Synthesis of 3-halogenated flavonoids via electrophile-promoted cyclization of 2-(3-aryl-2-propynoyl)anisoles

Article abstract of DOI:10.1002/jccs.200400027

Treatment of 2-(1-aryl-3-propynoyl) anisoles 1 with N-chlorosuccinimide (NCS) or N-bromosuccinimide (NBS) gave the 3-halogenated flavones and their related molecules in moderate yields.

Full text of DOI:10.1002/jccs.200400027

Journal of the Chinese Chemical Society, 2004, 51, 183-186
183
Synthesis of 3-Halogenated Flavonoids via Electrophile-Promoted
Cyclization of 2-(3-Aryl-2-propynoyl)anisoles
Chi-Fong Lin (
Jeng-Lin Lee (
Chin-Chau Chen (
), Tsai-Hui Duh (
), Chia-Ying Lee (
) and Ming-Jung Wu* (
), Wen-Der Lu (
),
),
)
School of Chemistry, Kaohsiung Medical University, Kaohsiung, Taiwan, R.O.C.
Treatment of 2-(1-aryl-3-propynoyl) anisoles 1 with N-chlorosuccinimide (NCS) or N-bromosuc-
cinimide (NBS) gave the 3-halogenated flavones and their related molecules in moderate yields.
Keywords: Electrophiclic cyclization; Flavonoids.
Flavonoids are a series of the earliest discovered natu-
ral products, which occur in most families of higher plant
kingdom. As a major class of plant components, over 4000
flavonoid compounds have been identified1 that exhibit a va-
riety of pharmacological activities, including antiflammatic,
antioxidant, antithrombogentic, antiviral, anticarcinogenic
and antiproliferative effects.2 Some flavonoids have also
been demonstrated to possess the binding affinities for the es-
trogen receptor.3 Despite an abundance of flavonoids from
natural sources, it is still of interest to obtain them by synthe-
sis since novel biological activities are continuously discov-
ered for these compounds and their derivatives.4 Herein, we
report a new synthetic method to obtain 3-halogenated
flavonoids 2 by electrophile-promoted cyclization of 2-(3-
substituted 2-propynonyl)anisoles 1 (Eq. 1), and which had
no investigation about the route.
Scheme I
O
O
Ph
n-BuLi
OH
CH3I, DMF
25oC, 12h
H
H
THF, 0oC
2h
Ph
OH
OMe
4 (92%)
OMe
3
5a ( 85%)
O
MnO2
CH2Cl2, 25 oC
Ph
OMe
1a ( 96%)
Compound 1a was first treated with 3 equivalents of iodine,
N-iodosuccinimide (NIS), NBS, or NCS in refluxing CH2Cl2.
No product was isolated in all reactions even after the reac-
tion time was extended to 24 h. Only the starting materials
were recovered. When the solvent CH2Cl2 was replaced by
DMF, reaction of 1a with NIS at 100 °C for 2 h gave the unde-
sired product 7aa in 50% yield. Treatment of 1a with NBS
under the same reaction conditions gave 3-bromoflavone 6ab
in 36% yield together with addition product 7ab in 30%
yield. Reaction of 1a with NCS gave 3-chloroflavone 6ac in
57% yield along with the addition adduct 7ac in 15% yield.
The structure of compound 6ac was unambiguously deter-
mined by X-ray crystallography (Fig. 1). The results con-
firmed that the electrophilic cyclization of 2-(3-phenyl-2-
propynoyl)anisole takes a 6-endo pathway instead of a 5-exo
pathway to generate 3-chloroflavone (6ac). Under the same
reaction conditions, reaction of 1a with iodine gave neither
addition adduct nor the cyclization adduct. Moreover, DMSO
O
O
E
E
(1)
Ar
O
Ar
OR
The synthesis of flavone precursor 1a is summarized in
Scheme I. Treatment of salicyclic aldehyde (3) with methyl
iodide in DMF for 12 h produced 2-methoxybenzaldehyde
(4) in 92% yield. Compound 4 was reacted with lithium
phenylacetylide (from treatment of 1.0 eq. phenylacetylene
with 1.2 eq. n-BuLi in THF) at 0 °C for 2 h to yield the alcohol
5a in 85% yield. Oxidation of 3a with MnO2 afforded the
2-(3-phenyl-2-propynonyl)anisoles 1a in 96% yield.
Several sets of conditions for the cyclization reaction
have been tested and the results are summarized in Table 1.
* Corresponding author. Tel: +886-7-3121101 ext 2220; fax: +886-7-3125339; e-mail: mijuwu@cc.kmu.edu.tw

