Synthesis of 2,2′-biflavanones from flavone via electrolytic reductive coupling

Article abstract of DOI:10.1002/jccs.200200159

Flavone (1) was easily reduced by using the electrochemical method to give two hydrodimers of 2,2′-biflavanone(racemate) (5a) and 2,2′-biflavanone(meso) (5b) and one reductive product of flavanone (6). Their yields were dependent on the nature of electrodes, the kinds of supporting electrolytes and the reaction temperature. They were found to afford higher yields of 2,2′-biflavanone(racemate) (5a) and 2,2′-biflavanone (meso) (5b) (32.4% and 24.8%, 35.8% and 13.4%, respectively,) in the reaction conditions of Pb(-)/C(+)-H₂SO₄-TF/mol and C(-)/C(+)-H ₂SO₄-5F/mol.

Full text of DOI:10.1002/jccs.200200159

Journal of the Chinese Chemical Society, 2002, 49, 1105-1109
1105
Synthesis of 2,2 -Biflavanones from Flavone via Electrolytic Reductive
Coupling
Arh-Hwang Chen* (
), Chieh-Yuan Cheng (
) and Chia-Wen Chen (
)
Department of Chemi s t r y, National Kaohsiung Normal University, Kaohsiung 802, Taiwan, R.O.C.
Flavone (1) was easily reduced by using the electrochemical method to give two hydrodimers of
2,2 -biflavanone(racemate) (5a) and 2,2 -biflavanone(meso) (5b) and one reductive product of flavanone (6).
Their yields were dependent on the nature of electrodes, the kinds of supporting electrolytes and the reaction
temperature. They were found to afford higher yields of 2,2 -biflavanone(racemate) (5a) and 2,2 -biflavanone
(meso) (5b) (32.4% and 24.8%, 35.8% and 13.4%, respectively,) in the reaction conditions of Pb(-)/C(+)-
H 2SO4-7F/mol and C(-)/C(+)-H2SO4-5F/mol.
INTRODUCTION
Biflavonoids are widely distributed in natural plants.1
(3) in the presence of acid with a yield of 32.0%, as shown in
Scheme I.11
Early on, they were found to have strong biological activities
including spasmolysis,2a peripheral vasodilatation, anti-
bradykinin activity and antispasmogenic action against pros-
taglandin PGE1,2b inhibition of cyclic GMP and cyclic AMP
phosphodiesterase2c~d and inhibition of hepatoma cells.2e Re-
cently, some biflavonoids were demonstrated to enhance sup-
pression of lymphocyte preliferation,3a inhibition of phos-
pholipaseCr1,3b anti-inflammatory activity,3c anti-HIV activ-
ity,3d~e anticomplementatory activity,3f antiviral activity3g and
chemoprevention of hepatotoxicity.3h
Scheme I
OH
O
OH
CH3
OCOPh
CH3
O
KOH, pyridine
72.8%
PhCOCl, pyridine
69.6%
Ph
O
O
3
1
2
O
O
H2SO4, acetic acid
32.0%
4
Many synthetic attempts including Ullmann coupling,4
Baker-Venkataraman rearrangement and cyclization,5 cy-
clization from bichalcone,6 oxidative coupling7 and reductive
coupling8 were developed for preparations of some biflavonoids.
Recently, Pd-cathode reduction9 and photoinduced electron
transfer reaction10 were carried out for transformation of fla-
vones to biflavanones. In our continuous study for synthetic
application of biflavonoids, we report herein synthesis of
2,2 -biflavanones from flavones via electrolytic reductive
coupling.
The electrochemical reduction of flavone (4) was car-
ried out by using the H-type cell with a glass-filter diaphragm
equipped with a series of electrodes and methanol with sulf u -
ric acid or p-toulenesulfonic acid used as supporting electro-
lytes. Flavone (4) was found to be easily reduced to yield two
dimers of 2,2 -biflavanone(racemate) (5a) and 2,2 -biflavan-
one(meso) (5b) and one reductive product of flavanone (6),
as shown in Scheme II.
