Synthesis of a Range of Polyhydroxy 8-Aryl Flavones

Article abstract of DOI:10.1080/00397910802710682

The 8-iodo flavones formed by cyclization of benzyl-protected chalcones with iodine in dimethyl sulfoxide have been transformed by a Suzuki coupling reaction into a variety of 8-aryl derivatives. Deprotection with boron tribromide has generated a family of new 8-aryl flavones containing four to eight hydroxyl groups.

Full text of DOI:10.1080/00397910802710682

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Synthesis of a Range of
Polyhydroxy 8-Aryl Flavones
Lesley Larsen a , Dong Hee Yoon b & Rex T. Weavers b
a Plant Extracts Research Unit, New Zealand
Institute for Crop and Food Research Limited,
Department of Chemistry, University of Otago,
Dunedin, New Zealand
b Department of Chemistry, University of Otago,
Dunedin, New Zealand
Published online: 14 Jul 2009.
To cite this article: Lesley Larsen , Dong Hee Yoon & Rex T. Weavers (2009)
Synthesis of a Range of Polyhydroxy 8-Aryl Flavones, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 39:16,
2935-2948, DOI: 10.1080/00397910802710682
To link to this article: http://dx.doi.org/10.1080/00397910802710682
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Synthetic Communications1, 39: 2935–2948, 2009
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910802710682
Synthesis of a Range of Polyhydroxy
8-Aryl Flavones
Lesley Larsen,1 Dong Hee Yoon,2 and Rex T. Weavers2
1Plant Extracts Research Unit, New Zealand Institute for Crop and Food
Research Limited, Department of Chemistry, University of Otago,
Dunedin, New Zealand
2Department of Chemistry, University of Otago, Dunedin, New Zealand
Abstract: The 8-iodo flavones formed by cyclization of benzyl-protected
chalcones with iodine in dimethyl sulfoxide have been transformed by a Suzuki
coupling reaction into a variety of 8-aryl derivatives. Deprotection with boron
tribromide has generated a family of new 8-aryl flavones containing four to eight
hydroxyl groups.
Keywords: Chalcone cyclization, selective iodination, Suzuki coupling
Although biflavonoids incorporating a C-C connection to C-8 of a
flavone are well known (278 structures in a recent SciFinder1 search),
the number of known compounds involving C-8 connection to a simple
unfused benzene ring is relatively small (32 structures from SciFinder1).
Few of the known structures have oxygenation in ring B. Simple 8-aryl
flavones are rare in nature,[1] but some were identified in early structural
investigations of biflavonoids involving degradative studies.[2] Initial
attempts at synthesis employed Ullmann coupling of iodoaryl com-
pounds, but yields were poor.[3] Photolysis of an 8-iodoflavone in
benzene has been reported to yield an 8-phenyl derivative,[4] and some
phenyl flavones have been prepared by cyclization of appropriately
substituted chalcones.[5] More recently, Suzuki couplings have been used
with considerable success.[6]
Received October 12, 2008.
Address correspondence to Rex T. Weavers, Department of Chemistry,
University of Otago, Box 56, Dunedin 9054, New Zealand. E-mail: rweavers@
chemistry.otago.ac.nz
2935

2936
L. Larsen, D. H. Yoon, and R. T. Weavers
Polyhydroxyflavones have attracted considerable attention as
potential antioxidants. One study[7] has identified a 203040-trihydroxylation
pattern as being particularly effective in a radical scavenging role, and a
more recent investigation has found variable effects on ultraviolet
(UV)–induced apoptosis in keratinocytes with varying hydroxylation pat-
terns.[8] In this study, we set out to use Suzuki coupling of iodo flavones for
the introduction of a benzene ring in the 8-position, a locus for introduc-
tion of further hydroxylation. Thus, our goal was to produce flavones with
new patterns of hydroxylation, functionalized in ring B, as found in the
well-known natural products, but with additional phenolic centers in the
newly introduced benzene ring. Exploration of the potential bioactivity
of such compounds would be highly valuable. We have also achieved
synthesis of 8-bromo and 8-benzyl tetrahydroxy flavones.
A selection of chalcones (1–5) (Scheme 1) was obtained from acet-
ophenone derivatives by condensation with appropriately substituted
benzaldehydes, using aqueous sodium hydroxide (NaOH) in dioxane.[9]
Compounds 4 and 5 have not been reported previously. Cyclization of
chalcones to form flavones has been achieved previously by heating
with catalytic amounts of iodine in DMSO (dimethyl sulfoxide).[10]
Although the original reference gave no indication of the amount of
iodine used, a more recent study[11] employed a 1:9 ratio of iodine to
chalcone. In our hands, reaction of compound 1 using this ratio of
reactants yielded the expected flavone 6 in poor yield (16%) but gave
a significant quantity (8%) of an 8-iodoflavone 7 that had been
demethylated at C-5. Incorporation of iodine in the I2=DMSO reaction
has been noted previously, where the use of a 1:1 ratio of iodine to
chalcone yielded diiodoflavones.[12] Mixtures containing monoiodo deri-
vatives were obtained with a 1:2 ratio of iodine to substrate.[13] Com-
pound 7 has been reported previously from iodination of a flavone.[14]
Such iodo compounds offered promise as substrates for the introduc-
tion of further C-8 functionality, and we found that increasing the
amount of iodine used to a 1:1 ratio enabled the isolation of 7 in 85%
yield. In similar fashion, reaction of the benzyl-protected chalcones 2
and 3 gave the new mono-iodoflavones 8 and 9 in 59 and 70% yields
respectively. It is noteworthy that a C-5 benzyloxy grouping was
Scheme 1.

