Oxidative dimerisation of isoflavones: Synthesis of kudzuisoflavone a and related compounds

Article abstract of DOI:10.1071/CH12108

Kudzuisoflavone-A was successfully synthesised via oxidative dimerisation of daidzein in the presence of cuprous chloride. Appropriately substituted isoflavones also undergo regioselective oxidative dimerisation when treated with thallium trifluoroacetate to give novel 6′,6′″-biisoflavones in good yield. A rationale for the regioselectivity is proposed.

Full text of DOI:10.1071/CH12108

RESEARCH FRONT
CSIRO PUBLISHING
Aust. J. Chem. 2012, 65, 1377–1383
Full Paper
http://dx.doi.org/10.1071/CH12108
Oxidative Dimerisation of Isoflavones: Synthesis
of Kudzuisoflavone A and Related Compounds*
A
A
A
Mandar Deodhar, Kasey Wood, David StClair Black,
A B
,
and Naresh Kumar
A
School of Chemistry, The University of New South Wales, Sydney,
NSW 2052, Australia.
B
Corresponding author. Email: n.kumar@unsw.edu.au
Kudzuisoflavone-A was successfully synthesised via oxidative dimerisation of daidzein in the presence of cuprous
chloride. Appropriately substituted isoflavones also undergo regioselective oxidative dimerisation when treated with
thallium trifluoroacetate to give novel 60,6000-biisoflavones in good yield. A rationale for the regioselectivity is proposed.
Manuscript received: 20 February 2012.
Manuscript accepted: 12 April 2012.
Published online: 20 June 2012.
5Ј
8Љ
Introduction
OH
O
O
OH
6Ј
2Љ
R1
O
O
2ٞ
The flavonoids are widely distributed in the plant kingdom.
Many natural flavonoids exist as dimers comprising two fla-
vonoid molecules joined together at various positions. These
dimeric flavonoids have been shown to possess a wide range of
physiological and biological properties including antioxidant,[1]
anticancer,[2] antiinflammatory[3] and antiviral[4] activities.
Some of the major limitations in using these compounds as
medicaments include their low abundance in plant material,
tedious methods of extraction and purification and limited
availability of biological data. This has driven the development
of efficient synthetic methodologies for these interesting
compounds.
3Ј
3ٞ
3
6Љ
6
2Ј
2
R2
6ٞ
HO
HO
5ٞ
8
1 R1 ϭ H, R2 ϭ H
2 R1 ϭ H, R2 ϭ OH
3 R1 = OH, R2 = OH
OH
R1
A
O
B
C
HO
O
4 R1 ϭ H
5 R1 ϭ OH Genistein
Daidzein
Kudzuisoflavone A 1 is a biisoflavonoid isolated from the
treatment of Pueraria lobata cell cultures with an elicitor yeast
extract (Fig. 1).[5] Interestingly, the related biisoflavonoids 2
and 3 show 5a-reductase inhibitor activity, and have been
investigated for the treatment of prostate hyperplasia.[6] Biiso-
flavonoid 1 contains two daidzein molecules joined together at
the C30 and C3000 positions. It has been proposed that 1 is
probably formed by the oxidation of daidzein 4 with a peroxi-
dase. In compound 2, a daidzein 4 and a genistein 5 molecule are
directly attached to each other via a C30–C3000 linkage, whereas
in compound 3 this linkage is between two genistein 5 mole-
cules. There are no reports of the total synthesis of these natural
products in the literature.
The oxidative coupling of phenols has been postulated as a
biosynthetic pathway for many aromatic heterocyclic pro-
ducts[7] including alkaloids and antibiotics. Various reagents
have been reported for oxidative coupling reactions and these
include FeCl3, FeCl3-DMF complex,[8] FeCl3 bound to silica,[9]
copper(II) diamine complexes,[10] alkaline K3[Fe(CN)6],[11]
(NH4)2Ce(NO3)6-H2O[212] and photochemical conditions.[13]
In addition, other reagents that have been reported to give
Fig. 1. Isoflavone based natural products.
high yields of intramolecularly coupled products include
vanadium oxytrichloride (VOCl3),[14] vanadium oxytrifluoride
(VOF3),[15–18] manganese tris(acetylacetonate) (MTA),[19]
thallium(III) trifluoroacetate (TTFA)[20,21] and lead
tetraacetate (LTA).[22,23]
Intrigued by the wide range of useful properties associated
with dimeric flavonoids, and in continuation of our interest in
the synthesis of bis-heterocyclic systems and natural pro-
ducts,[24–27] we set out to synthesise novel biflavones and
biisoflavones using an oxidative dimerisation strategy.
Results and Discussion
As a starting point to our investigation into the synthesis of
biisoflavonoids such as 1, daidzein 4 was subjected to oxidative
dimerisation under various conditions. The use of various
*Dedicated to Emeritus Professor Roger Bishop on the occasion of his retirement.
Journal compilation Ó CSIRO 2012
www.publish.csiro.au/journals/ajc

1378
M. Deodhar et al.
reagents and conditions including FeCl3/DMF, FeCl3/AlCl3/
CH3NO2,[28] FeCl3/CH3OH/H2O, FeCl3 (solid phase),[29] PhI
(AcO)2,[30] CuCl2/PhCH2NH2/MeOH[31] and photochemical
conditions[13] were unsuccessful. In all cases, no reaction was
observed and the unreacted starting material was recovered.