Scheme II
RESULTS AND DISCUSSION
O
O
O
O
O
O
O
O
+ e-
o-Hydroxyacetophenone (1) underwent an esterifica-
tion with benzoyl chloride in the presence of pyridine to give
o-benzoyloxyacetophenone (2) with a yield of 69.6%. o-
Benzoyloxyacetophenone (2) followed a base-catalyzed
Fries rearrangement to convert into o-hydroxydibenzoyl-
methane (3) with a yield of 72.8%. Finally, flavone (4) was
obtained from cyclization of o-hydroxydibenzoylmethane
+
4
5a (racemates)
b (meso)
6
As shown in Table 1 and Table 2, yields were largely af-
fected by the nature of electrodes, the kinds of supporting

1106 J. Chin. Chem. Soc., Vol. 49, No. 6, 2002
Chen et al.
Table 1. The Yields of Products for the Electrochemical Reduction of Flavone (4) at 0 C
Entries
Reaction Conditions*1
Conversion
(%)
Yields of Products (%)*2
Current Efficiency
(%)
5a
5b
6
1
2
3
4
5
6
7
8
Zn(-)/C(+), 0.1M H2SO4, 10F/mol
Al(-)/C(+), 0.1M H2SO4, 17F/mol
Pb(-)/C(+), 0.1M H2SO4, 7F/mol
C(-)/C(+), 0.1M H2SO4, 5F/mol
Cu(-)/C(+), 0.1M H2SO4, 10F/mol
Pt(-)/C(+), 0.1M H2SO4, 10F/mol
Ni(-)/C(+), 0.1M H2SO4, 15F/mol
Zn(-)/C(+), 0.1M PTSA, 5F/mol
Al(-)/C(+), 0.1M PTSA, 8F/mol
Pb(-)/C(+), 0.1M PTSA, 4F/mol
C(-)/C(+), 0.1M PTSA, 4F/mol
Cu(-)/C(+), 0.1M PTSA, 6F/mol
Pt(-)/C(+), 0.1M PTSA, 6F/mol
Ni(-)/C(+), 0.1M PTSA, 6F/mol
59.6
70.0
68.3
79.6
100.0
93.9
50.3
62.8
77.5
87.9
83.7
72.3
69.6
83.7
10.1
15.8
32.4
35.8
4.1
30.2
19.5
24.8
13.4
2.0
2.1
0.8
8.5
4.9
7.3
12.4
2.2
1.1
6.2
4.0
3.5
8.5
9.8
6.8
3.6
0.4
6.6
2.4
7.2
8.9
9.7
3.4
2.9
24.1
2.0
62.1
31.7
5.6
2.1
1.1
24.8
14.7
21.5
23.3
2.8
9
10
11
12
13
14
53.7
18.2
1.3
11.4
*1 PTSA: p-toulenesulfonic acid.
*2 Yield based on consumed flavone (4).
Table 2. The Temperature Effects of the Product Yields for the Electrochemical Reduction of
Flavone (4)
Entries
Reaction Temperature at
a Specified Condition*3
Yields of Products (%)*4
Current Efficiency
(%)
5a
5b
6
1
2
3
4
5
6
7
8
-10 C at A Condition
0 C at A Condition
+10 C at A Condition
-10 C at B Condition
0 C at B Condition
+10 C at B Condition
-10 C at C Condition
0 C at C Condition
+10 C at C Condition
-10 C at D Condition
0 C at D Condition
+10 C at D Condition
28.2
35.8
16.8
9.8
23.3
13.0
17.8
32.4
5.1
9.9
13.4
11.1
5.1
12.4
8.9
12.1
24.8
6.1
7.6
9.8
6.1
2.9
8.9
6.8
4.5
8.5
5.9
6.3
7.2
10.8
2.7
12.8
1.9
2.0
9
30.4
10
11
12
15.5
21.5
16.0
9.6
7.3
9.9
17.5
*3 A Condition: C(-)/C(+), 0.1M H2SO4, 5F/mol; B Condition: C(-)/C(+), 0.1M PTSA,
4F/mol; C Condition: Pb(-)/C(+), 0.1M H2SO4, 7F/mol; D Condition: Pb(-)/C(+), 0.1M
PTSA, 4F/mol.
