Photochemical synthesis of 2,2′-biflavanones from flavone

Article abstract of DOI:10.1002/jccs.200300017

Photolysis of flavone (4) with the electron-donating amines including triethylamine or 2-(N,N-dimethylamino)ethanol in acetonitrile, benzene or methylene dichloride can easily afford two hydrodimers of 2,27prime;-bi- flavanone(racemate) (5a) and 2,2′-biflavanone(meso) (5b) and one reductive product of flavanone (6). Their yields were dependent on the molar ratios of substrate to amine, the kinds of amines, the solvents used and the irradiation sources. Higher yields were afforded 2,27prime;-biflavanone(racemate) (5a), 2,27prime;-biflavanone(meso) (5b) and flavanone (6) (30.0%, 20.9% and 15.8%, respectively) in the reaction condition of 1/2 molar ratio of flavone (4) to triethylamine in acetontrile with fourteen hours of irradiation.

Full text of DOI:10.1002/jccs.200300017

Journal of the Chinese Chemical Society, 2003, 50, 123-127
123
Photochemical Synthesis of 2,2¢-Biflavanones from Flavone
Arh-Hwang Chen* (
Department of Chemistry, National Kaohsiung Normal University, Kaohsiung 802, Taiwan, R.O.C.
), Wei-Bao Kuo (
) and Chia-Wen Chen (
)
Photolysis of flavone (4) with the electron-donating amines including triethylamine or 2-(N,N-dimethyl-
amino)ethanol in acetonitrile, benzene or methylene dichloride can easily afford two hydrodimers of 2,2¢-bi-
flavanone(racemate) (5a) and 2,2¢-biflavanone(meso) (5b) and one reductive product of flavanone (6). Their
yields were dependent on the molar ratios of substrate to amine, the kinds of amines, the solvents used and the
irradiation sources. Higher yields were afforded 2,2¢-biflavanone(racemate) (5a), 2,2¢-biflavanone(meso)
(5b) and flavanone (6) (30.0%, 20.9% and 15.8%, respectively) in the reaction condition of 1/2 molar ratio of
flavone (4) to triethylamine in acetontrile with fourteen hours of irradiation.
Keywords: Flavone; Flavanone; Biflavanones; Photolysis; Hydrodimerization.
INTRODUCTION
Biflavonoids are widely distributed in natural plants,
esterification of o-Hydroxyacetophenone (1) with benzoyl
chloride in the presence of pyridine to give a yield of 69.6%.
The base-catalyzed Fries rearrangement of o-benzoyloxy-
acetophenone (2) gave o-hydroxydibenzoylmethane (3) with
a yield of 72.8%. Finally, Flavone (4) was obtained from
cyclization of o-hydroxydibenzoylmethane (3) in the pres-
ence of acid with a yield of 32.0%, as shown in Scheme I.12
such as Psilotopside and Lycopside of Pteridophta, Cycadeae
and Conifeae of Gymnospermae and Anqiospermae1 etc.
They were found to have strong biological activities includ-
ing spasmolysis,2a peripheral vasodilatation, antibradykinin
activity and antispasmogenic action against prostaglandin
PGE1,2b inhibition of cyclic GMP and cyclic AMP phospho-
diesterase2c~d and inhibition of hepatoma cells.2e Recently,
some biflavonoids were demonstrated to enhance suppersion
of lymphocyte proliferation,3a inhibition of phospholi-
paseCr1,3b anti-inflammatory activity,3c anti-HIV activity,3d~e
anticomplementatory activity,3f antiviral activity3g and chemo-
prevention of hepatotoxicity.3h
Many synthetic attempts including Ullmann coupling,4
Baker-Venkataraman rearrangement and cyclization,5 cy-
clization from bichalcone,6 oxidative coupling,7 reductive
coupling,8 Pd-cathode reduction9 and photoinduced electron
transfer reaction10 were developed for preparations of some
biflavonoids. We have communicated that the transformation
of flavones to biflavanones was carried out via an electrolytic
reductive Coupling.11 In our continuous study on synthetic
application of biflavonoids, we report herein a photochemi-
cal synthesis of 2,2¢-biflavanones from flavones.