Polyhydroxy 8-Aryl Flavones
2937
Scheme 2.
unaffected, unlike the C-5 methoxyl, which was removed in the conver-
sion of 1 into 7 (Scheme 2). Flavones such as 6 characteristically show
1
two doublets (J ꢀ 2 Hz) for H-6 and H-8 in the H NMR spectrum.
1
The H NMR spectrum of the iodo derivatives showed one singlet that
showed heteronuclear multiple bond correlation (HMBC) correlation
to C-5, consistent with assignment of this peak to H-6 rather than H-8.
The iodinated carbon signal in the 13C NMR spectrum was characteris-
tically upfield (dC ¼ 66.4 for 8 and 66.3 for 9).
When the cyclization reaction was conducted using the 8-benzylchalcone 4
or the 8-bromo derivative 5, the new iodine-free flavones 10 and 11 were
obtained in 86 and 87% yields respectively (Scheme 2). In addition to the
lack of iodination in this case, we found no significant levels of diiodina-
tion with any of the substrates used, even when the iodine-to-chalcone
ratio was raised to 11:4. Unlike our substrates, the literature examples of
compounds undergoing diiodination had no substitution at C-7.[12,13]
Suzuki arylation reactions on the two iodoflavones 8 and 9 with
p-methoxyphenylboronic acid led to two new polyalkoxy flavones 12
and 13 in 80 and 96% yields, respectively. Reaction of 9 with 3,4-dimethoxy
and 3,4,5-trimethoxyphenylboronic acids gave two more highly substituted
derivatives, 14 and 15, in 73 and 58% yields (Scheme 3). Each alkoxyfla-
vone produced in this study was dealkylated with boron tribromide in
good yield to generate a collection of six new polyhydroxy flavones 16–
21 (Scheme 4).
In summary, the overall scheme is illustrated in Scheme 5 for the
production of the heptahydroxyflavone 20. In the course of this
Scheme 3.

2938
L. Larsen, D. H. Yoon, and R. T. Weavers
Scheme 4.
Scheme 5. Synthesis of heptahydroxyflavone 20.
investigation, we have synthesized two new chalcone derivatives and 14
new substituted flavones. Most notably this work has led to the produc-
tion of six new highly phenolic flavones. Antioxidant properties of the
compounds produced in this study are currently under investigation.
EXPERIMENTAL
NMR spectra were recorded at 500 MHz (1H) and 125 MHz (13C) on a
Varian Inova-500 spectrometer. Spectra were recorded in CDCl3,
methanol-d4, or DMSO-d6. 1H spectra were referenced to residual

Polyhydroxy 8-Aryl Flavones
2939
1H-bearing solvent (dH ¼ 7.26, 3.30, and 2.50), and 13C spectra were refer-
enced to the central line of the solvent resonance (dC ¼ 77.1, 49.0, and
39.5). Infrared (IR) spectra were recorded as KBr disks on a
Perkin-Elmer Spectrum BX Fourier transform (FT)-IR system spectro-
meter. High-resolution mass spectra (HRMS) were recorded on a Bruker
Microtof-Q spectrometer.
Column fractionation was performed using Merck 60 silica (200–400
mesh, 40–63 mm) as adsorbent. Columns were pre-equilibrated with the
starting solvent before use. All solvents were distilled before use. Known
compounds are referenced by their Chemical Abstracts reference number
in square brackets.
Chalcone Formation
Aqueous NaOH (50% w=w, 10 ml) was added to a stirred solution of
the substituted acetophenone and the aldehyde in dioxane (10 ml). After
vigorous stirring for 24 h at room temperature, the reaction mixture was
neutralized with HCl (1 mol Lꢀ1, 20 ml) and extracted into ethyl acetate
(EtOAc) (3 ꢁ 20 mL). Removal of the EtOAc in vacuo and recrystalliza-
tion from ethanol (EtOH) gave the chalcone. Experiments are summar-
ized as follows: acetophenone (mass, amount), aldehyde (mass,
amount), product (mass yield, % yield), data.
(E)-1-(2,4-Bis(benzyloxy)-6-hydroxyphenyl)-3-(benzo[d][1,3]dioxol-5-
yl)prop-2-en-1-one (2)
1-(2,4-Bis(benzyloxy)-6-hydroxyphenyl)ethanone [18065–05-9][15] (0.500 g,
1.44 mmol), piperonal [120–57-0] (0.250 g, 1.67 mmol), and 2 [120980-
03-2][16] (0.450g, 65%). 1H NMR (CDCl3) d 7.71 (d, J ¼ 16 Hz, 1H), 7.67
(d, J ¼ 16 Hz, 1H), 7.35–7.45 (10H, m, 10H), 6.68 (d, J ¼ 6 Hz, 1H), 6.70
(dd, J ¼ 1.5, 6 Hz, 1H), 6.50 (d, J ¼ 1.5 Hz, 1H), 6.22 (d, J ¼ 2.4 Hz, 1H),
6.16 (d, J ¼ 2.4 Hz, 1H), 5.99 (s, 2H), 5.10 (s, 2H), 5.05 (s, 2H).
(E)-1-(2,4-Bis(benzyloxy)-6-hydroxyphenyl)-3-(3,4,5-trimethoxyphenyl)
prop-2-en-1-one (3)
1-(2,4-Bis(benzyloxy)-6-hydroxyphenyl)ethanone [18065-05-9][15] (0.500 g,
1.44 mmol), 3,4,5-trimethoxybenzaldehyde [86-81-7] (0.250 g, 1.36 mmol),
1
and 3 [120980-02-1] (0.51 g, 71%). H NMR data as reported.[17]