*4 Yield based on consumed flavone (4).
electrolytes and the reaction temperature. The reaction cond i -
tions of Pb(-)/C(+)-H2SO4-7F/mol (Ent r y 3 in Tab l e 1) and
C(-)/C(+)-H2SO4-5F/mol (Entry 4 in Table 1) were found to
afford higher yields of 2,2 -biflavanone(racemate) (2a) and
2,2 -biflavanone(meso) (2b) (32.4% and 24.8%, 35.8% and
13.4%, respectively). However, there was a higher yield of
flavanone (6) (62.1%) in the reaction condition of Cu(-)/
C(+)-H2SO4-10F/mol (Entry 5 in Table 1).
pled at the -carbon, the other is at the -carbon.12 Often a
, -coupled compound is given as a major product. Although
flavone (4) has a phenyl substitutent at the 2-position, the
coupling at the 2-position was still achieved. Therefore the
mechanism of the electrochemical reduction of flavone (4) is
proposed as showed in Scheme III. Flavone (4) was first pro-
tonated to yield a cation (7)9 and then followed to accept one
electron to give a radical (8). The radical (8) could undergo
either to couple with a radical (8) and then to follow tautom-
erism to afford 2,2 -biflavanone (5a) and 2,2 -biflavanone
Electrolytic coupling of , -unsaturated carbonyl com-
pounds may have two main ways of dimerization; one is cou-

Electroorganic Chemistry of Flavonoids
J. Chin. Chem. Soc., Vol. 49, No. 6, 2002 1107
GC/MS spectrometer. Elemental analyses were measured on
a Heraeus CHN-O-Rapid Analyzer.
Scheme III
Synthesis of Flavone (4)
+H+
+ e-
O
O
O
.
+
(a) o-Benzoyloxyacetophenone (2)
OH
A solution of o-hydroxyacetophenone (1) (10.04 g,
73.74 mmol) and pyridine (14.50 g, 103.15 mmol) in a flask
was stirred in a water bath at 40 C and to which was added
benzoyl chloride (14.50 g, 103.15 mmol). The reaction sol u -
tion was stirred for 30 minutes at 40 C and was poured into a
solution of 1 M HCl (120 mL). The precipitate was filtered
and was washed with water. The product was recrystallized
from methanol to give a white crystal of 12.32 g of o-benzo-
yloxyacetophenone (2) with a yield of 69.6%, m.p. 87-8 C.
1H NMR (CDCl3, 500 MHz): 2.55 (s, 3H), 7.23-7.26 (m,
1H), 7.35-7.40 (m, 1H) 7.51-7.66 (m, 4H), 7.86-7.89 (m, 1H),
8.20-8.24 (m, 2H); 13C NMR (CDCl3, 125 MHz): 29.78,
123.90, 126.16, 128.69, 129.21, 130.26, 130.29, 131.26,
133.40, 133.81, 149.35, 165.14, 197.55; MS (FAB, m/z, %):
105 (100), 136 (55.2), 154 (64.5), 241 (14.2, M), 242 (4.3,
M+1); Anal.: Found: C: 74.32%, H: 5.03%; Calcd. for
C15H12O3: C: 74.99%, H: 5.03%.
O
OH
8
4
7
O
O
O
8
+
+
OH
OH
OH
OH
9b
9a
O
O
O
O
tautom.
O
O
O
5b (meso)
5a (racemates)
.
O
O
O
+H
tautom.