Scheme I
OH
O
OH
CH3
OCOPh
CH3
KOH, pyridine
72.8%
PhCOCl, pyridine
69.6%
Ph
O
O
O
3
1
2
O
O
H2SO4, acetic acid
32.0%
4
Photolysis of flavone (4) with amines was carried out
by using a quartz cell equipped with a Sankyo 254 nm Germi-
cidal Lamp or 306 nm UV-B Lamp. Flavone (4) was found to
be easily hydrodimerized to afford two dimers of 2,2¢-bi-
flavanone(racemate) (5a) and 2,2¢-biflavanone(meso) (5b)
and one reductive product of flavanone (6), as shown in
Scheme II. Their yields were largely affected by the molar ra-
tios of substrate to amine, the kinds of amines, the solvents
used and the irradiation sources, as shown in Table 1. The re-
action conditions of 1/2 molar ratio of flavone (4) to triethyl-
amine in acetontrile with irradiation of fourteen hours (Entry
RESULTS AND DISCUSSION
o-Benzoyloxyacetophenone (2) was obtained from an
Dedicated to Professor Fa-Ching Chen on the occasion of his ninetieth birthday.

124 J. Chin. Chem. Soc., Vol. 50, No. 1, 2003
Chen et al.
flavanone with irradiation of the wavelength of 254 nm or
306 nm of light and to afford 2,2¢-biflavones and 2,4¢-bi-
flavanol with the wavelength longer than 300 nm of light.
Photochemistry of a,b-unsaturated carbonyl com-
pounds with amines can undergo a dominant pathway of sin-
gle electron transfer (SET).13 Photolysis of flavone (4) was
proposed as shown in Scheme III. Flavone (4) excited via ir-
radiation followed a SET photochemical process with amines
serving as electron donors to produce an exciplex (7) or a
contact ion radical pair (CIRP) (8) and then to follow a hydro-
gen transfer or a proton transfer to form a radical pair (9-10)
in a cage. After escape out of a cage, the radical (9) could go
two ways: one attacked a molecule of flavone (4), accepted a
hydrogen atom and then followed tautomerism to afford
2,2¢-biflavanone(racemate) (5a) and 2,2¢-biflavanone(meso)
(5b); the other accepted a hydrogen atom to afford enol (13)
and then underwent tautomerism to flavanone (6).
Scheme II
O
O
O
O
O
O
hv
+
O
O
4
5a (racemate)
b (meso)
6
4) and 1/2 molar ratio of flavone (4) to triethylamine in ben-
zene with irradiation of twenty five hours (Entry 1) were
found to afford higher yields of 2,2¢-biflavanone(racemate)
(5a) and 2,2¢-biflavanone(meso) (5b) (30.0% and 20.9%,
22.3% and 22.0%, respectively). Dr. Xu et al. reported that ir-
radiation of flavone in the presence of trimethylamine with
light (l > 300 nm) gave three hydrodimers of meso-2,2¢-bi-
flavanone, (±)-2,2¢-biflavanone and flavone[I-4, II-2]-flavan-
4-ol in a solvent of acetonitrile and two hydrodimers of meso-
2,2¢-biflavanone and flavone[I-4, II-2]-flavan-3-ol in a sol-
vent of benzene.10b But our finding showed that photolysis of
flavone with amines by using irradiation of light (l 254 nm or
306 nm) afforded two dimers of 2,2¢-biflavanone(racemate)
and 2,2¢-biflavanone(meso) and a reductive product of
flavanone, not a 2,4¢-biflavanol of flavone[I-4, II-2]-flavan-
3-ol. The reason for this product difference is probably due to
using different kinds of irradiation sources, one with the
wavelength longer than 300 nm of light, the other with the
wavelength of 254 nm or 306 nm of light. Therefore photo-
lysis of flavone can be favored to afford 2,2¢-biflavones and
CONCLUSION
Photolysis of flavone (4) with amines was found to be
easily hydrodimerized to afford two dimers of 2,2¢-biflava-
none(racemate) (5a) and 2,2¢-biflavanone(meso) (5b) and
one reductive product of flavanone (6) with irradiation of the
wavelength of 254 nm or 306 nm of light. Their yields were
dependent on the molar ratios of substrate to amine, the kinds
of amines, the solvents used and the irradiation sources.
