A convenient synthesis of 3-bromoflavones

Article abstract of DOI:10.1081/SCC-120004255

The reaction of flavones with 2,4,4,6-tetrabromo-2,5-cyclo hexadienone(1) gave the corresponding 3-bromoflavones under the mild reaction condition. Flavones containing easily oxidizable functional groups were also brominated without deleterious oxidation

Full text of DOI:10.1081/SCC-120004255

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A CONVENIENT SYNTHESIS OF 3-BROMOFLAVONES
Yung Hyup Joo a , Jin Kwan Kim a & Seon-Hwa Kang a
a Pharmaceutical and Health Research Institute, Pacific Corporation, 449-900, Kyounggi-do,
Korea
Published online: 16 Aug 2006.
To cite this article: Yung Hyup Joo , Jin Kwan Kim & Seon-Hwa Kang (2002) A CONVENIENT SYNTHESIS OF 3-BROMOFLAVONES,
Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry, 32:11,
1653-1658, DOI: 10.1081/SCC-120004255
To link to this article: http://dx.doi.org/10.1081/SCC-120004255
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SYNTHETIC COMMUNICATIONS, 32(11), 1653–1658 (2002)
A CONVENIENT SYNTHESIS OF
3-BROMOFLAVONES
*
Yung Hyup Joo, Jin Kwan Kim, andSeon-Hwa Kang
Pacific Corporation, Pharmaceutical and Health
Research Institute, Kyounggi-do 449-900, Korea
ABSTRACT
The reaction offlavones with 2,4,4,6-tetrabromo-2,5-cyclo-
hexadienone(1) gave the corresponding 3-bromoflavones
under the mild reaction condition. Flavones containing
easily oxidizable functional groups were also brominated
without deleterious oxidation products.
The standard method of ꢀ-bromination ofenone system is the reaction
ofenones with various bromine atom sources, such as molecular bromine,
N-bromosuccinimide, pyridinium tribromide and copper(II) bromide in the
[1–5]
absence or presence ofcatalysts, respectively.
Using these reagents, ꢀ,ꢁ-
unsaturated carbonyl compounds are selectively transformed into the
corresponding ꢀ- or ꢀ0-bromo derivatives. Although these reagents are com-
monly used in organic synthesis, a powerful Br source, such as Br2 in AcOH
or in base, was not able to be used for the bromination of a deactivated
system containing easily oxidizable substituent because ofits powerufl
oxidation potential; an undesired oxidation by-product also was formed.
*Corresponding author.
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JOO, KIM, AND KANG
In order to minimize the side reaction, it was necessary to find a new reagent
with fine-tuned brominating power.
In our ongoing program for a search of biologically active com-
pounds, 3-bromoflavones were necessary as intermediates and could be
obtained using the pyridinium bromide perbromide/pyridine as a mild bro-
minating reagent. However, in the reaction offlavones containing sulfide
side chains with this reagent, undesired sulfoxide derivatives were obtained
as a major product.[6] In order to minimize an undesired product and find a
more efficient brominating reagent, we have investigated the brominating
power of2,4,4,6-tetrabromo-2,5-cyclohexadienone ( 1), which has been used
for the aromatic bromination,[7] brominative cyclization ofpolyene, [8] selec-
tive ꢀ0-bromination of ꢀ,ꢁ-unsaturated ketones,[9] and oxidation ofthiols to
disulfides.[10] In this communication, we report an efficient, simple, and
practical method for the conversion of flavones to ꢀ-bromoflavone deriva-
tives using reagent 1 under the mild reaction conditions.
First, when the simple flavones were treated with compound 1 in
CH2Cl2 at room temperature, 3-bromoflavones were obtained. As shown
in Table 1, flavone (2a) was transformed into 3-bromoflavone (3a) in 63%
0
yield at room temperature. Bromination ofelectron donating 4 -methoxy
substituted flavone 2b proceeded fast and gave 3-bromo derivative 3b i0n
good yield. In the case ofan electron withdrawing group such as 4 -
fluoro, 40-methylsulfonyl substituted flavones 2c, 2d, and 3-bromo deriva-
tives were obtained in low yield and needed a prolonged reaction time. And
the reaction ofhighly electron withdrawing nitro substituted flavone 2e with
compound 1 was not proceeded at all in boiling chloroform. In addition, 1-
thioflavone afforded 3-bromo-1-thioflavone in high yield under the standard
reaction condition. The above results apparently indicate that C-40 substi-
tuent ofa flavone B ring plays an important role in electrophilic attack ofBr
at C-3.
Chem 1.

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3-BROMOFLAVONES
1655
Table 1. Bromination ofFlavones with 2,4,4,6-Tetrabromo-2,5-cyclohexadienone
(1) in CH2Cl2 at Room Temperature
Time
(h)
Yieldsa
(%)
Substrates
X
Products
2a
2b
2c
2d
H
OCH3
F
SO2CH3
NO2
3a
3b
3c
3d
78
2
72
120
12
24
63
87
50
26
2e
1-Thioflavone
3e
3-Bromo-1-thioflavone
NRb
89
aIsolated yields.
bIn boiling CHCl3.
By substitution ofan electron donating group at C-4 0 or sulfur in place
ofoxygen at C-1, the reaction rate and product yield were improved. This
fact is closely related to the increased electron density at the C-3 position by
the C-40 or C-1 substitutent. In case offlavone 2f containing a sulfide side
chain, bromination using compound 1 under the standard reaction con-
dition afforded 3-bromoflavone 3f without side products such as sulfoxide
and an A ring bromination product (Table 2, Entry 1). On the contrary,
when the bromination was performed in the presence of N-bromosuccini-
mide (NBS) or molecular bromine, 3-bromo derivatives were obtained in
low yield (Entry 2) or oxidation products (Entry 3) were obtained major
component.[6] Also, in the presence ofwater, sulfoxide was obtained as the
sole product[11] but not detected the 3-bromo derivative (Entry 4).
Although compound 1 has been used for aromatic ring bromination,
the reaction offlavone 2g, having an electron donating methoxy group at
Chem 2.