2940
L. Larsen, D. H. Yoon, and R. T. Weavers
(E)-1-(3-Benzyl-4,6-bis(benzyloxy)-2-hydroxyphenyl)-3-(benzo[d][1,3]
dioxol-5-yl) prop-2-en-1-one (4)
1-(3-Benzyl-4,6-bis(benzyloxy)-2-hydroxyphenyl)ethanone [18065-06-0][15]
(0.500g, 1.14mmol), piperonal [120-57-0] (0.250g, 1.67mmol), and 4
1
(0.57 g, 88%). H NMR (CDCl3) d 7.68 (d, J ¼ 15.5 Hz, 1H), 7.65 (d,
J ¼ 15.5 Hz, 1H), 7.13–7.45 (m, 15H), 6.71 (dd, J ¼ 2.5, 10 Hz, 1H), 6.68
(d, J ¼ 10 Hz, 1H), 6.15 (s, 1H), 6.52 (d, J ¼ 2.5 Hz, 1H), 5.98 (s, 2H), 5.15
(s, 2H), 5.03 (s, 2H), 4.03 (s, 2H). 13C NMR (CDCl3) d 192.9, 164.9,
162.5, 160.7, 149.4, 148.1, 142.6, 141.7, 136.3, 135.5, 129.9, 129.0 (2C),
128.9 (2C), 128.8 (2C), 128.7 (2C), 128.5 (2C), 128.2, 128.1 (2C), 127.3,
125.9, 125.5, 124.8, 110.6, 108.5, 107.1, 106.6, 101.4, 88.8, 71.5, 70.3,
28.2. IR (KBr): 3061, 3028, 2881, 1615, 1556, 1501, 1488, 1421, 1418,
1248, 1143, 1105, 1038, 755, 736, 698 cmꢀ1. HRMS (ESI) calcd for
C37H30O6Na=C37H30O6K 593.1935=609.1679, found 593.1921=609.1661
[Mþ þ Na] = [Mþ þ K].
(E)-1-(4,6-Bis(benzyloxy)-3-bromo-2-hydroxyphenyl)-3-(benzo[d][1,3]
dioxol-6-yl)prop-2-en-1-one (5)
1-(4,6-Bis(benzyloxy)-3-bromo-2-hydroxyphenyl)ethanone [141238-45-1][18]
(0.500 g, 1.25 mmol), piperonal [120-57-0] (0.250 g, 1.67 mmol), and 5
1
(0.480 g, 72%). H NMR (CDCl3) d 7.68 (d, J ¼ 15.5 Hz, 1H), 7.67 (d,
J ¼ 15.5 Hz, 1H), 7.13–7.45 (m, 10H), 6.72 (dd, J ¼ 2 Hz, J ¼ 8 Hz, 1H),
6.69 (d, J ¼ 8 Hz, 1H), 6.49 (d, J ¼ 2 Hz, 1H), 6.20 (s, 1H), 5.99 (s,
CH2, 2H), 5.27 (s, CH2, 2H), 5.04 (s, 2H). 13C NMR (CDCl3) d 192.7,
165.7, 163.8, 161.2, 161.0, 148.2, 144.0, 135.7, 135.0, 129.6, 129.2 (2C),
129.2, 128.9 (2C), 128.7, 128.6 (2C), 128.4, 126.9 (2C), 125.2, 124.9,
108.5, 107.0, 101.5, 89.9, 71.8, 71.0. This compound was characterized
fully as the cyclized flavone 11.
Chalcone Cyclizations
A solution of the chalcone and iodine in dry DMSO (volume) was heated
at 150ꢂC under reflux in a nitrogen atmosphere for the specified time.
After cooling, the mixture was diluted with aqueous Na2SO3
(2 ꢁ volume), then extracted three times with dichloromethane (DCM,
volume). The solution was dried (Na2SO4), and the solvent was removed
in vacuo. The resulting material was purified (method) to give the fla-
vone. Experiments are summarized as follows: chalcone (mass, amount),
iodine (mass, amount), DMSO (volume), time, purification method,
product (mass yield, % yield).