OH
6
10
(b) o-Hydroxydibenzoylmethane (3)
o-Benzoyloxyacetophenone (2) (3.01 g, 12.54 mmol)
was dissolved in 5 mL of dry pyridine. The solution was
heated to 50 C in a water bath and to which was added 1.06 g
of dry potassium hydroxide (18.89 mmol). The reaction sol u -
tion was stirred for 30 minutes at 50 C. The solution was
acidified by adding 10% acetic acid (30 mL) and the precipi-
tate was collected by suction filtration. The precipitate was
recrystallized to afford a yellow crystal of 2.19 g of o-hydro-
xydibenzoylmethane (3) with a yield of 72.8%, m.p. 120-1
C. 1H NMR (CDCl3, 500 MHz): 6.85 (s, 1H), 6.90-7.03 (m,
2H), 7.45-7.57 (m, 4H), 7.78-7.81 (m, 1H), 7.93-7.97 (m,
2H), 12.10 (s, 1H), 15.51 (s, 1H); 13C NMR (CDCl3, 125
MHz): 92.26, 118.80, 118.94, 119.08, 126.80, 128.49,
128.78, 128.88, 132.42, 135.84, 162.45, 177.48, 195.67; MS
(EI, m/z, %): 105 (100), 121 (13.0), 240 (m, 8.6), 241 (M+1,
1.2); MS (FAB, m/z, %): 154 (100), 240 (19.8), 241 (M+1,
46.5); Anal.: Found: C: 74.90%, H: 5.10%; Calcd. for
C15H12O3: C:74.99%, H: 5.03%.
(5b) or to accept a proton to afford enol (10) and then to fol-
low tautomerism to form flavanone (6).
CONCLUSION
Flavone (4) was easily coupled by using the electro-
chemical method to give two dimers of 2,2 -biflavanone
(racemate) (5a) and 2,2 -biflavanone(meso) (5b) and one re-
ductive product of flavanone (6). Their yields were depend-
ent on the nature of electrodes, the kinds of supporting elec-
trolytes and the reaction temperature. Therefore 2,2 -bi-
flavanoves were easily synthesized from flavones via an elec-
trolytic reductive coupling.
EXPERIMENTAL SECTION
(c) Flavone (4)
General
A solution of o-hydroxydibenzoylmethane (3) (7.74 g,
32.25 mmol) dissolved in 55 mL of glacial acetic acid was
heated in a boiling water bath and to which was added 5 mL
of concentrated sulfuric acid. The reaction solution was
stirred for 1 hour in a boili n g water bath and was poured into
200 mL of wat e r. The precipitate was filtered and was recrys-
tallized from n-hexane to produce a white crystal of 2.29 g of
The melting points were measured without correction
on a Yanagimoto Micromelting Point Apparatus. 1H and 13
C
nuclear magnetic resonance spectra were measured on a
Varian INOVA-500 spectrometer. Mass spectral were deter-
mined on a VG Quattro GC/MS/MS DS spectrometer. High
resolution mass spectra were determined on a VG 70-250S

1108 J. Chin. Chem. Soc., Vol. 49, No. 6, 2002
Chen et al.
1
flavone (4) with a yield of 32.0%, m.p. 98-9 C. H NMR
(CDCl3, 500 MHz): 6.84 (s, 1H), 7.41-7.43 (m, 1H), 7.53-
7.60 (m, 4H), 7.69-7.71 (m, 1H), 7.93-7.96 (m, 1H), 8.23-
8.26 (m, 1H); 13C NMR (CDCl3, 125 MHz): 107.62, 118.09,
123.97, 125.24, 125.72, 126.31, 129.05, 131.61, 131.80,
133.78, 156.27, 163.42, 178.49; MS (EI, m/z, %): 92 (75.7),
120 (96.8), 165 (13.0), 194 (45.3), 222 (M, 100); MS (FAB,
m/z, %): 136 (89.4), 154 (100), 233 (M+1, 40.3); Anal.:
Found: C:81.06%, H: 4.63%; Calcd. for C15H10O2: C:
81.07%, H: 4.54%.