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JOO, KIM, AND KANG
Table 2. Reaction of4 -(Methylthio)flavones with Various Br Sources
0
Time
(h)
Yieldsa
(%)
Entry
Substrates
Br Source
Products
1
2
3
4
5
2f
2f
2f
2f
2g
1
NBS
Br2
1
3f
3f
2
7
4
17
2
80
42b
4 þ 5
37 þ 33
4
3g
80c
70
1
aIsolated yields.
bIn boiling CHCl3.
cIn 80% aqueous THF.
C-6 ofA ring with 1 afforded 3-bromoflavone 3 g in 70% yield and no A
ring bromination took place (Entry 5).
In conclusion, we developed a mild and convenient method for the
bromination offlavones having various substituents using 2,4,4,6-tetra-
bromo-2,5-cyclohexadienone without an undesired side reaction product.
Typical experimental procedure: To a solution ofthe flavone ( 2a)
(0.2 g, 0.9 mmol) in dry CH2Cl2(10 ml) under nitrogen was added 2,4,4,6-
tetrabromo-2,5-cyclohexadienone(1) (0.53 g, 1.3 mmol) at room tempera-
ture. After stirring at room temperature for 78 h, the reaction mixture
was diluted with CH2Cl2 (20 ml) and washed with saturated aqueous
NaHCO3 solution (20 ml) and brine (20 ml). The organic layer was
dried over anhydrous MgSO4. After evaporation of the organic layer,
the residue was purified by flash chromatography (SiO2, CH2Cl2) to
give 3-bromoflavone (3a) (0.17 g, 63%). Their spectroscopic data are as
follows.
3a: M.p. 123–124ꢀC (lit.[5] m.p. 126ꢀC); 1H NMR (300 MHz, CDCl3) ꢂ
7.40–7.60 (m, 5H), 7.70–7.76 (m, 1H), 7.84–7.88 (m, 2H), 8.31 (dd, 1H,
J ¼ 7.8, 1.5 Hz).
3b: M.p. 139–141ꢀC (lit.[6] m.p. 140–141ꢀC); 1H NMR (300 MHz,
CDCl3) ꢂ 3.91 (s, 3H), 7.02–7.07 (m, 2H), 7.43–7.53 (m, 2H), 7.68–7.75
(m, 1H), 7.86–7.92 (m, 2H), 8.30 (dd, 1H, J ¼ 7.8, 1.5 Hz).
3c: M.p. 167–169ꢀC; 1H NMR (300 MHz, CDCl3) ꢂ 7.20–7.30 (m, 2H),
7.44–7.53 (m, 2H), 7.70–7.78 (m, 1H), 7.85–7.92 (m, 2H), 8.30 (dd, 1H,
J ¼ 7.8, 1.5 Hz); MS (70 eV) m/z (rel. intensity) 120 (78), 183 (40), 239
(62), 290 (41), 292 (40), 318 (Mþ, 100), 320 (Mþ þ 2, 99); Anal. calcd for
C15H8BrFO2: C, 56.45; H, 2.53. Found: C, 56.10; H, 2.47.

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3-BROMOFLAVONES
1657
3d: M.p. 205–208ꢀC (lit.[6] m.p. 207–209ꢀC); 1H NMR (300 MHz,
CDCl3) ꢂ 3.15 (s, 3H), 7.48–7.54 (m, 2H), 7.73–7.80 (m, 1H), 8.05–8.16
(m, 4H), 8.32 (dd, 1H, J ¼ 8.7, 1.8 Hz).
3-Bromo-1-thioflavone: M.p. 130–132ꢀC; H NMR (300 MHz, CDCl3)
1
ꢂ 7.50–7.70 (m, 8H), 8.60–8.64 (m, 1H); MS(70 eV) m/z (rel. intensity) 136
(32), 165 (51), 208 (46), 237 (58), 288 (35), 290 (36), 316 (Mþ, 99), 318
(Mþ þ 2, 100); Anal. calcd for C15H9BrOS: C, 56.80; H, 2.86. Found:
C, 56.70; H, 2.83.
3f: M.p. 159–160ꢀC (lit.[6] m.p. 160–161ꢀC); 1H NMR (300 MHz,
CDCl3) ꢂ 2.56 (s, 3H), 7.34–7.40 (m, 2H), 7.44–7.52 (m, 2H), 7.68–7.75
(m, 1H), 7.80–7.85(m, 2H), 8.29 (dd, 1H, J ¼ 8.1, 1.5 Hz).
3g: M.p. 152–154ꢀC; H NMR (300 MHz, CDCl3) ꢂ 2.56 (s, 3H), 3.93
1
(s, 3H), 7.27–7.46 (m, 4H), 7.62–7.64 (m, 1H), 7.78–7.83 (m, 2H); MS
(70 eV) m/z (rel. intensity) 150 (44), 226 (23), 228 (19), 346 (5), 348 (9),
376 (Mþ, 98), 378 (Mþ þ 2, 100); Anal. calcd for C17H13BrO3S: C, 54.12;
H, 3.47. Found: C, 54.40; H, 3.68.
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Received in Japan March 26, 2001