A facile preparation of 3-haloflavones using hypervalent iodine* chemistry

Article abstract of DOI:10.1081/SCC-100104459

Various 3-haloflavones were prepared by the reaction of the corresponding flavone derivatives with iodobenzene diacetate and trimethylsilyl halide under mild reaction conditions. The iodobenzene diacetate could be replaced by the polymer-supported iodoben

Full text of DOI:10.1081/SCC-100104459

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A FACILE PREPARATION OF 3-HALOFLAVONES USING
HYPERVALENT IODINE* CHEMISTRY
Ho Sik Rho a , Byoung-Seob Ko b & Young-Sung Ju c
a Department of Applied Skin Biology Institute , Pacific Corporation, 314–1, Borari,
Kiheung-eup, Yongin-si, Kyounggi-do, 449-900, S. Korea
b Korea Institute of Oriental Medicine , Chongdamdong, Kangnam-ku, Seoul, 135-100, S.
Korea
c College of Oriental Medicine , Woosuk University , Jeonju, S. Korea
Published online: 09 Nov 2006.
To cite this article: Ho Sik Rho , Byoung-Seob Ko & Young-Sung Ju (2001) A FACILE PREPARATION OF 3-HALOFLAVONES
USING HYPERVALENT IODINE* CHEMISTRY, Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, 31:14, 2101-2106, DOI: 10.1081/SCC-100104459
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SYNTHETIC COMMUNICATIONS, 31(14), 2101–2106 (2001)
A FACILE PREPARATION OF
3-HALOFLAVONES USING
HYPERVALENT IODINE* CHEMISTRY
Ho Sik Rho,1,{ Byoung-Seob Ko,2 and Young-Sung Ju3
1Department of Applied Skin Biology Institute, Pacific
Corporation, 314-1, Borari, Kiheung-eup, Yongin-si,
Kyounggi-do 449-900, S. Korea
2Korea Institute of Oriental Medicine, Chongdamdong,
Kangnam-ku, Seoul 135-100, S. Korea
3College of Oriental Medicine, Woosuk University,
Jeonju, S. Korea
ABSTRACT
Various 3-haloflavones were prepared by the reaction of the
corresponding flavone derivatives with iodobenzene diacetate
and trimethylsilyl halide under mild reaction conditions. The
iodobenzene diacetate could be replaced by the polymer-
supported iodobenzene diacetate without the decreasing
activity.
The synthesis of a-haloenones from a,b-unsaturated carbonyl com-
pounds provides an important functional group that facilitates palladium
catalyzed carbon-carbon bond formation.2 The application of this type of
methodology to flavone has been rare despite the widespread synthetic uti-
lity of bisflavonoid intermediate. Therefore, new methods for the convenient
* See Reference 1.
{ Corresponding author. E-mail: thiocar@channeli.net
2101
Copyright & 2001 by Marcel Dekker, Inc.
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RHO, KO, AND JU
synthesis of 3-haloflavone derivatives are of interest in flavonoid chemistry.3
Recently, it has been shown that the PhI(OAc)2/TMSX system served as an
effective reagent for halogenation of cyclic enones1d and aromatic com-
pounds.1b,1f There are two reactive sites in flavone with this halogenation
system such as cyclic enone and aromatic ring. In this communication, we
wish to report on the selective cyclic enone halogenation of flavone using the
PhI(OAc)2/TMSX system under mild conditions. The polymer-supported4
PhI(OAc)2 can be substituted to PhI(OAc)2 in the same activity (Scheme 1).
Scheme 1.
To determine suitable reaction conditions, a series of experiments were
performed on the substrate 1a with trimethylsilyl chloride. We first reacted
flavone 1a with PhI(OAc)2 (1.5 equiv) and TMSCl (3 equiv) in CH2Cl2 at
0ꢀC to afford 3-chloro flavone 2a3b in 48% yield without aromatic chlorina-
tion (entry 1, Table 1). The electrophilic addition of cyclic enone must be
faster than that of the aromatic ring. When the temperature was higher than
0ꢀC, aromatic chlorination compound was detected in the crude product.
To improve yield, PhI(OAc)2 was replaced by PhI(OCOCF3)2, we could
not find any difference of two reagents (entry 2, Table 1). But the yields
Table 1. Reaction Conditions for Chlorination of Flavone 1a
Time
(h)
Yield
(%)b
Entry
Iodine Reagenta
Base
None
None
Triethylamine
Pyridine
1
2
3
4
PhI(OAc)2(1.5)
PhI(OCOCF3)2(1.5)
PhI(OAc)2(1.5)
PhI(OAc)2(1.5)
5
4.5
3
48
50
80
82
3.5
aWith TMSCl (3 equiv), CH2Cl2, 0ꢀC. The molar equivalents are given in paren-
b
theses. Isolated yields.