Polyhydroxy 8-Aryl Flavones
2941
5-Hydroxy-8-iodo-7-methoxyflavone (7)
a. 20-Hydroxy-40,60-dimethoxychalcone
[1775-97-9]
(1)
(0.250 g,
0.88 mmol), iodine (0.020 g, 0.079 mmol), and DMSO (10 ml), 4 h,
chromatography on silica [DCM=ether (Et2O) gradient] gave
5,7-dimethoxyflavone [21392-57-4] (6) (0.040 g, 16%) (1H NMR data
as reported[19]) and 7 [26505-96-4][14] (0.028 g, 8%). 1H NMR (CDCl3)
d 8.05 (m, 2H), 7.47 (m, 3H), 6.74 (s, 1H), 6.42 (s, 1H), 4.04 (s, 3H).
b. 20-Hydroxy-40,60-dimethoxychalcone (1) (0.250 g, 0.88 mmol), iodine
(0.200 g, 0.79 mmol), and DMSO (10 ml), 4 h, chromatography on
silica (DCM=Et2O gradient) gave 7 (0.170 g, 85%).
2-(Benzo[d][1,3]dioxol-5-yl)-5,7-bis(benzyloxy)-8-iodo-4
H-chromen-4-one (8)
Chalcone 2 (0.500 g, 1.04 mmol), iodine (0.550 g, 2.17 mmol), and
DMSO (30 ml), 5 h, recrystallization from EtOH gave 8 (0.37 g, 59%).
1H NMR (CDCl3) d 7.56 (dd, J ¼ 5, 8.5 Hz, 1H), 7.30–7.52 (m, 10H),
7.44 (d, J ¼ 5 Hz, 1H), 6.92 (d, J ¼ 8.5 Hz, 1H), 6.58 (s, 1H), 6.49 (s,
1H), 6.07 (s, 2H), 5.21 (s, 2H), 5.17 (s, 2H). 13C NMR (CDCl3) d
177.1, 161.5, 160.9, 160.5, 157.7, 150.5, 148.5, 136.2, 135.5, 128.8
(2C), 128.8 (2C), 128.4, 128.0, 127.1 (2C), 126.8 (2C), 125.3, 108.9,
108.7, 107.5, 106.7, 106.2, 102.1, 96.1, 71.4, 71.4, 66.4. IR (KBr):
3050, 3030, 3004, 2900, 1642, 1589, 1503, 1488, 1450, 1380, 1322,
1254, 1123, 1037, 751 cmꢀ1. HRMS (ESI) calcd. for C30H22O6I
605.0456, found 605.0467 [Mþ þ H].
5,7-Bis(benzyloxy)-8-iodo-2-(3,4,5-trimethoxyphenyl)-
4H-chromen-4-one (9)
Chalcone 3 (0.500 g, 0.95 mmol), iodine (0.550 g, 2.17 mmol), and DMSO
1
(30 ml), 5 h, recrystallization from EtOH gave 9 (0.43 g, 70%). H NMR
(CDCl3) d 7.54 (d, J ¼ 8 Hz, 2H), 7.30–7.43 (m, 6H), 7.39 (d, J ¼ 7 Hz,
2H), 7.33 (s, 2H), 6.67 (s, 1H), 6.46 (s, 1H), 5.25 (s, 2H), 5.18 (s, 2H),
3.97 (s, 6H), 3.93 (s, 3H). 13C NMR (CDCl3) d 177.2, 161.6, 160.8,
160.6, 153.6 (2C), 141.0, 136.1, 135.5, 128.8 (2C), 128.8 (2C), 128.4,
128.0, 127.0 (2C), 126.8 (2C), 126.3, 110.7, 107.9, 104.2 (2C), 103.9,
96.2, 71.4 (2C), 66.3, 61.1, 56.4 (2C). IR (KBr): 3050, 3030, 3004, 2939,
1640, 1593, 1505, 1456, 1419, 1394, 1342, 1246, 1128, 1058, 836,
734 cmꢀ1. HRMS (ESI) calcd. for C32H27INaO7 673.0694; found
673.0693 [Mþ þ Na].

