Synthesis of 3-bromo derivatives of flavones

Article abstract of DOI:10.1081/SCC-120003625

Various 3-halo flavones were prepared by reaction of the corresponding flavone derivatives with R₄NBr/PhI(OAc)₂ system under mild reaction conditions.

Full text of DOI:10.1081/SCC-120003625

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SYNTHESIS OF 3-BROMO DERIVATIVES OF FLAVONES
Ho Sik Rho a , Byoung-Seob Ko b , Ho Kyoung Kim b & Young-Sung Ju c
a Skin Research Institute , Pacific R&D Center , 314-1, Bora-ri, Kiheung-eup, Yongin-si,
Kyounggi-do, 449-900, South Korea
b Korea Institute of Oriental Medicine , Chongdam-dong, Kangnam-ku, Seoul, 135-100, South
Korea
c College of Oriental Medicine , Woosuk University , Jeonju, South Korea
Published online: 17 Aug 2006.
To cite this article: Ho Sik Rho , Byoung-Seob Ko , Ho Kyoung Kim & Young-Sung Ju (2002) SYNTHESIS OF 3-BROMO
DERIVATIVES OF FLAVONES, Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic
Chemistry, 32:9, 1303-1310, DOI: 10.1081/SCC-120003625
To link to this article: http://dx.doi.org/10.1081/SCC-120003625
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SYNTHETIC COMMUNICATIONS, 32(9), 1303–1310 (2002)
SYNTHESIS OF 3-BROMO DERIVATIVES
OF FLAVONES
Ho Sik Rho,1, Byoung-Seob Ko,2 Ho Kyoung Kim,2
*
and Young-Sung Ju3
1Skin Research Institute, Pacific R&D Center,
314-1, Bora-ri, Kiheung-eup, Yongin-si,
Kyounggi-do 449-900, South Korea
2Korea Institute of Oriental Medicine,
Chongdam-dong, Kangnam-ku,
Seoul 135-100, South Korea
3College of Oriental Medicine, Woosuk University,
Jeonju, South Korea
ABSTRACT
Various 3-halo flavones were prepared byreaction of the
corresponding flavone derivatives with R4NBr/PhI(OAc)2
system under mild reaction conditions.
Halogenated compounds are important intermediates for converting
1–3
efficientlyinto other functionalitybysimple chemical transformations.
4,5
Theyare usuallyprepared byusing molecular halogens.
But molecular
halogens can be difficult to manipulate and theyhave environmental draw-
backs. To overcome these difficulties, alternative methods have been devel-
oped such as HX/H2O2,6,7 NBS/PhI(OH)(OTs),8,9 TiCl4/tert-BuOOH,10
*Corresponding author. E-mail: thiocarbon@freechal.com
1303
Copyright & 2002 byMarcel Dekker, Inc.
www.dekker.com

1304
RHO ET AL.
12–14
NaX/Oxone,11 TMSX/PhI(OAc)2
and KBr/NaBO3.15 The halogen or
positive halogen species are generated in situ and theyare used for halo-
genation of organic substrate. Recently, Kirschning16,17 reported that a
combination of Et4NBr and PhI(OAc)2 was used in a bromoacetoxylation
of olefin. But it has not been used for a bromination of a,b-unsaturated
carbonyl compounds. As a flavone has a a,b-unsaturated ketone moiety, it
was interested to make its 3-bromo derivatives. 3-Bromo flavones are im-
portant intermediates for the C-3 modification. However, there are few
reports on methods to prepare these compounds. In previous reports,
18–24
molecular bromine is generallyused in various reaction conditions.
As an alternative of molecular bromine, R4NBr/PhI(OAc)2 system is a
good bromination source for flavone. In this communication, we wish to
report a selective C-3 bromination of flavones byR 4NBr/PhI(OAc)2 system
under mild conditions (Scheme 1).
To determine optimal reaction conditions, a series of experiments were
performed on the substrate 1a with several alkyl ammonium salts. The results
are summarized in Table 1. Treatment of flavone 1a with 3 equivalent of
PhI(OAc)2 and 3 equivalent of Me4NBr in CH2Cl2 at room temperature
afforded the corresponding 3-bromo flavone 2a in 75% yield (Entry 1 in
Scheme 1.
Table 1. Reaction Conditions for Bromination of Flavone 1a
Time
(h)
Yield
(%)b
a
EntryAmmonium Salt
Base
1
2
3
4
Me4NBr(3)
Et4NBr(3)
Bu4NBr(3)
Bu4NBr(3)
None
None
None
Pyridine
10
10
8
75
76
84
80
8
aWith PhI(OAc)2 (3 equiv.), CH2Cl2, RT. The molar equivalents
b
are given in parentheses. Isolated yields.