Table 1. The Yields of Products for Photolysis of Flavone (4)
Yields of Products(%)*4
Reaction Conditions
Entries
Molar ratios*1, Amines*2, Solvents,
Irradiation Time, Irradiation Source*3
Conversion (%)
5a
5b
6
1
2
3
4
5
6
7
8
1/2, TEA, C6H6, 25 hrs, A
1/4, TEA, C6H6, 25 hrs, A
1/1, TEA, MeCN, 14 hrs, A
1/2, TEA, MeCN, 14 hrs, A
1/4, TEA, MeCN, 14 hrs, A
1/10, TEA, MeCN, 14 hrs, A
1/2, DMAE, C6H6 12 hrs, A
1/2, TEA, CH2Cl2, 16 hrs, A
1/2, TEA, C6H6, 25 hrs, B
1/2, TEA, MeCN, 14 hrs, B
1/2, DMAE, C6H6, 14 hrs, B
75.0
78.4
88.5
78.0
85.4
82.6
88.8
71.1
78.7
75.8
79.1
22.3
26.1
9.7
30.0
14.6
13.5
22.8
7.9
22.0
15.9
12.2
20.9
16.7
29.7
15.2
17.4
17.6
12.5
9.6
13.0
10.2
11.6
15.8
14.4
15.8
13.7
16.9
8.9
9
10
11
7.5
4.8
19.3
11.9
11.2
*1 Molar ratio of substrate to amine.
*2 Amine: TEA: triethylamine, DMAE: 2-(N,N-dimethylamino)ethanol.
*3 Irradiation Source:
A: Sankyo 254 nm Germicidal Lamp.
B: Sankyo 306 nm UV-B Lamp.
*4 Yield based on consumed flavone (4).

Photochemical Synthesis of 2,2¢-Biflavanones from Flavone
J. Chin. Chem. Soc., Vol. 50, No. 1, 2003 125
equipped with Sankyo 254 nm Germicidal Lamp or 306 nm
UV-B Lamp.
Scheme III
Synthesis of Flavone (4)
O
O
O
O
O
h v
-
+
or
.
Et3N
.
Et3N
(a) o-Benzoyloxyacetophenone (2)
Et3N
O
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). After being stirred
for 30 minutes at 40 °C, the reaction mixture was poured into
a solution of 1M HCl (120 mL). The precipitate was filtered
and then was washed with water. The product was recrys-
tallized from methanol to give a white crystal of 12.32 g of
o-benzoyloxyacetophenone (2) with a yield of 69.6%, m.p.
87-8 °C. 1H NMR (CDCl3, 500 MHz): d 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 (M+,
14.2), 242 (M+1, 4.3); Anal.: Found: C: 74.32%, H: 5.03%;
Calcd. for C15H12O3: C: 74.99%, H: 5.03%.
8
7
4
.
O
hydrogen transfer
or proton transfer
.
+
CH3CHNEt2
OH
10
9
O
O
O
4
O
O
+
+
.
.
OH
OH
11b
12b
11a
.
O
O
O
O
O
+H
OH
OH
12a
(b) o-Hydroxydibenzoylmethane (3)
O
O
O
O
O
O
tautom.
