢀ), 1.19–1.27 (14H, m, H3ꢀꢀ–H9ꢀꢀ), 1.41–1.51
(2H, m, H2ꢀꢀ), 2.39–2.44 (2H, m, H1ꢀꢀ), 6.18 (1H, d, J 2.1, H6),
6.31 (1H, d, J 2.1, H8), 6.88 (1H, d, J 8.2, H5ꢀ), 6.93 (1H, dd, J
2.0, 8.2, H6ꢀ), 7.01 (1H, d, J 2.0, H2ꢀ), 9.40 (1H, s, 3ꢀ-OH), 9.65
(1H, s, 4ꢀ-OH), 10.82 (1H, s, 7-OH), 13.09 (1H, s, 5-OH). δC
([D6]DMSO) 14.0 (C10ꢀꢀ), 22.1 and 31.3 (C8ꢀꢀ and C9ꢀꢀ), 24.4
(C1ꢀꢀ), 28.3 (C2ꢀꢀ), 28.6, 28.7, 28.9, and 29.0 (C3ꢀꢀ–C7ꢀꢀ), 93.3
(C8), 98.5 (C6), 103.1 (C10), 115.5 (C5ꢀ), 115.7 (C2ꢀ), 118.4
(C3), 120.4 (C6ꢀ), 123.4 (C1ꢀ), 145.2 (C3ꢀ), 147.8 (C4ꢀ), 157.3
(C9), 161.5 (C5), 162.3 (C2), 164.1 (C7), 181.8 (C4). m/z 427
[M + H]+, 449 [M + Na]+. Found: m/z 426.2036. M+• requires
426.2042.
General Procedure for the Synthesis of 3-Alkyl-
3ꢀ,4ꢀ,5,7-tetrahydroxyflavones 9a–d
A solution of the appropriate 3-alkyl-3ꢀ,4ꢀ,5,7-tetramethoxy-
flavone 8a–d (0.6 mmol) in dry CH2Cl2 (5 mL) was cooled in
a propan-2-ol bath at −78◦C and then a solution of BBr3 in
CH2Cl2 (1 M, 6.0 mL, 6.0 mmol) was added dropwise. After the
addition, the bath was removed and the reaction mixture was
stirred under nitrogen, at room temperature, for 48 h. After that
period, the solution was poured into ice (10 g) and water (15 mL).
The solid obtained was filtered off and washed with water
(5 × 15 mL) and then with light petroleum (5 × 15 mL). The
pure 3-alkyl-3ꢀ,4ꢀ,5,7-tetrahydroxyflavones 9a–d were collected
in each case as yellow powders.
Acknowledgements
Thanks are due to the University of Aveiro, Fundação para a Ciên-
cia e a Tecnologia, and Fundo Europeu de Desenvolvimento Regional
(FEDER) for funding the Organic Chemistry Research Unit and Project
POCI/QUI/59284/2004. R. S. G. R. Seixas also thanks FEDER and Project
POCI/QUI/59284/2004 for funding a research grant.
3ꢀ,4ꢀ,5,7-Tetrahydroxy-3-methylflavone 9a
References
Yield: (176 mg, 98%), mp 281–283◦C (dec.). δH ([D6]DMSO)
2.02 (3H, s, 3-CH3), 6.19 (1H, d, J 2.0, H6), 6.34 (1H, d, J
2.0, H8), 6.90 (1H, d, J 8.2, H5ꢀ), 7.03 (1H, dd, J 2.1 and 8.2,
H6ꢀ), 7.10 (1H, d, J 2.1, H2ꢀ), 9.43 (1H, s, 3ꢀ-OH), 9.73 (1H, s, 4ꢀ-
OH), 10.85 (1H, s, 7-OH), 13.09 (1H, s, 5-OH). δC ([D6]DMSO)
13.6 (3-CH3), 93.4 (C8), 98.6 (C6), 102.8 (C10), 113.5 (C3),
115.5 (C5ꢀ), 116.1 (C2ꢀ), 121.2 (C6ꢀ), 123.2 (C1ꢀ), 145.2 (C3ꢀ),
148.0 (C4ꢀ), 157.3 (C9), 161.4 and 161.5 (C2 and C5), 164.1
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