When iodine was used as an oxidant,[32] 30-iododaidzein 6 was
isolated as the main product (Scheme 1). Meanwhile, attempted
oxidation with ceric ammonium nitrate gave 30-nitrodaidzein 7
as the sole product. 30-Nitrodaidzein 7 (also known as K3D3) is a
natural product isolated from the culture broth of genetically
engineered Streptomyces K2[33] and its synthesis has not yet
been reported in the literature. When the oxidation was carried
out using potassium ferricyanide under aqueous and non-
aqueous conditions, a complex mixture was obtained.
The oxidative dimerisation of daidzein 4 was eventually
achieved by aerial oxidation in the presence of CuCl,[34] to yield
kudzuisoflavone-A 1 in 10 % yield (Scheme 2).
OH
O
I2, KOH, MeOH
88 %
I
Oxidative dimerisation of isoflavones proved to be problem-
atic because the isoflavonoids were extremely insoluble in most
solvents, even at elevated temperatures. The dimeric products
resulting from these reactions were even less soluble and thus
their separation from reaction impurities and by-products by
solvent extraction or chromatography proved difficult.
HO
HO
O
O
6
OH
(NH4)2Ce(NO3)6
AcOH, 92 %
NO2
4
The solubility of flavonoids in many organic solvents,
especially halogenated solvents such as dichloromethane,
chloroform, dichloroethane, and ethereal solvents such as THF
or dioxane can be substantially increased by converting their
free hydroxyl groups into ether or ester derivatives. Therefore,
we decided to investigate oxidative dimerisation of 40,7-
dimethoxyisoflavone, which has much better solubility in
dichloromethane compared with daidzein 4. We also turned
our attention to vanadium-based reagents that have been previ-
ously reported to give high yields of intramolecularly coupled
products.[17,20,21,23] However, when 40,7-dimethoxyisoflavone,
prepared via methylation of daidzein 4, was subjected to
oxidative dimerisation under a variety of conditions including
CuCl, TTFA or VOF3, no reaction was observed and the
unreacted isoflavone was recovered. This result suggested that
40,7-dimethoxyisoflavone was not reactive enough to undergo
facile oxidative dimerisation.
O
7
K3[Fe(CN)6], NaOH, H2O
Complex mixtures
or
K3[Fe(CN)6], TEA, MeOH
Scheme 1.
OH
O
O
OH
O
O
Air, CuCl
4
DMF, 100ЊC
10 %
HO
HO
1
Scheme 2.
It has been reported that electron-rich substrates undergo
oxidative dimerisation more readily.[20] Furthermore, the addi-
tion of Lewis acids such as BF3ꢀOEt2 has been reported to
increase the electrophilic character of TTFA[35] in the dimerisa-
tion. In order to further improve the solubility and reactivity of
the isoflavones, it was decided to introduce an additional
methoxy group to ring B. Dimethoxyisoflavone 12 was synthe-
sised from resorcinol 8 and 3,4-dimethoxyphenylacetic acid 9
through BF3ꢀOEt2 catalysed acylation, followed by cyclisation
of the resulting ketone 10 and subsequent acetylation of isofla-
vone 11 (Scheme 3).
As compound 12 contains two methoxy groups in ring B, we
envisaged that one of three isomeric dimeric biisoflavones,
namely the 50,5000-isomer, 60,6000-isomer and 50,6000-isomer, or a
mixture thereof would be isolated. Surprisingly, when isofla-
vone 12 was treated with TTFA in the presence of BF3ꢀOEt2 in
dichloromethane at 08C, the 60,6000-biisoflavone product 13 was
OMe
OMe
OH
CH2COOH
O
BF3·OEt2
+
110ЊC, 52 %
HO
OMe
HO
OH
10
8
OMe
BF3·OEt2, DMF
MeSO2Cl
110ЊC, 74 %
OMe
9
OMe
OMe
OMe
Ac2O, pyridine
100ЊC, 87 %
O
O
O
HO
O
AcO
12
11
Scheme 3.
OMe
OMe
R4
OMe
R1
O
O
R1
R3
O
R3
R1
TTFA,
BF3·OEt2
O
O
R2
CH2Cl, 0ЊC
R2
R2
O
R3
MeO
OMe
13–20
Scheme 4.

Oxidative Dimerisation of Isoflavones
1379
isolated exclusively in 71 % yield (Scheme 4, Table 1, entry 1).
The structure of compound 13 was assigned on the basis of the
1H NMR spectrum, which showed two sharp singlets corre-
sponding to the H20, H2000 and H50, H5000 protons. The structure of
dimer 13 was further confirmed through NOE and HMBC 2D
NMR correlations.
This result was very encouraging and prompted us to apply
this methodology to dimethoxy-substituted isoflavones with
different substitution patterns in the A-ring. Isoflavone starting
materials were prepared in three steps following the route
outlined in Scheme 3 and then subjected to oxidative
dimerisation with TTFA and BF3ꢀOEt2 in dichloromethane to
give the corresponding 60,6000-dimers 14–16 in 76, 65, and 74 %
yield respectively (Table 1, entries 2–4). In the case of
30,40,7-trimethoxyisoflavone and 7-acetyoxy-30,40-dimethoxy-
8-methylisoflavone, the corresponding 60,6000-dimers 17 and 19
were isolated in 76 % yield, together with the corresponding
monodemethylated products 18 and 20 in 10 and 22 % yield
respectively (Table 1, entries 5–6).
Having successfully developed a facile method for the
oxidative dimerisation of isoflavones, the oxidative dimerisa-
tion of the isomeric flavones was investigated. We hypothesised
that the oxidative dimerisation of flavones with similar substi-
tution patterns under similar reaction conditions would yield
50,5000- or 60,6000-biflavonoid dimers or mixtures thereof.