A solution of o-benzoyloxyacetophenone (2) (3.01 g,
12.54 mmol) dissolved in 5 mL of dry pyridine was heated to
50 °C in a water bath and then to which was added 1.06 g
(18.89 mmol) of dry potassium hydroxide. After being stirred
for 30 minutes at 50 °C, the reaction solution was acidified by
adding 10% acetic acid (30 mL) and the precipitate was col-
lected by suction filtration. Then the precipitate was recrys-
tallized to afford a yellow crystal of 2.19 g of o-hydroxydi-
benzoylmethane (3) with a yield of 72.8%, m.p. 120-1 °C. 1H
NMR (CDCl3, 500 MHz): d 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%.
+
O
5b (meso)
5a (racemate)
.
O
O
+H
tautom.
O
OH
6
13
Therefore 2,2¢-biflavanoves were easily synthesized from
photolysis of flavones.
EXPERIMENTAL SECTION
General
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 spectra were deter-
mined on a VG Quattro GC/MS/MS DS spectrometer. High
resolution mass spectra were determined on a VG 70-250S
GC/MS spectrometer. Elemental analyses were measured on
a Heraeus CHN-O-Rapid Analyzer. Photolysis was carried
out on a PanChum Photochemical Reaction Apparatus,
(c) Flavone (4)
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 then to which was added 5
mL of concentrated sulfuric acid. After being stirred for 1
hour in a boiling water bath, the reaction solution was poured
into 200 mL of water. The precipitate was filtered and was re-

126 J. Chin. Chem. Soc., Vol. 50, No. 1, 2003
Chen et al.
crystallized from n-hexane to produce a white crystal of 2.29
g of flavone (4) with a yield of 32.0%, m.p. 98-9 °C. 1H NMR
(CDCl3, 500 MHz): d 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%.
ACKNOWLEDGEMENT
This study was financially supported by the National
Science Council of the Republic of China (NSC90-2113-M-
017-001).
Received July 19, 2002.
REFERENCES
1. (a) Harborne, J. B.; Mabry, T. J. The Flavonoids: Advances
in Research, Chapman and Hall, New York, 1982, pp
505-533. (b) Ferreira, D.; Steynberg, J. P.; Roux, D. G.;
Brandt, E. V. Tetrahedron 1992, 48, 1743.
2. (a) Horhammer, L.; Wagner, H.; Reinharht, H. Z. Natur-
forsch 1967, 22B, 768. (b) Natarajan, S.; Murti, V. V. S.;
Seshadri, T. R.; Ramaswami, A. S. Curr. Sci. 1970, 39, 533.
(c) Ruckstuhl, M.; Beretz, W. B.; Anton, R.; Landry, Y.
Biochem. Pharmacol. 1979, 28, 535. (d) Beretz, A.; Joly, N.;
Stochet, J. C.; Anton, R. Planta. Med. 1979, 36, 193. (e)
Joly, M.; Beck, J. P.; Haag-Berrcuier, M.; Anton, R. Planta.
Med. 1980, 39, 230.
3. (a) Lee, S. L.; Choi, J. H.; Son, K. H.; Chang, H. W.; Kong, S.
S.; Kim, H. P. Life Sci. 1995, 57, 551. (b) Lee, H. S.; Ko, H.
R.; Ryu, S. Y.; Oh, W. K.; Kim, B. Y.; Ahn, S. C.; Mheen, T.
I.; Ahn, J. S. Planta Med. 1997, 63, 266. (c) Gil, B.; Sanz, M.
J.; Terencio, M. C.; Gunasegaran, R.; Paya, M.; Alcaraz, M.
J. Biochem. Pharmacol. 1997, 53, 733. (d) Lin, Y. M.; An-
derson, H.; Flavin, M. T.; Pai, Y. H. J. Nat. Prod. 1997, 60,
884. (e) Vlietinck, A. J.; Breuyne, T. D.; Apers, S.; Pieters, L.