2942
L. Larsen, D. H. Yoon, and R. T. Weavers
2-(Benzo[d][1,3]dioxol-5-yl)-8-benzyl-5,7-bis(benzyloxy)-4H-chromen-
4-one (10)
Chalcone 4 (0.500 g, 0.88 mmol), iodine (0.550 g, 2.17 mmol), and DMSO
(30 ml), 5 h, recrystallization from EtOH gave 10 (0.43 g, 86 %) as yellow
1
solid. H NMR (CDCl3) d 7.58 (2H, d, J ¼ 7 Hz, 2H), 7.33 (ddm, J ¼ 7,
7 Hz, 2H), 7.32 (ddm, J ¼ 7, 7 Hz, 2H), 7.30 (m, 1H), 7.29 (dd, J ¼ 2,
8 Hz, 1H), 7.24 (m, 1H), 7.23 (d, J ¼ 8 Hz, 2H), 7.21 (d, J ¼ 7 Hz, 2H),
7.17 (ddm, J ¼ 7, 7 Hz, 1H), 7.13 (d, J ¼ 2 Hz, 1H), 6.85 (d, J ¼ 8 Hz,
1H), 6.52 (s, 1H), 6.52 (s, 1H), 6.03 (s, 2H), 5.23 (s, 2H), 5.08 (s, CH2,
2H), 4.25 (s, CH2, 2H). 13C NMR (CDCl3) d 177.9, 167.8, 160.7, 160.4,
158.4, 156.7, 150.2, 148.4, 140.5, 136.7, 136.0, 128.7 (2C), 128.7 (2C),
128.4 (2C), 128.3 (3C), 127.8, 127.4 (2C), 126.8 (2C), 126.0, 125.9,
121.1, 110.2, 109.8, 108.7, 107.8, 106.2, 101.8, 95.9, 71.4, 70.7. IR
(KBr): 3050, 3031, 2882, 1621, 1582, 1557, 1501, 1489, 1446, 1423,
1247, 1215, 1167, 1105, 1038, 980, 932, 817 cmꢀ1. HRMS (ESI) calcd.
for C37H28O6Na 591.1778; found 591.1775 [Mþ þ Na].
2-(Benzo[d][1,3]dioxol-5-yl)-5,7-bis(benzyloxy)-8-bromo-4H-chromen-
4-one (11)
Chalcone 5 (0.500g, 0.89mmol), iodine (0.550g, 2.17mmol), and DMSO
(30 ml), 5 h, recrystallization from EtOH gave 11 (0.43 g, 87 %) as yellow
1
solid. H NMR (CDCl3) d 7.64 (dd, J ¼ 2, 7.5 Hz, 1H), 7.52 (d, J ¼ 2 Hz,
1H), 7.30–7.52 (m, 10H), 6.95 (d, J ¼ 7.5 Hz, 1H), 6.59 (s, 1H), 6.47 (s,
1H), 6.07 (s, 2H), 5.24 (s, 2H), 5.18 (s, 2H). 13C NMR (CDCl3) d
177.2, 160.7, 159.2, 158.9, 155.3, 150.6, 148.5, 136.2, 135.5, 128.8 (2C),
128.7 (2C), 128.4, 128.0, 127.1 (2C), 126.8 (2C), 125.2 (C10), 121.5,
110.6 (C4a), 108.9, 107.4, 106.4, 101.9, 96.5, 92.3 (C8), 71.4, 71.3. IR
(KBr): 3050, 3030, 3004, 2902, 1641, 1592, 1503, 1488, 1450, 1380,
1324, 1254, 1127, 1036, 732 cmꢀ1
.
HRMS (ESI) calcd. for
C30H22O679Br=C30H22O681Br 557.0594=559.0574; found 557.0581=
559.0565 [Mþ þ H].
Suzuki Arylation of 8-Iodoflavones
Tetrakis(triphenylphosphine)palladium (0) [14221-01-3] was added to
a solution of the 8-iodoflavone in dimethoxyethane (DME) (volume).
The solution was degassed under vacuum and stirred at room tem-
perature for 20 min, then saturated Na2CO3 solution (0.5 ꢁ volume)

Polyhydroxy 8-Aryl Flavones
2943
was added. The resulting mixture was degassed again and then stir-
red in an atmosphere of nitrogen for 1 h. The substituted phenyl-
boronic acid was added, and the mixture was heated at 80ꢂC under
nitrogen for 4 h. After cooling to room temperature, the mixture
was diluted with dichloromethane (2 ꢁ volume); and water
(2 ꢁ volume); the organic phase was separated, washed with water,
and dried (MgSO4). The solvent was evaporated in vacuo, and the
product was purified (method) to give the 8-aryl flavone. Experi-
ments are summarized as follows: 8-iodoflavone (mass, amount),
(Ph3P)4P (mass, amount), DME (volume), substituted phenylboronic
acid (mass, amount), purification method, product (mass yield, %
yield).
2-(Benzo[d][1,3]dioxol-5-yl)-5,7-bis(benzyloxy)-8-(4-methoxyphenyl)-4H-
chromen-4-one (12)
8-Iodoflavone 8 (0.100 g, 0.17 mmol), (Ph3P)4Pd (0.010g, 0.009 mmol),
DME (10 ml), and p-methoxyphenylboronic acid [5720-07-0] (0.070g,
0.46mmol), recrystallization from EtOH gave 12 (0.085g, 80%). 1H NMR
(CDCl3) d 7.58 (d, J ¼ 7 Hz, 2H), 7.39 (m, 4H), 7.38 (d, J ¼ 8 Hz, 2H),
7.29 (ddm, J ¼ 7, 8 Hz, 2H), 7.21 (d, J ¼ 8 Hz, 2H), 7.13 (dd, J ¼ 1.5,
8 Hz, 1H), 7.03 (d, J ¼ 8 Hz, 2H), 6.99 (d, J ¼ 1.5 Hz, 1H), 6.79 (d, J ¼
8Hz, 1H), 6.54 (s, 1H), 6.54 (s, 1H), 6.00 (s, 2H), 5.24 (s, 2H), 5.07 (s,
2H), 3.90 (s, 3H). 13C NMR (CDCl3) d 177.9, 160.4, 159.6, 159.0, 158.7,
156.1, 150.2, 148.3, 136.6, 136.3, 132.3 (2C), 128.7 (2C), 128.7 (2C), 128.0,
127.8, 126.8 (2C), 126.7 (2C), 125.5, 124.4, 121.0, 113.5 (2C), 112.7, 109.9,
108.6, 107.1, 106.2, 101.8, 96.6, 71.3, 70.7, 55.4. IR (KBr): 3050, 3030,
3005, 2936, 2836, 1645, 1591, 1500, 1489, 1451, 1384, 1321, 1251, 1178,
1120, 1035, 834, 813, 733, 696cmꢀ1
. HRMS (ESI) calcd. for
C37H39O7=C37H38NaO7 585.1908=607.1727; found 585.1931=607.1745
[Mþ þ H] = [Mþ þ Na].
5,7-Bis(benzyloxy)-2-(3,4,5-trimethoxyphenyl)-8-(4-methoxyphenyl)-4H-
chromen-4-one (13)
8-Iodoflavone 9 (0.100 g, 0.15 mmol), (Ph3P)4Pd (0.010g, 0.009 mmol),
DME (10 ml), and p-methoxyphenylboronic acid [5720-07-0] (0.070g,
0.46mmol), recrystallization from EtOH gave 13 (0.091g, 96%). 1H NMR
(CDCl3) d 7.57 (d, J ¼ 8 Hz, 2H), 7.40 (dd, J ¼ 7, 7 Hz, 2H), 7.36 (dd,
J¼ 2, 7 Hz, 2H), 7.32 (ddm, J ¼ 7, 8 Hz, 2H), 7.29 (m, 1H), 7.28 (m, 1H),
7.19 (d, J ¼ 8 Hz, 2H), 7.00 (dd, J ¼ 2, 7 Hz, 2H), 6.75 (s, 2H), 6.63 (s, 1H),
6.54(s, 1H), 5.26 (s, 2H), 5.07 (s, 2H), 3.852 (s, 3H), 3.848 (s, 3H), 3.72