30,40,5,7-Tetramethoxyflavone 25 was synthesised from
acetophenone 21 in three steps. Acetophenone 21 was
methylated to give intermediate 22, which was condensed with
3,4-dimethoxybenzaldehyde 23. The resulting chalcone 24 was
oxidatively cyclised with iodine to give the desired flavone 25
(Scheme 5).
However, treatment of flavone 25 with TTFA using the
optimised conditions did not yield the desired dimer 26. When
the temperature of the reaction was increased to room tempera-
ture, 8-iodoflavone 27 was isolated in 70 % yield (Scheme 6).
This result indicated that the B-ring in flavones is much less
activated than the B-ring in isoflavones, and flavone 25 under-
goes preferential electrophilic thallation at C8 to give an
arylthallium compound that reacts with KI during work-up to
give 8-iodoflavone 27.[19,20,36,37]
In order to avoid iodination at C8, the oxidative
dimerisation of 30,40-dimethoxyflavone was investigated. 30,40-
Dimethoxyflavone contains two fewer methoxy substituents in
ring A compared with flavone 25, rendering ring A much less
reactive towards electrophilic attack. 30,40-Dimethoxyflavone
was synthesised following the route outlined in Scheme 5 from
20-hydroxyacetophenone and 3,4-dimethoxybenzaldehyde.
However, when 30,40-dimethoxyflavone was reacted with TTFA
in the presence of BF3ꢀOEt2 at 08C, room temperature, or even
under reflux, no reaction was observed by TLC analysis. Upon
work-up, the unreacted starting material was recovered.
OMe
MeO
OMe O
O
OMe
MeO
O
O
OMe
Table 1. Synthesis of 69,690-biisoflavones
OMe
26
TTFA,
BF3·OEt2
OMe
Entry
60,6000- dimer
R1
R2
R3
R4
% Yield
25
OMe O
0ЊC to r.t.
1
2
3
4
5
13
14
15
16
17
18
19
20
H
Me
H
OAc
OAc
OAc
OMe
OMe
OMe
OAc
OAc
H
H
OMe
OMe
OMe
OMe
OMe
OH
71
76
65
74
76
10
76
22
OAc
Me
H
MeO
O
H
I
H
27
OMe
H
H
OMe
6
H
Me
Me
OMe
OH
H
Scheme 6.
OH
O
OMe O
Me2SO4, K2CO3
ϩ
Acetone, reflux
72 %
OMe
HO
OH
OH
MeO
OMe
23
22
21
NaOH
EtOH
87 %
OMe
O
O
OMe
O
I2, DMSO
MeO
150ЊC, 81 %
OH
MeO
25
OMe
24
OMe
OMe
OMe
Scheme 5.

1380
M. Deodhar et al.
O
O
OMe
Electron
density
heated to 1008C and air was bubbled through the mixture for 5 h.
The reaction mixture was cooled to r.t. and poured into hydro-
chloric acid (1 M , 200 mL). The precipitated solid was filtered,
washed with water (20 mL ꢁ 2) and air-dried. The solid was
dissolved in THF and adsorbed onto silica gel. Chromatography
(SiO2, 60 % ethyl acetate/hexane) gave the title compound 1 as
an off-white solid (48 mg, 10 %), mp .3008C (lit.[38] .3008C).
OMe
O
O
OMe
Electron
density
OMe
n
max(KBr)/cmꢂ1 3393, 3227, 1624, 1576, 1506, 1456, 1261,
1195, 1099. lmax (MeOH)/nm 239 (e 43863 cmꢂ1Mꢂ1), 243
(44440), 246 (44890), 248 (44845), 298 (20663). dH (300 MHz,
acetone-d6) 6.88 (d, J 2.3, 2H), 6.97 (dd, J 2.3, 8.7, 2H), 7.04
(d, J 8.3, 2H), 7.55 (dd, J 2.3, 8.3, 2H), 7.59 (d, J 2.3, 2H), 8.04
(d, J 8.7, 2H), 8.25 (s, 2H). dC (75.6 MHz, DMSO-d6) 102.5,
115.5, 115.9, 117.0, 122.8, 123.8, 126.0, 127.7, 128.8, 129.2,
132.3, 153.3, 155.0, 157.8, 162.9, 175.1. Spectral data are
consistent with the data reported in the literature.
Fig. 2. Comparative electron density distribution in flavones and
isoflavones.
A plausible explanation for the reduced reactivity of flavones
in comparison to the corresponding isoflavones can be deduced
by an analysis of the electronic distribution in the two types of
compounds. In methoxy-substituted isoflavones, the B-ring and
benzopyran oxygen are conjugated by the C2–C3 double bond
and the net result of this delocalisation is the increase in the
electron density in the B-ring via donation of the oxygen lone
pair (Fig. 2). According to the resonance structures, increased
electron density is found at C20, C40 and C60, activating these
positions towards oxidative dimerisation. Since C40 is already
occupied and the C20 position is hindered by the adjacent
methoxy group and the benzopyran ring, the reaction occurs
exclusively at the C60 position and regioselectively produces
60,6000-biisoflavones.
Conversely, in flavones the B-ring is conjugated with the C4
carbonyl group and the net result of this delocalisation is the
lowering of the electron density in ring B. This decreased
electron density is the most likely reason for the inability of
flavones to undergo oxidative dimerisation, despite the two
methoxy groups in the B-ring.