3-BROMO DERIVATIVES OF FLAVONES
1305
Table 1). None of the aromatic bromination or bromoacetoxylation com-
pounds were detected in crude product. Of the alkyl ammonium salt tested,
the best choice was Bu4NBr. In the presence of base, there was no noticeable
difference in both reaction time and yield (Entry 4 in Table 1). The initial step
in this reaction is the formation of bromonium intermediate byaddition of
Br-OAc to double bond. There are two reaction pathways such as proton
elimination and addition of acetate anion. The pathwayof elimination must
be faster than that of addition (Scheme 2).
Scheme 2.
Alternatively, treatment of 1a under the same condition using MeOH
as solvent, bromomethoxylation product was obtained as the sole product.25
In case of Br-OMe, addition pathwaywas preferred. We extended this
optimized reaction condition to other flavones. The results are summarized
in Table 2. The flavones 1b–e and 1f which have methyl or methoxy sub-
stituent in the A or B ring gave the 3-bromo flavones in the moderate to high
yield. In the case of 1b, 1c and 1d which have electron-donating groups at
para position in B ring, give the 3-bromo derivatives in high yields. The
stabilizing effect to the cationic intermediate increased the yields. However,
the flavone 1g bearing a bromo substituent converted into corresponding
3-bromo flavone in low yield (Entry 7 in Table 2). In contrast to above cases,
the destabilizing effect of bromo substituent decreased the rate of the
addition of Br-OAc and the elimination process. Finally, for 4-chloro fla-
vone 1h in the same condition, bromo flavone 2h was obtained in 52% yield
(Entry8).
In summary, we have developed a mild and convenient procedure for
the preparation of 3-bromo derivatives of flavones.

1306
RHO ET AL.
Table 2. Synthesis of 3-Bromo Derivatives of Flavonesa
b
EntrySubstrate
Time (h)
Product
Yield (%)
1
8
7
84
89
2
3
4
7
92
89
8.5
5
6
9
8
78
80
7
8
10
50
52
10
aAll the reactions were run with Bu4NBr (3 equiv.) and PhI(OAc)2
b
(3 equiv.) in CH2Cl2. The yields are for isolated compounds.

3-BROMO DERIVATIVES OF FLAVONES
EXPERIMENTAL
Materials
1307
PhI(OAc)2 (98%) and Bu4NBr (98%) were purchased from Aldrich
Chemical Co.
Typical Procedure
3-Bromo-2-phenyl-4H-chromen-4-one (2a):(20,24) PhI(OAc)2 (434 mg,
1.35 mmol) was suspended in anhydrous CH2Cl2 (5 ml) under atmosphere
of nitrogen at room temperature. Bu4NBr (435 mg, 1.35 mmol) was added
and the mixture was stirred at room temperature for 30 min. The flavone 1a
(100 mg, 0.45 mmol) in anhydrous in CH2Cl2 (2 ml) was added and the
mixture was stirred at room temperature for 8 h. The reaction mixture
was quenched with saturated aqueous ammonium chloride and aqueous
portion was separated and extracted with CH2Cl2. The organic layer was
dried over MgSO4 and evaporated in vacuo. The crude product was purified
bySiO 2 column chromatography(EtOAc/hexanes 1 : 2, Rf ¼ 0.64) to give 2a
(113 mg, 84%). M.p. 124–125ꢀC. H NMR (CDCl3, 300 MHz) d 8.32 (dd,
1
1H, J ¼ 7.8, 1.5 Hz), 7.84–7.90 (m, 2H), 7.70–7.75 (m, 1H), 7.44–7.57 (m,
5H). MS (m/e) 302 (Mþ þ 2), 300 (Mþ), 272, 221, 165, 120 (base peak), 92.
3-Bromo-2-(4-methylphenyl)-4H-chromen-4-one (2b):24 TLC, SiO2,
EtOAc/hexanes 1 : 2, Rf ¼ 0.82. M.p. 165–166ꢀC. 1H NMR (CDCl3,
300 MHz) d 8.31 (dd, 1H, J ¼ 8.1, 1.5 Hz), 7.79 (d, 2H, J ¼ 8.4 Hz), 7.71
(m, 1H), 7.48 (m, 2H), 7.33 (d, 2H, J ¼ 8.4 Hz), 2.46 (s, 3H). MS (m/e)
316 (Mþ þ 2), 314 (Mþ), 286, 235 (base peak), 120, 89.
3-Bromo-2-(4-methoxyphenyl)-4H-chromen-4-one (2c):24 TLC, SiO2,
EtOAc/hexanes 1 : 2, Rf ¼ 0.43. M.p. 140–142ꢀC. 1H NMR (CDCl3,
300 MHz) d 8.30 (dd, 1H, J ¼ 7.8, 1.5 Hz), 7.86 (d, 2H, J ¼ 8.7 Hz),
7.68–7.74 (m, 1H), 7.42–7.50 (m, 2H), 7.05 (d, 2H, J ¼ 8.7 Hz), 3.90 (s,
3H). MS (m/e) 332 (Mþ þ 2), 330 (Mþ), 302, 251 (base peak), 210, 195, 152.
3-Bromo-2-(3,4,5-trimethoxyphenyl)-4H-chromen-4-one (2d): TLC,
SiO2, EtOAc/hexanes 1 : 2, Rf ¼ 0.36. M.p. 155–156ꢀC. H NMR (CDCl3,
1
300 MHz) d 8.32 (dd, 1H, J ¼ 7.8, 1.5 Hz), 7.76 (m, 1H), 7.54 (m, 2H), 7.10
(s, 2H), 3.95 (s, 3H), 3.94 (s, 6H). MS (m/e) 392 (Mþ þ 2), 390 (Mþ, base
peak), 375, 347, 253, 121. Anal. calcd for C18H15BrO5: C, 55.26; H, 3.86.
Found: C, 55.20; H, 3.78.
3-Bromo-7-methoxy-2-phenyl-4H-chromen-4-one (2e): TLC, SiO2,
EtOAc/hexanes 1 : 2, Rf ¼ 0.52. M.p. 151–152ꢀC. 1H NMR (CDCl3,
300 MHz) d 8.22 (d, 2H, J ¼ 8.7 Hz), 7.86 (m, 2H), 7.56 (m, 3H),