2944
L. Larsen, D. H. Yoon, and R. T. Weavers
(s, 6H). 13C NMR (CDCl3) d 177.9, 160.1, 159.7, 158.9, 158.8, 156.2, 153.4,
140.6, 136.6, 136.2, 132.2 (2C), 128.7 (2C), 128.7 (2C), 128.1, 127.9, 126.8
(2C), 126.7 (2C), 126.5, 124.8, 113.6 (2C), 112.7, 109.8, 107.5, 102.9 (2C),
96.5, 71.3, 70.6, 61.0, 56.2 (2C), 55.2. IR (KBr): 3050, 3030, 3005, 2934,
1642, 1594, 1506, 1456, 1419, 1340, 1244, 1189, 1128, 1056, 1029,837,
735 cmꢀ1
.
HRMS
(ESI)
calcd.
for
C39H35O8=C39H34NaO8
631.2326=653.2146; found 631.2334=653.2145 [Mþ þ H] = [Mþ þ Na].
5,7-Bis(benzyloxy)-2-(3,4,5-trimethoxyphenyl)-8-
(3,4-dimethoxyphenyl)-4H-chromen-4-one (14)
8-Iodoflavone 9 (0.100 g, 0.15 mmol), (Ph3P)4Pd (0.010 g, 0.009 mmol),
DME (10 ml), and 3,4-dimethoxyphenylboronic acid [122775-35-3]
(0.070 g, 0.41 mmol), recrystallization from EtOH gave 14 (0.072 g,
73%). 1H NMR (CDCl3) d 7.58 (d, J ¼ 8 Hz, 2H), 7.40 (ddm, J ¼ 8,
8 Hz, 2H), 7.32 (ddm, J ¼ 7, 8 Hz, 2H), 7.29 (m, 1H), 7.28 (m, 1H),
7.22 (d, J ¼ 8 Hz, 2H), 7.00 (dd, J ¼ 2, 8 Hz, 1H), 6.97 (d, J ¼ 8 Hz,
1H), 6.95 (d, J ¼ 2 Hz, 1H), 6.77 (s, 2H), 6.63 (s, 1H), 6.56 (s, 1H), 5.29
(s, 2H), 5.07 (s, 2H), 3.95 (s, 3H), 3.92 (s, 3H), 3.81 (s, 3H), 3.72 (s,
6H). 13C NMR (CDCl3) d 177.9, 160.1, 159.7, 158.9, 156.2, 153.4 (2C),
149.2, 148.5, 140.6, 136.6, 136.1, 128.7 (2C), 128.7 (2C), 128.1, 127.9,
126.8 (4C), 126.4, 125.1, 123.5, 114.4, 112.7, 110.7, 109.8, 107.4, 102.9
(2C), 96.4, 71.3, 70.6, 61.0, 56.1, 55.9 (2C), 55.9. IR (KBr): 3050, 3030,
3005, 2936, 2836, 1642, 1595, 1500, 1457, 1419, 1387, 1341, 1250, 1226,
1189, 1170, 1129, 1058, 1028,912, 837, 734 cmꢀ1. HRMS (ESI) calcd.
for C40H37O9=C40H36NaO9 661.2432=683.2252; found 661.2422=
691.2247 [Mþ þ H] = [Mþ þ Na].
5,7-Bis(benzyloxy)-2,8-bis(3,4,5-trimethoxyphenyl)-4H-chromen-4-one (15)
8-Iodoflavone 9 (0.100 g, 0.15 mmol), (Ph3P)4Pd (0.010 g, 0.009 mmol),
DME (10 ml), and 3,4,5-trimethoxyphenylboronic acid [182163-96-8][20]
(0.070 g, 0.39 mmol), purification by column chromatography (DCM=
Et2O gradient) gave 15 (0.060 g, 58%). 1H NMR (CDCl3) d 7.58 (d,
J ¼ 8 Hz, 2H), 7.40 (ddm, J ¼ 7, 8 Hz, 2H), 7.30 (m, 4H), 7.20 (dd,
J ¼ 2, 8 Hz, 2H), 6.80 (s, 2H), 6.66 (s, 1H), 6.65 (s, 2H), 6.57 (s, 1H),
5.30 (s, 2H), 5.07 (s, 2H), 3.90 (s, 3H), 3.85 (s, 3H), 3.78 (s, 6H), 3.73
(s, 6H). 13C NMR (CDCl3) d 177.9, 160.2, 159.6, 159.0, 156.0, 153.4
(2C), 152.8 (2C), 140.8, 137.7, 136.4, 136.0, 128.7 (2C), 128.6 (2C),
128.1, 127.9, 127.9, 126.9 (2C), 126.8 (2C), 126.2, 112.8, 109.6, 108.2
(2C), 107.3, 102.9 (2C), 96.3, 71.2, 70.6, 61.0, 60.8, 56.1 (2C), 56.0 (2C).
IR (KBr): 3001, 2939, 2839, 1640, 1601, 1498, 1490, 1459, 1452, 1420,