40,7-Dihydroxy-30-iodoisoflavone (30-iododaidzein) (6)
To a suspension of 40,7-dihydroxyisoflavone (daidzein) 4
(1.6 g, 5.91 mmol) in methanol (100 mL) was added powdered
KOH (6.0 g, 107 mmol) and the mixture was stirred under argon
for 30 min. A solution of iodine (2.3 g, 10 mmol) in methanol
(40 mL) was added dropwise over 1 h and the mixture was
stirred at ambient temperature for 1 h. Again a solution of iodine
(0.22 g, 0.86 mmol) in methanol (20 mL) was added over 30 min
and stirring was continued further for 30 min. The mixture was
poured into water (400 mL) and acidified to pH 2 using conc.
hydrochloric acid. The precipitated solid was filtered, washed
with water and air-dried to give the compound title 6 (2.0 g,
88 %), mp .3008C. nmax (KBr)/cmꢂ1 2600–3500 (br), 1623,
1577, 1457, 1419, 1264, 1195, 1099, 784. dH (300 MHz,
acetone-d6) 6.89 (d, J 2.3, 1H), 6.99 (d, J 8.3, 1H), 6.99 (dd,
J 2.3, 8.7, 1H), 7.48 (dd, J 2.3, 8.3, 1H), 8.01 (d, J 2.3, 1H), 8.04
(d, J 8.7, 1H), 8.21 (s, 1H), 9.50 (br s, 2H). dC (75.6 MHz,
acetone-d6) 83.0, 102.1, 114.3, 115.0, 117.1, 122.8, 125.2,
127.4, 130.1, 139.3, 152.8, 156.5, 157.9, 162.7, 170.5. m/z
(HR-ESI) calc. for C15H9O4INa (M þ Na)þ, 402.9438. Found
402.9440.
Conclusion
We have shown that a range of different dimers can be generated
from the oxidative dimerisation of various isoflavonoids.
Kudzuisoflavone A was isolated by oxidative dimerisation of
daidzein using CuCl in air. Moderate to high yields of novel
60-6000 biisoflavones were also obtained regioselectively using
methoxy substituted isoflavones as activated substrates. How-
ever, the oxidative dimerisation of the corresponding flavone
analogues was unsuccessful under similar reaction conditions.
30-Nitrodaidzein (7)[33]
To a stirred suspension of ammonium cerium(IV) nitrate
(1.0 g, 1.82 mmol) in acetic acid (20 mL) was added a solution of
daidzein 4 (0.46 g, 1.82 mmol) in DMF (3 mL). The mixture was
stirred overnight at r.t. and then poured into stirring cold water
(150 mL). The resulting yellow solid was filtered, washed with
water and air-dried to give the title compound 7 (0.5 g, 92 %),
mp 310–3128C. nmax (KBr)/cmꢂ1 3272, 1627, 1587, 1577, 1533,
1309, 1278, 1238, 1177. dH (300 MHz, acetone-d6) 6.91
(d, J 2.3, 1H), 7.02 (dd, J 2.3, 8.7, 1H), 7.24 (d, J 8.7, 1H),
7.95 (dd, J 2.3, 8.7, 1H), 8.05 (d, J 8.7, 1H), 8.40 (s, 1H), 8.45
(d, J 2.3, 1H), 9.78 (br s, 1H), 10.47 (br s, 1H). m/z (HR-ESI)
calc. for C15H9O6NNa (M þ Na)þ 322.0322. Found 322.0319.
Spectral data are consistent with the data reported in the
literature.
Experimental
General
Melting points were measured using a Mel-Temp melting point
apparatus and are uncorrected. Microanalyses were performed
on a Carlo Erba Elemental Analyser EA 1108 at the Campbell
Microanalytical Laboratory, University of Otago, New Zealand.
1H and 13C NMR spectra were obtained on Bruker DPX300
(300 MHz) and Bruker DPX600 (600 MHz) spectrometers.
Mass spectra were recorded on either a Bruker FT-ICR MS (EI)
or Micromass ZQ2000 (ESI) mass spectrometers. Infrared
spectra were recorded with a Thermo Nicolet 370 FTIR Spec-
trometer using KBr discs. Column chromatography was carried
out using Merck 230–400 mesh ASTM silica gel, whilst pre-
parative thin-layer chromatography was performed using Merck
silica gel 7730 60GF254.
2,4-Dihydroxyphenyl-3,4-dimethoxybenzylketone (10)
A
mixture of resorcinol 8 (2.8 g, 25 mmol), 3,4-
dimethoxyphenylacetic acid 9 (4.9 g, 25 mmol) and BF3ꢀOEt2
(60 mL) was heated with stirring under an argon atmosphere at
1108C for 1.5 h. The mixture was cooled and kept in a refrigera-
tor overnight. The precipitated solid was filtered, washed with
saturated sodium acetate solution (12 %, 100 mL) and air-dried
to give the title compound 8 (3.8 g, 52 %). The product was used
Kudzuisoflavone-A (1)
Daidzein 4 (500 mg, 1.96 mmol) was added to a suspension
of CuCl (500 mg, 5.05 mmol) in DMF (10 mL). The mixture was

Oxidative Dimerisation of Isoflavones
1381
in the next step without further purification. Mp 178–1808C
(lit.[39] 182–1838C).