1308
RHO ET AL.
7.04 (d, 1H, J ¼ 8.7 Hz), 6.89 (s, 1H), 3.92 (s, 3H). MS (m/e) 332 (Mþ þ 2),
330 (Mþ), 302, 287, 251 (base peak), 195, 152, 122. Anal. calcd for
C16H11BrO3: C, 58.03; H, 3.35. Found: C, 57.97; H, 3.27.
3-Bromo-6-methoxy-2-phenyl-4H-chromen-4-one (2f):24 TLC, SiO2,
EtOAc/hexanes 1 : 2, Rf ¼ 0.50. M.p. 123–125ꢀC. 1H NMR (CDCl3,
300 MHz) d 7.83–7.86 (m, 2H), 7.43–7.62 (m, 5H), 7.27–7.33 (m, 1H),
3.93 (s, 3H). MS (m/e) 332 (Mþ þ 2) 330 (Mþ), 252, 150 (base peak), 79.
3-Bromo-2-(4-bromophenyl)-4H-chromen-4-one (2g): TLC, SiO2,
EtOAc/Hexanes 1 : 2, Rf ¼ 0.77. M.p. 188–189ꢀC. 1H NMR (CDCl3,
300 MHz) d 8.31 (dd, 1H, J ¼ 7.8, 1.5 Hz), 7.67–7.77 (m, 5H), 7.26–7.51
(m, 2H). MS (m/e) 382 (Mþ þ 4) 380 (Mþ þ 2), 378 (Mþ), 352, 220, 120
(base peak). Anal. calcd for C15H8Br2O2: C, 47.41; H, 2.12. Found: C,
47.35; H, 2.08.
3-Bromo-2-(4-chlorophenyl)-4H-chromen-4-one (2h): TLC, SiO2,
EtOAc/hexanes 1 : 2, Rf ¼ 0.55. M.p. 179–180ꢀC. 1H NMR (CDCl3,
300 MHz) d 8.31 (dd, 1H, J ¼ 7.8, 1.5 Hz), 7.64–7.73 (m, 5H), 7.24–7.52
(m, 2H). MS (m/e) 338 (Mþ þ 4), 336 (Mþ þ 2) 334 (Mþ), 306, 255, 281,
207, 120 (base peak). Anal. calcd for C15H8BrClO2: C, 53.69; H, 2.40.
Found: C, 53.58; H, 2.32.
ACKNOWLEDGMENT
The author is grateful to Dr. Y. H. Joo, Miss S. M. Ahn, and
Professor S. K. Kang, for valuable discussions during the preparation of
this manuscript.
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Received in Japan December 8, 2000