Polyhydroxy 8-Aryl Flavones
2945
1401, 1348, 1337, 1301, 1250, 1228, 1172, 1137, 1110, 1058, 1005, 910, 839,
823, 734, 697 cmꢀ1. HREIMS calcd. for C41H39O10=C41H38NaO10
691.2538=713.2357; found 691.2548=713.2330 [Mþ þ H] = [Mþ þ Na].
Dealkylation to form Polyhydroxy Flavones
A solution of boron tribromide (1 M) in DCM was added to a solution of
the protected flavone in dry DCM (volume). The mixture was stirred for
the specified time. MeOH (2 ꢁ volume) was added to quench the reaction,
and the solution was evaporated under vacuum. The residue was purified
as specified. Experiments are summarized as follows: protected flavone
(mass, amount), 1 M BBr3 (volume, amount), and DCM (volume), reac-
tion time, purification method, product (mass yield, % yield).
8-Benzyl-5,7-dihydroxy-2-(3,4-dihydroxyphenyl)-4H-chromen-4-
one (16)
Protected flavone 10 (0.085 g, 0.15 mmol), 1 M BBr3 (3 ml, 3.00 mmol),
and DCM (10 ml), 2 h, chromatography on silica (5:1, DCM=MeOH)
gave tetrahydroxyflavone 16 (0.053, 94%). 1H NMR (methanol-d6) d
7.54 (d, J ¼ 2 Hz, 1H), 7.42 (dd, J ¼ 2, 8 Hz, 1H), 7.33 (d, J ¼ 6 Hz,
2H), 7.27 (dd, J ¼ 6, 7 Hz, 2H), 7.13 (d, J ¼ 6 Hz, 1H), 6.97 (d, J ¼ 8 Hz,
Hz, 1H), 6.58 (s, 1H), 6.38 (s, 1H), 4.23 (s, 2H). 13C NMR (methanol-d6)
d 184.2, 166.3, 163.7, 161.3, 156.7, 150.9, 147.0, 142.1, 129.3 (2C), 129.2
(2C), 126.8, 123.9, 120.4, 116.7, 114.2, 107.7, 105.3, 103.7, 99. 6, 29.2. IR
(KBr): 3205, 1602, 1575, 1516, 1451, 1394, 1363, 1330, 1261, 1193, 1121,
1012, 989, 841, 814, 786, 696 cmꢀ1. HRMS (ESI) calcd. 377.1020 for
C22H17O6; found 377.1030 [Mþ þ H].
8-Bromo-5,7-dihydroxy-2-(3,4-dihydroxyphenyl)-4H-chromen-4-
one (17)
Protected flavone 11 (0.370 g, 0.66 mmol), 1 M BBr3 (3 ml, 3.00 mmol),
DCM (10 ml), 2 h, chromatography on silica (5:1, DCM=MeOH) gave
1
tetrahydroxyflavone 17 (0.172 g, 71%). H NMR (methanol-d6) d 7.67
(d, J ¼ 2 Hz, 1H), 7.59 (dd, J ¼ 2, 8 Hz, 1H), 7.04 (d, J ¼ 8 Hz, 1H),
6.72 (s, 1H), 6.52 (s, 1H). 13C NMR (methanol-d6) d 183.7, 167.0,
166.3, 161.5, 155.5, 151.5, 147.1, 123.3, 120.6, 116.8, 114.4, 108.8,
103.7, 100.1, 89.5. IR (KBr): 3350, 1652, 1601, 1560, 1436, 1390, 1254,
1125 cmꢀ1. HRMS (ESI) calcd. for C15H1079BrO10=C15H1081BrO10
364.9655=366.9635; found 364.9692=366.9674 [Mþ þ H].