(SiO2, 2 % ethyl acetate/dichloromethane) gave the title
compound 14 as pale yellow crystals (234 mg, 78 %), mp
258–2608C (from MeOH). nmax (KBr)/cmꢂ1 1773, 1648,
1608, 1508, 1449, 1255, 1197, 1144, 1018. lmax (MeOH)/nm
214 (e 62029 cmꢂ1Mꢂ1), 245 (55576), 296 (18152). dH
(300 MHz, CDCl3) 2.31 (s, 6H), 2.36 (s, 6H), 3.80 and 3.86
(2 ꢁ s, 12H), 6.77 (d, J 2.3, 2H), 6.82 and 6.87 (2 ꢁ s, 4H), 7.02
(d, J 2.3, 2H), 7.50 (s, 2H). dC (75.6 MHz, CDCl3) 21.0, 22.8,
55.8, 55.9, 108.8, 114.2, 114.3, 120.6, 121.0, 122.9, 124.9,
132.6, 143.1, 147.7, 148.5, 152.8, 153.5, 158.0, 168.3, 177.7.
m/z (HR-ESI) calc. for C40H34O12Na (M þ Na)þ 729.1943.
7-Hydroxy-30,40-dimethoxyisoflavone (11)
BF3ꢀOEt2 (4.3 mL, 34 mmol) was slowly added to a stirred
solution of ketone 10 (2.0 g, 6.9 mmol) in DMF (16 mL). The
mixture was warmed to 508C under an argon atmosphere and
then a solution of methanesulfonyl chloride (2 mL, 25.8 mmol)
in DMF (4 mL) was added dropwise. The mixture was then
heated at 1108C for 2 h, cooled to r.t. and poured into cold water
(150 mL). The resulting solid was filtered, washed with water
and air-dried to give the title compound 11 (1.54 g, 74 %). The
product was used in the next step without further purification.
Mp. 254–2578C (from EtOH) (lit.[39] 257–2588C).
1
Found 729.1943. Anal. Calc. for C40H34O12ꢀ /2H2O: C 67.13,
H 4.93. Found: C 67.25, H 5.13 %.
7,700,8,8000-Tetraacetoxy-30,3000,40,4000-tetramethoxy-
60,6000-biisoflavonyl (15)
7-Acetoxy-30,40-dimethoxyisoflavone (12)
The title compound was synthesised following the procedure
for dimer 13 using 7,8-diacetoxy-30,40-dimethoxyisoflavone
(350 mg, 0.87 mmol), TTFA (238 mg, 0.44 mmol) and BF3ꢀOEt2
(0.5 mL) except that the reaction was carried out at 108C
instead of 08C. Chromatography (SiO2, 2 % ethyl acetate/
dichloromethane) gave the title compound 15 as off-white
crystals (230 mg, 65 %), mp 1678C. nmax (KBr)/cm- 1781,
1653, 1506, 1447, 1256, 1195, 1168, 1031. lmax (CHCl3)/nm
244 (e 40991 cmꢂ1Mꢂ1), 249 (39508), 294 (17467). dH
(300 MHz, CDCl3) 2.34 and 2.37 (2 ꢁ s, 12H), 3.71 and 3.85
(2 ꢁ s, 12H), 6.79 and 6.82 (2 ꢁ s, 4H), 7.14 (d, J 9.0, 2H), 7.82
(d, J 9.0, 2H), 7.86 (s, 2H). dC (75.6 MHz, CDCl3) 20.2, 20.6,
55.8, 114.1, 114.3, 119.8, 122.1, 122.8, 123.5, 125.1, 131.1,
132.7, 146.3, 147.7, 148.6, 149.3, 154.6, 167.0, 167.4, 175.3.
m/z (HR-ESI) calc. for C42H34O16Na (M þ Na)þ 817.1739.
Found 817.1729. Anal. Calc. for C42H34O16ꢀH2O: C 62.07,
H 4.46. Found: C 62.01, H 4.78 %.
A mixture of isoflavone 11 (1.0 g, 3.4 mmol), acetic
anhydride (5 mL, 52.9 mmol) and pyridine (1 mL, 12.3 mmol)
was heated at 1008C for 2 h. The mixture was cooled to r.t.,
poured into hydrochloric acid (1 M, 50 mL) and stirred for
10 min. The solid was filtered, washed with water and air-dried
to give the title compound 12 (1.0 g, 87 %), mp 166–1688C
(from MeOH) (lit.[40] 163–1648C). dH (300 MHz, CDCl3) 2.35
(s, 3H), 3.91 (s, 3H), 3.92 (s, 3H), 6.92 (d, J 8.3, 1H), 7.05 (dd,
J 2.3, 8.3, 1H), 7.16 (dd, J 2.3, 8.6, 1H), 7.18 (d, J 2.3, 1H), 7.29
(d, J 2.3, 1H), 7.99 (s, 1H), 8.31 (d, J 8.6, 1H).
7,700-Diacetoxy-30,3000,40,4000-tetramethoxy-60,6000-
biisoflavonyl (13)
A solution of isoflavone 12 (500 mg, 1.47 mmol) in dichloro-
methane (11 mL) was cooled to 08C under an argon atmosphere.