NMR (CDCl3, 500 MHz): 2.86-2.90 (m, 1H), 3.05-3.11 (m,
1H), 5.46-5.49 (m, 1H), 7.03-7.06 (m, 2H), 7.37-7.50 (m,
6H), 7.9-7.93 (m, 1H); 13C NMR (CDCl3, 125 MHz): 30.91,
44.66, 79.59, 118.12, 121.61, 126.13, 127.03, 128.77,
128.84, 136.20, 207.01; MS (EI, m/z, %): 92 (85.0), 104
(44.7), 120 (100), 121 (22.9), 147 (45.3), 223 (21.7), 224 (M,
24.8), 225 (M+1, 3.1); HRMS: 224.0834 (M+), calcd.
224.0837.
ACKNOWLEDGEMENT
Typical Anodic Dimerization of Flavone (4)
Cathodic dimerization of flavone (4) was carried out in
a 40 mL H-type cell with a glass-filter diaphragm equipped
with a Pb-plat (2 2 cm) as a cathode and a graphite rod (di-
ameter: 0.7 cm) as an anode. The cathode compartment con-
tained a solution of flavone (4) (100.0 mg, 0.35 mmol) in 2
mL of metha n o l with sulfuric acid (0.1 mL, 0.1 M) used as
supporting electrolytes. The anode compartment contained a
solution of 20 mL of methanol with sulfuric acid (0.1 mL, 0.1
M) used as supporting electrolytes. After 7 F/mol of electric-
ity was passed with constant current of 10 mA und e r the con-
dition of external cooling (0 C), the cathode solution was
evaporated to remove the solvent under a reduced pressure.
The residue was dissolved in ethyl ether and was washed with
saturated aqueous sodium bicarbonate and saturated brine.
The organic layer was dried over sodium sulfate and evapo -
rated to remove the solvent. The residue was chromato-
graphed on silica gel and was eluted with benzene to give
three white crystals: 2,2 -biflavanone(recemate) (5a) (32.5
mg, 0.07 mmol, 32.4%, m.p. 212-5 C), 2,2 -biflavanone
(meso) (5b) (24.9 mg, 0.06 mmol, 24.8%, m.p. 288-290 C)
and flavone (6) (2.3 mg, 2.0%, m.p. 77-80 C); 2,2 -biflavan-
one(recemate) (5a): 1H NMR (CDCl3, 500 MHz): 3.35 (d,
2H, J = 16.5 Hz), 3.96 (d, 2H, J = 16.5 Hz), 6.91-6.94 (m,
4H), 7.08-7.18 (m, 10H), 7.50-7.47 (m, 2H), 7.67-7.65 (m,
2H); 13C NMR (CDCl3, 125 MHz): 41.02, 87.96, 118.23,
121.40, 121.47, 126.48, 127.74, 128.61, 128.84, 135.00,
136.18, 159.27, 191.24; MS (EI, m/z, %): 92 (16.1), 103
(14.9), 121 (54.6), 223 (M/2, 100), 224 (M/2+1, 14.2);
HRMS: 446.1515 (M+), calcd. 446.1518; 2,2 -biflavanone
(meso) (5b): 1H NMR (CDCl3, 500 MHz): 3.12 (d, 2H, J =
16.0 Hz), 3.65 (d, 2H, J = 16.0 Hz), 6.88-6.91 (m, 2H). 7.12
(d, 2H, J = 8.0 Hz), 7.22-7.39 (m, 8H), 7.39 (d, 2H, J = 6.5
Hz), 7.46-7.49 (m, 2H), 7.58-7.60 (m, 2H); 13C NMR (CDCl3,
125 MHz): 42.42, 87.11, 117.94, 121.34, 121.50, 126.50,
128.10, 128.48, 129.09, 135.91, 126.22, 158.76, 190.50; MS
(EI, m/z, %): 121 (14.2), 223 (M/2, 100), 224 (M/2+1, 14.2);
HRMS: 446.1517 (M+), calcd. 446.1518; flavanone (6): 1H
This study was financially supported by the National
Science Council of the Republic of China (NSC89-2113-M -
017-001).
Received March 28, 2002.
Key Words
Flavone; Flavanone; Biflavanones; Electrolytic
reductive coupling; Hydrodimerization.
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