2946
L. Larsen, D. H. Yoon, and R. T. Weavers
5,7-Dihydroxy-2-(3,4-dihydroxyphenyl)-8-(4-hydroxyphenyl)-4H-
chromen-4-one (18)
Protected flavone 12 (0.085 g, 0.13), 1 M BBr3 (3 ml, 3.00 mmol), and
DCM (10 ml), 2 h, chromatography on silica (5:1, DCM=MeOH) gave
1
pentahydroxyflavone 18 (0.046 g, 94%). H NMR (DMSO-d4) d 7.36
(d, J ¼ 8 Hz, 2H), 7.16 (d, J ¼ 2 Hz, 1H), 7.12 (dd, J ¼ 2, 8 Hz, 1H),
6.88 (d, J ¼ 8 Hz, 2H), 6.80 (d, J ¼ 8 Hz, 1H), 6.65 (s, 1H), 6.42 (s,
1H). 13C NMR (DMSO-d6) d 182.1, 164.1, 161.3, 159.7, 156.4,
115.6, 154.0, 149.6, 145.6, 132.1 (2C), 122.0, 121.8, 118.8, 115.6,
114.7 (2C), 113.8, 108.1, 103.7, 102.5, 98.7. IR (KBr): 3406, 1650,
1610, 1577, 1555, 1516, 1503, 1411, 1371, 1314, 1256, 1228, 1124,
833, 819 cmꢀ1. HRMS (ESI) calcd. 379.0812 for C21H15O7; found
379.0816 [Mþ þ H].
5,7-Dihydroxy-2-(3,4,5-trihydroxyphenyl)-8-(4-hydroxyphenyl)-4H-
chromen-4-one (19)
Protected flavone 13 (0.0.091 g, 0.14 mmol), 1 M BBr3 (3 ml, 3.00 mmol),
DCM (10 ml), 2 h, chromatography on silica (5:1, DCM=MeOH) gave
1
hexahydroxyflavone 19 (0.045 g, 82%). H NMR (methanol-d4) d 7.23
(d, J ¼ 9 Hz 2H), 6.88 (d, J ¼ 9 Hz, 2H), 6.71 (s, 2H), 6.48 (s, 1H), 6.32
(s, 1H). 13C NMR d 184.2, 166.9, 163.0, 161.6, 157.8, 156.1, 147.2 (2C),
139.1, 133.4 (2C), 124.0, 122.7, 116.1 (2C), 110.1, 107.2 (2C), 105.4,
103.6, 99.9. IR (KBr): 3354, 1653, 1610, 1559, 1501, 1457, 1323, 1252,
1033, 819 cmꢀ1. HRMS (ESI) calcd. for C21H15O8 395.0761; found
395.0780 [Mþ þ H].
5,7-Dihydroxy-2-(3,4,5-trihydroxyphenyl)-8-(3,4-dihydroxyphenyl)-4H-
chromen-4-one (20)
Protected flavone 14 (0.0.088 g, 0.13 mmol), 1 M BBr3 (3 ml, 3.00 mmol),
DCM (10 ml), 2 h, chromatography on silica (5:1, DCM=MeOH) gave
heptahydroxyflavone 20 (0.051 g, 96%). 1H NMR (DMSO-d6) d 6.84
(d, J ¼ 8 Hz, 1H), 6.80 (d, J ¼ 2 Hz, 1H), 6.72 (s, 2H), 6.70 (dd, J ¼ 2,
8 Hz, 1H), 6.49 (s, 1H), 6.37 (s, 1H). 13C NMR (DMSO-d6) d 182.0,
164.5, 161.3, 159.6, 154.1, 146.1 (2C), 144.6, 144.4, 137.8, 122.3,
122.0, 120.8, 118.4, 115.2, 108.4, 106.1 (2C), 103.7, 102.6, 98.6. IR
(KBr): 3412, 1650, 1612, 1560, 1510, 1455, 1400, 1327, 1272, 1032,
834 cmꢀ1. HRMS (ESI) calcd. for C21H15O9 411.0711; found 411.0667
[Mþ þ H].

Polyhydroxy 8-Aryl Flavones
2947
5,7-Dihydroxy-2,8-bis(3,4,5-trihydroxyphenyl)-4H-chromen-4-one (21)
Protected flavone 15 (0.0.095 g, 0.14 mmol), 1 M BBr3 (3 ml, 3.00 mmol),
and DCM (10 ml), 2 h, chromatography on silica (5:1, DCM=MeOH)
gave octahydroxyflavone 21 (0.053 g, 89%). 1H NMR (DMSO-d6) d 6.75
(s, 2H), 6.47 (s, 1H), 6.38 (s, 2H), 6.31 (s, 1H). 13C NMR (DMSO-d6) d
182.0, 164.5, 161.4, 159.5, 154.0, 146.1 (2C), 146.1 (2C), 137.6, 132.2,
132.0, 120.8, 109.8 (2C), 108.8, 108.7, 106.2 (2C), 103.6, 98.7. IR
(KBr): 3418, 1651, 1604, 1563, 1531, 1451, 1356, 1265, 1198, 1078,
1034, 838, 697 cmꢀ1. HRMS (ESI) calcd. for C21H15O10 427.0660; found
427.0615 [Mþ þ H].
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