Thallium(III) trifluoroacetate (TTFA) (400 mg, 0.73 mmol) was
added followed by addition of BF3ꢀOEt2 (0.5 mL). The reaction
was stirred for 2.5 h and then quenched by addition of KI
solution (2.0 g in 20 mL water) followed by stirring at ambient
temperature for 30 min. Sodium metabisulfite solution (0.1 g
dissolved in minimum amount of water) was added followed by
further stirring for 10 min. The yellow precipitate was filtered
and washed with dichloromethane (10 mL ꢁ 3). The organic
layer was separated and the aqueous layer was extracted with
dichloromethane (20 mL). The combined organic layer was
dried over anhydrous sodium sulfate and concentrated under
vacuum. Chromatography (SiO2, dichloromethane) gave the
title compound 13 as pale yellow crystals (354 mg, 71 %), mp
257–2598C (from MeOH). nmax (KBr)/cmꢂ1 1768, 1650, 1618,
1506, 1439, 1250, 1201, 1176 cmꢂ1. lmax (MeOH)/nm 218
(e 44090 cmꢂ1Mꢂ1), 241 (36524), 296 (15479). dH (300 MHz,
CDCl3) 2.34 (s, 6H), 3.75 and 3.86 (2 ꢁ s, 12H), 6.83 and 6.87
(2 ꢁ s, 4H), 7.02 (dd, J 2.3, 8.6, 2H), 7.21 (d, J 2.3, 2H), 7.75
(s, 2H), 7.80 (d, J 8.6, 2H). dC (75.6 MHz, CDCl3) 21.1, 55.8,
55.9, 110.7, 114.2, 114.3, 119.2, 121.9, 122.4, 124.2, 127.2,
132.5, 147.7, 148.5, 154.3, 155.2, 156.4, 168.3, 175.8. m/z
(HR-ESI) calc. for C38H30O12Na (M þ Na)þ 701.1629. Found
701.1640. Anal. Calc. for C38H30O12: C 67.25, H 4.46. Found:
C 67.32, H 4.57 %.
30,3000,40,400,7,700-Hexamethoxy-8,800-dimethyl-
60,6000-biisoflavonyl (16)
The title compound was synthesised following the procedure
for dimer 13 using 8-methyl-30,40,7-trimethoxyisoflavone
(470 mg, 1.44 mmol), TTFA (392 mg, 0.72 mmol) and BF3ꢀOEt2
(0.5 mL). Chromatography (SiO2, 2 % ethyl acetate/
dichloromethane) gave the title compound 16 as off-white
crystals (345 mg, 74 %), mp 301–3038C (from MeOH). nmax
(KBr)/cmꢂ1 1635, 1623, 1601, 1505, 1271, 1250, 1197, 1170,
1100, 785. lmax (CHCl3)/nm 245 (e 56885 cmꢂ1Mꢂ1), 252
(54850), 294 (29035). dH (300 MHz, CDCl3) 2.27 (s, 6H),
3.60, 3.84 and 3.95 (3 ꢁ s, 18H), 6.86 and 6.78 (2 ꢁ s, 4H),
7.93 (d, J 8.7, 2H), 7.94 (d, J 8.7, 2H), 8.06 (s, 2H). dC
(75.6 MHz, CDCl3) 8.0, 55.6, 55.7, 56.0, 108.4, 113.9, 114.0,
114.2, 118.1, 123.3, 124.4, 124.4, 133.4, 147.4, 148.0, 155.1,
155.3, 161.1, 173.7. m/z (HR-ESI) calc. for C38H34O10Na (M þ
Na)þ 673.2044. Found 673.2032. Anal. Calc. for C38H34O10:
C 70.14, H, 5.27. Found: C 69.95, H 5.39 %.
30,3000,40,4000,7,700-Hexamethoxy-60,6000-
biisoflavonyl (17)
The title compound was synthesised following the
procedure for dimer 13 using 30,40,7-trimethoxyisoflavone
(230 mg, 0.737 mmol), TTFA (199 mg, 0.36 mmol) and
BF3ꢀOEt2 (0.25 mL). Chromatography (SiO2, 2 % ethyl acetate/
dichloromethane) gave the title compound 17 as off-white
crystals (175 mg, 76 %), mp256–2588C (from MeOH). nmax
(KBr)/cmꢂ11673, 1625, 1605, 1505, 1440, 1248, 1201, 1170,
7,700-Diacetoxy-30,3000,40,4000-tetramethoxy-5,500-
dimethyl-60,6000-biisoflavonyl (14)
The title compound was synthesised following the
procedure for dimer 13 using 7-acetyoxy-30,40-dimethoxy-5-
methylisoflavone (300 mg, 0.847 mmol), TTFA (253 mg,
0.466 mmol) and BF3ꢀOEt2 (0.3 mL). Chromatography

1382
M. Deodhar et al.
1
1031. lmax (MeOH)/nm 216 (e 60803 cmꢂ1Mꢂ1), 248 (43627)
sh, 296 (25721). dH (300 MHz, CDCl3) 3.71 and 3.86 (2 ꢁ s,
12 H), 3.89 (s, 6H), 6.78 (d, J 2.3, 2H), 6.81 and 6.90 (2 ꢁ s, 4H),
6.85 (dd, J 2.3, 9.0, 2H), 7.75 (d, J 9.0, 2H), 7.76 (s, 2H). dC
(75.6 MHz, CDCl3) 55.8, 99.9, 114.1, 114.3, 114.4, 118.1,
123.0, 124.1, 127.2, 132.7, 147.5, 148.3, 154.7, 157.8, 163.8,
175.9. m/z (HR-ESI) calc. for C36H30O10Na (M þ Na)þ
715.1767. Anal. Calc. for C39H32O12ꢀ /2H2O: C 66.76, H 4.70.
Found: C, 66.75, H, 4.77 %.