A. Planta Med. 1998, 64, 97. (f) Cimanga, K.; Bruyne, T. D.;
Aper, S.; Pireters, L.; Totte, J.; Kambu, K.; Tona, L.; Bakana,
P.; Ufford, L. Q.; Beukelman, C.; Labadie, R.; Vlietinok, A.
J. Planta Med. 1999, 65, 213. (g) Lin, Y. M.; Flavin, M. T.;
Schure, R.; Chen, F. C.; Sidwell, R.; Barnard, D. L. Planta
Med. 1999, 65, 120. (h) Farombi, E. O.; Tahnteng, J. G.;
Agboola, A. O. Food Chem. Toxicol. 2000, 38, 1535.
4. Mitsuhashi, H.; Shimizu, Y. Chem. Pharm. Bull. Jpn. 1959,
7, 748.
Typical Photolysis of Flavone (4)
Photolysis of flavone (4) was carried out by using a
quartz flask equipped with a Sankyo 306 nm UV-B Lamp. A
solution of flavone (4) (0.09 g, 0.40 mmol) and triethyl amine
(0.08 g, 0.80 mmol) in acetonitrile (40 mL) was irradiated for
fourteen hours under a dry nitrogen atmosphere. Then the re-
action solution was evaporated to remove the solvent under
reduced pressure. The residue was chromatographed on silica
gel and was eluted with benzene to give three white crystals:
2,2¢-biflavanone(recemate) (5a) (26.6 mg, 30.0%, m.p. 212-5
°C), 2,2¢-biflavanone(meso) (5b) (18.5 mg, 20.9%, m.p.
288-290 °C) and flavone (6) (14.0 mg, 15.8%, m.p. 77-80
°C); 2,2¢-biflavanone(recemate) (5a): 1H NMR (CDCl3, 500
MHz): d 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¢-biflava-
none(meso) (5b): 1H NMR (CDCl3, 500 MHz): d 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 NMR (CDCl3, 500 MHz): d 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.
5. (a) Moriyama, S.; Okigawa, M.; Kawano, N. Tetrahedron
Lett. 1972, 2105. (b) Zhu, J.; Wang, Q.; Li, Y. J. Chem. Soc.
Chem. Commun. 1988, 1549.
6. (a) Ahmad, S.; Razaq, S. Tetrahedron 1976, 32, 503. (b)
Ahmad, S.; Razaq, S. Tetrahedron Lett. 1971, 4633.
7. (a) Berge, D. D.; Kale, A. V.; Sharma, T. C. Chem. Ind. (Lon-
don) 1979, 282. (b) Molyneux, R. J.; Waiss, A. C.; Haddon,
W. F. Tetrahedron 1970, 26, 1409.
8. (a) Kirrsretter, R. G. H.; Vagt, U. Chem. Ber. 1981, 114, 630.
(b) Li, Y. L.; Zhang, F. J.; Wang, Q. G. Chin. J. Chem. 1992,
10, 359.

Photochemical Synthesis of 2,2¢-Biflavanones from Flavone
J. Chin. Chem. Soc., Vol. 50, No. 1, 2003 127
9. Lu, K. K.; Tan, Z.; Li, Y. L.; Wang, X. Chin. Chem. Lett.
1995, 6, 143.
10. (a) Yokoe, I.; Taguchi, H.; Shirataki, Y.; Komatsu, M. J.
Chem. Soc. Chem. Commun. 1979, 333. (b) Chen, C. F.; Zha,
Y.; Liu, Y. C.; Xu, J. H. Tetrahedron Lett. 1995, 36, 2835.
11. Chen, A. H.; Cheng, C. Y.; Chen, C. W. J. Chin. Chem. Soc.
2002 (in press).
12. Furniss, B. S.; Hannaford, A. J.; Smith, P. W. G.; Tatchell, A.
R. Vogel’s Textbook of Practical Organic Chemistry,
Longman Scientific & Technical, New York, 1989, pp
1193-1195.
13. Yoon, U. C.; Mariano, P. S. Acc. Chem. Res. 1992, 25, 233.