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were increased dramatically using the different base. In the presence of
triethylamine (4 equiv), 3-chloro flavone 2a was obtained in 80%
yield (entry 3, Table 1). The yield of 2a was further improved using
pyridine (entry 4, Table 1). The substitution of chlorine is considered
to involve the addition of Cl2 to the double bond, followed by proton
elimination. The proton elimination rate was increased by the base.
We extended this optimized reaction condition to other flavones and poly-
mer-supported iodine reagent. The results are summarized in Table 2.
Table 2. Synthesis of 3-Halo Derivatives of Flavones

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RHO, KO, AND JU
In this reaction, the halogenated product was contaminated with the
iodobenzene. We had to use chromatographic techniques for isolating the
product from iodobenzene. Polymer-supported PhI(OAc)2 was expected
to solve this problem. We have prepared the polymer-supported
PhI(OAc)2 according to the literature method.4a The loading capacity
of the polymer was determined to be 3.20 mmol/g by elemental analysis.5
Treatment of 1a with Poly PhI(OAc)2 (1.5 equiv)/TMSCl (3 equiv) and
pyridine (4 equiv) afforded 3-chloro flavone 2a in 80% yield (entry 2,
Table 2). The work-up procedure was simple. After the reaction, simple
filteration seperated the product and polymeric iodobenzene. There
was no noticeable difference in both reaction time and yield. The flavone
1b which has a methoxy substituent in B ring gave 3-chloro or 3-bromo
flavone 2b3b and 2c3g in moderate to high yield (entry 3, 4 and 5). Aromatic
activating substituent has no effect on the preference of electrophilic
addition of cyclic enone. Finally, in case of flavone 1c bearing a methoxy
group in A ring in the same conditions, bromo flavone 2d3g was obtained
in 73% and 70% yields without aromatic halogenation (entry 6 and 7).
When trimethylsilyl iodide was used as an iodination source, none of the
desired product was obtained. This result is due to fact that the iodine,
obtained by TMSI and PhI(OAc)2, has no capability of the addition to
double bond.
In summary, we have found a selective 3-halogenation of flavones with
TMSX/PhI(OAc)2 system in mild conditions. The polymer-supported
PhI(OAc)2 had same activity in this reaction. The use of polymer-supported
reagent offered advantages in purification.
EXPERIMENTAL SECTION
Typical Procedure
3-Chloro-2-phenyl-4H-chromen-4-one(2a)
Method A
PhI(OAc)2 (217 mg, 0.67 mmol) was suspended in anhydrous CH2Cl2
(3 ml) and cooled with stirring to 0ꢀC under an atmosphere of nitrogen.
Trimethylsilyl chloride (147 mg, 1.35 mmol) was added dropwise and the
mixture stirred with at 0ꢀC for 30 min. The flavone 1a (100 mg,
0.45 mmol) in anhydrous CH2Cl2 (2 ml) and pyridine (142 mg, 1.80 mmol)
were added and the mixture was stirred at 0ꢀC for 3.5 h. The reaction
mixture was quenched with saturated aquous sodium thiosulfate and the
solution was extracted with CH2Cl2 (20 ml ꢁ 2). The organic layer was dried

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over MgSO4 and evaporated in vacuo. The crude product was purified by
SiO2 column chromatography (EtOAc/hexanes 1 : 2, Rf ¼ 0.57) to give 2a
(95 mg, 82%). Mp 123–124ꢀC. H NMR (CDCl3, 300 MHz) d 8.32(dd, 1H,
1
J ¼ 7.8, 1.5 Hz), 7.90–7.93 (m, 2H), 7.70–7.75(m, 1H), 7.44–7.57(m, 5H).]
MS(m/e) 259(Mþþ2), 257(Mþ), 229, 165, 136, 129(base peak), 92.
Method B
Poly PhI(OAc)2 (209 mg, 0.67 mmol) was suspended in anhydrous
CH2Cl2 (3 ml) and cooled with stirring to 0ꢀC under an atmosphere
of nitrogen. Trimethylsilyl chloride (147 mg, 1.35 mmol) was added
dropwise and the mixture stirred with at 0ꢀC for 30 min. The flavone
1a (100 mg, 0.45 mmol) in anhydrous CH2Cl2 (2 ml) and pyridine (142 mg,
180 mmol) were added and the mixture was stirred at 0ꢀC for 4 h.
Then diethyl ether (40 ml) was added and the resulting precipitate
filtered off. The filterate was washed with saturated aquous sodium thio-
sulfate. The organic layer was dried over MgSO4 and evaporated in
vacuo. The crude product was purified by simple crystalization to give 2a
(92 mg, 80%).
3-Chloro-2-(4-methoxyphenyl)-4H-chromen-4-one (2b). TLC, SiO2,
EtOAc/hexanes 1 : 2, Rf ¼ 0.46. Mp 134–135ꢀC. 1H NMR (CDCl3, 300 MHz)
d 8.24(dd, 1H, J ¼ 8.1, 1.2 Hz), 7.95(d, 2H, 1H), 7.43–7.53(m, 2H), 7.06(d,
2H, J ¼ 9.0 Hz), 3.91(s, 3H). MS(m/e) 289(Mþþ2), 287(Mþ), 259, 166(base
peak), 135.
3-Bromo-2-(4-methoxyphenyl)-4H-chromen-4-one (2c). TLC, SiO2,
1
EtOAc/hexanes
:
2, Rf ¼ 0.43. Mp 141–142ꢀC. 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, 1H, J ¼ 8.7 Hz), 3.90(s,
3H). MS(m/e) 333(Mþþ2), 331(Mþ, base peak), 303, 251(base peak),
210, 152.
3-Bromo-6-methoxy-2-phenyl-4H-chromen-4-one (2d). TLC, SiO2,
EtOAc/hexanes 1 : 2, Rf ¼ 0.41. Mp 123–124ꢀC. 1H NMR (CDCl3,
300 MHz) d 7.82–7.86(m, 2H), 7.40–7.63(m, 5H), 7.29–7.33(m, 1H),
3.92(s, 3H). MS(m/e) 333 (Mþþ2), 331(Mþ), 303, 165, 150(base peak), 122.
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 June 23, 2000

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