20-Hydroxy-40,60-dimethoxyacetophenone (22)
To a stirred mixture of 20,40,60-trihydroxyacetophenone 21
(2.5 g, 15 mmol), K2CO3 (4.1 g, 28 mmol) and acetone (45 mL)
was added dimethyl sulfate (2.7 mL, 28 mmol) and the mixture
was refluxed for 5 h. The reaction mixture was cooled to r.t. and
diluted with water (50 mL). The solid was filtered, washed with
water and air-dried. The title compound 22 was obtained as a
pale yellow solid (2.1 g, 72 %), mp 75–778C (from hexane)
(lit.[41] 75–778C) dH (300 MHz, CDCl3) 2.60 (s, 3H), 3.81
(s, 3H), 3.84 (s, 3H), 5.90 (d, J 2.3, 1H), 6.05 (d, J 2.3, 1H),
14.01 (s, 1H).
1
645.1731. Found 645.1729. Anal. Calc. for C36H30O10ꢀ /2H2O:
C 68.46, H 4.91. Found: C 68.66, H 4.93 %.
Further elution of the column gave compound 18 as a pale
yellow solid (24 mg, 10 %).
40-Hydroxy-30,3000,4000,7,700-pentamethoxy-60,6000-
biisoflavonyl (18)
Mp 265–2678C. nmax (KBr)/cmꢂ1 3434, 1627, 1607, 1507,
1441, 1270, 1202. lmax UV (MeOH)/nm 219
(e 62216 cmꢂ1Mꢂ1), 295 (27672). dH (300 MHz, CDCl3) 3.69
and 3.70 (2 ꢁ s, 6H), 3.85 (s, 3H), 3.88 and 3.89 (2 ꢁ s, 6H), 5.53
(br s, 1H), 6.77–6.91 (m, 8H), 7.70 and 7.89 (2 ꢁ s, 2H), 7.76
(2 ꢁ d, J 9.1, 2H)/ dC (75.6 MHz, CDCl3) 55.66, 55.74, 55.8,
99.89, 99.95, 113.6, 114.1, 114.2, 114.3, 114.4, 117.6, 118.1,
118.2, 122.9, 123.8, 124.1, 124.5, 127.2, 127.4, 132.5, 132.9,
144.3, 146.1, 147.5, 148.1, 154.2, 155.1, 157.76, 157.81, 163.7,
175.6, 176.1. m/z (HR-ESI) calc. for C35H28O10Na (M þ Na)þ
631.1575. Found 631.1560. Anal. Calc. for C35H28O10: C 69.07,
H 4.64. Found: C 68.82, H 4.94 %.
20-Hydroxy-3,4,40,60-tetramethoxychalcone (24)
A stirred mixture of acetophenone 22 (0.49 g, 2.5 mmol), 3,4-
dimethoxybenzaldehyde 23 (0.43 g, 2.59 mmol) and ethanol
(5 mL) was heated to 508C. A solution of NaOH (2.0 g, 50 %
w/w, 25 mmol) was added in one lot and the heating was
continued for further 30 min. The mixture was cooled to r.t.
and acidified to pH 5 using 2 M hydrochloric acid. The precipi-
tated product was filtered, washed with water and air-dried to
give the title compound 24 (0.75 g, 87 %). This was used in the
next step without further purification. Mp 155–1578C (from
ether) (lit.[42]154–1568C). dH (300 MHz, CDCl3) 3.83 (s, 3H),
3.90 (s, 3H), 3.92 (s, 3H), 3.93 (s, 3H), 5.95 and 6.10 (2 ꢁ d,
J 2.3, 2H), 6.89 (d, J 8.3, 1H), 7.12 (d, J 1.5, 1H), 7.21 (dd, J 1.5,
8.3, 1H), 7.75 and 7.82 (2 ꢁ d, J 15.4, 2H), 14.38 (bs, 1H). dC
(75.6 MHz, CDCl3) 55.4, 55.7, 55.8, 91.2, 93.7, 106.3, 110.4,
111.1, 122.5, 125.3, 128.5, 142.5, 149.1, 151.0, 162.3, 166.0,
168.3, 192.0.
7,700-Diacetoxy-30,3000,40,4000-tetramethoxy-8,800-
dimethyl-60,6000-biisoflavonyl (19)
The title compound was synthesised following the
procedure for dimer 13 using 7-acetyoxy-30,40-dimethoxy-8-
methylisoflavone (500 mg, 1.41 mmol), TTFA (383 mg,
0.70 mmol) and BF3ꢀOEt2 (1 mL). Chromatography (SiO2, 2 %
ethyl acetate/dichloromethane) gave the title compound 19 as
a pale yellow solid (380 mg, 76 %), mp 1588C (from EtOH).
nmax (KBr)/cmꢂ1 1766, 1646, 1603, 1506, 1205, 1183, 1053.
lmax (CHCl3)/nm 245 (e 54137 cmꢂ1Mꢂ1), 293 (23362). dH
(300 MHz, CDCl3) 2.26 (s, 6H), 2.37 (s, 6H), 3.71 and 3.85
(2 ꢁ s, 12H), 6.82 and 6.85 (2 ꢁ s, 4H), 7.01 (d, J 8.8, 2H), 7.81
(d, J 8.8, 2H), 7.95 (s, 2H). dC (75.6 MHz, CDCl3) 9.1, 20.7,
55.8, 114.1, 114.3, 119.4, 119.9, 122.1, 122.68, 124.0, 124.5,
132.9, 147.6, 148.3, 152.6, 155.1, 155.2, 168.4, 176.3. m/z
(HR-ESI) calc. for C40H34O12Na (M þ Na)þ 729.1942. Found
729.1939. Anal. Calc. for C40H34O12ꢀH2O: C 66.29. H, 4.97.
Found: C, 66.42;, H, 4.94 %.
30,40,5,7-Tetramethoxyflavone (25)
A mixture of chalcone 24 (750 mg, 2.18 mmol) and DMSO
(7.5 mL) was heated to 1508C under an argon atmosphere.
Iodine crystals (30 mg, 0.12 mmol) were added in one lot and
the heating was continued further for 30 min. The mixture was
cooled to r.t. and diluted with water (75 mL). Potassium meta-
bisulfite solution (5 % w/w) was added dropwise till the colour of
iodine was just discharged. The solid was filtered, washed with
water (25 mL ꢁ 2) and air-dried to give the title compound 25
(610 mg, 81 %), mp 189–1908C (from dichloromethane) (lit.[42]
190–1928C) dH (300 MHz, CDCl3) 3.92 (s, 3H), 3.95 (s, 3H),
3.96 (s, 3H), 3.97 (s, 3H), 6.37 (d, J 2.3, 1H), 6.56 (d, J 2.3, 1H),
6.68 (s, 1H), 6.96 (d, J 8.7, 1H), 7.32 (d, J 2.3, 1H), 7.51 (dd,
J 2.3, 8.7, 1H). dC (75.6 MHz, CDCl3) 55.7, 55.9, 56.0, 56.3,
92.8, 96.0, 107.8, 108.5, 108.9, 111.0, 119.4, 123.9, 149.1,
151.7, 159.7, 160.6, 160.7, 163.9, 177.6.
Further elution with the same solvent system gave mono-
demethylated dimer 20 as a pale yellow solid (110 mg, 22 %).
7,700-Diacetoxy-40-hydroxy-30,3000,4000-trimethoxy-8,800-
dimethyl-60,6000-biisoflavonyl (20)
30,40,5,7-Tetramethoxy-8-iodoflavone (27)
Mp 260–2628C. nmax (KBr)/cmꢂ1 3433, 1736, 1647, 1636,
1507, 1203, 1183, 1152, 1054. lmax (CHCl3)/nm 245
(e 43859 cmꢂ1Mꢂ1), 294 (17161). dH (300 MHz, CDCl3) 2.27
(s, 6H), 2.37 (s, 6H), 3.67 (s, 6H), 3.84 (s, 3H), 5.52 (br s, 1H),
6.78 and 6.79 (2 ꢁ s, 2H), 6.84 (s, 1H), 6.87 (s, 1H), 7.01 (d,
J 8.6, 1H), 7.04 (d, J 8.6, 1H), 7.84 (d, J 8.6, 1H), 7.92 (d, J 8.6,
1H), 7.93 (s, 1H), 8.12 (s, 1H). dC (75.6 MHz, CDCl3) 9.05, 9.09,
20.7, 55.76, 55.84, 113.5, 114.1, 114.3, 117.5, 119.4, 119.8,
120.0, 122.05, 122.13, 122.62, 123.5, 124.0, 124.1, 124.7,
125.0, 132.7, 133.2, 144.4, 146.1, 147.6, 148.1, 152.6, 154.6,
155.19, 155.22, 155.5, 168.36, 168.43, 176.0, 176.5. m/z
(HR-ESI) calc. for C39H32O12Na (M þ Na)þ 715.1786. Found
A stirred solution of flavone 25 (300 mg, 0.88 mmol) in
dichloromethane (11 mL) was cooled to 58C under an argon
atmosphere. TTFA (520 mg, 0.96 mmol) was added followed by
addition of BF3ꢀOEt2 (0.3 mL). The mixture was stirred at 58C
for 1 h. TLC analysis showed the absence of any new product.
The temperature was raised to r.t. when formation of new
product was observed on TLC. However, the progress of the
reaction ceased after 3 h. The reaction was quenched by addition
of aq. KI (10 % in water, 10 mL) followed by stirring for 30 min.
Sodium metabisulfite solution (500 mg dissolved in minimum
amount of water) was added and stirring was continued further

Oxidative Dimerisation of Isoflavones
1383
for 10 min. The yellow precipitate was filtered and washed with
dichloromethane (10 mL ꢁ 3). The filtrate was collected and the
organic layer was separated. The aqueous layer was extracted
with dichloromethane (10 mL). The combined organic layer was
dried with anhydrous sodium sulfate and concentrated under
vacuum. Chromatography (SiO2, 2 % ethyl acetate/dichloro-
methane) gave the title compound 27 as a yellow solid, mp 263–
2648C (from pyridine) (lit.[43] 268–2708C). dH (300 MHz,
CDCl3) 3.96 (s, 3H), 3.99 (s, 3H), 4.03 (s, 6H), 6.43 (s, 1H),
6.70 (s, 1H), 6.98 (d, J 8.6, 1H), 7.64 (dd, J 1.9, 8.6, 1H), 7.66 (d,
J 1.9, 1H). dC (75.6 MHz, CDCl3) 55.98, 56.04, 56.5, 56.7, 64.8,
91.7, 106.9, 109.2, 109.8, 111.1, 119.9, 123.5, 149.2, 151.8,
157.4, 160.9, 161.9, 162.5, 177.4.
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[25] M. Deodhar, D. StC. Black, N. Kumar, Tetrahedron 2007, 63, 5227.
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[26] M. Deodhar, D. StC. Black, D. S.-H. Chan, N. Kumar, Heterocycles
We thank the University of New South Wales and the Australian Research
Council (project number LP0455373) for financial support. MD was sup-
ported by an International Postgraduate Research Scholarship.
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[27] M. Deodhar, D. StC. Black, D. S.-H. Chan, N. Kumar, Heterocycles
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