184 J. Chin. Chem. Soc., Vol. 51, No. 1, 2004
Lin et al.
Table 1.
O
O
O
X
X
additive
+
Ph
Ph
Solvent, Temp.
OMe
O
Ph
OMe
6
7
1a
Solvent, Temp.
additive
yield (%)
CH2Cl2, reflux, 24 h
DMF, 100 °C, 2 h
DMSO, 100 °C, 48 h
I2
¾
¾
¾
¾
NIS
NBS
NCS
I2
¾
NIS
NBS
NCS
7aa (C = I, 50%)
7ab (C = Br, 30%)
7ac (C = Cl, 15%)
6ab (C = Br, 36%)
6ac (C = Cl, 57%)
NCS
7ac (C = Cl, 14%)
was also tested in this cyclization reaction. Reaction of 1a
with NCS in DMSO at 100 °C for 48 h gave 7ac in 14% yield
as the only product. The results suggested that NCS is the best
reagent and DMF is the best solvent to produce 3-halogen-
ated flavones.
60% yields, whereas no cyclized products were identifiable
for the precursor 1f-h. The results are summarized in Table
2. Compounds 1f and 1g carried electron-withdrawing
groups on the aryl ring and formed only the addition reaction
products in 40-45% yields when they were reacted with
NCS. No product was formed from treatment of 1h with
NCS. When 1h was reacted with NIS or NBS, only addition
products (7ha or 7hb) were obtained in 45% and 38% yields,
respectively. We believe that the aryl groups bearing elec-
tron withdrawing substituents might reduce the electron den-
sity of alkyne moiety, leading to reduction in the reaction to-
wards the electrophile and thus lowering the reactivity of
cyclization to offer the flavonoids (Scheme III). In contrast,
the withdrawing groups on the aryl ring facilitated the addi-
tion reactions.
After the achievement of the synthesis of flavonoids by
the described method, we then turn our attention to test the
generality of this cyclization reaction. T8hus, various 2-(3-
aryl-2-propynonyl)anisoles 1b-g were prepared (Scheme II).
Treatment of 1b-e with NCS under the described reaction
conditions gave the 3-chlorinated flavones 6b-e in 42% to
The benzyl and tert-butyldimethylsilyl analogs of 1a,
compound 1i and 1j, were prepared to test the protecting
group effect on these cyclization reactions. Treatment of 1j
with NCS under the optimal reaction conditions gave 6ic in
26% yield and treatment of 1j with NCS under the same reac-
tion conditions gave 8 in 39% yield. (Eq. 2) The formation of
O
O
O
Cl
NCS, DMF
100oC, 2h
(2)
+
Ph
Ph
O
O
Ph
OR
6
8
1
1i, R = CH2Ph
1j, R =TBDMS
6ic (26%)
Fig. 1. X-ray structure of 3-chloroflavon 6ac.
8 (39%)

Synthesis of 3-Halogenated Flavonoids
J. Chin. Chem. Soc., Vol. 51, No. 1, 2004 185
Scheme II
O
OH
R
O
MnO2
n-BuLi
H
THF, 0oC
CH2Cl2, 25 oC
R
R
OMe
OMe
OMe
2h
1b (R = p-CH3C6H4, 99%)
3b (R = p-CH3C6H4, 82%)
3c (R = p-CH3OC6H4, 86%)
1c (R = p-CH3OC6H4, 95%)
1d ( R = p-CH3(CH2)3C6H4, 96% )
1e ( R = 2,3-dimethylphenyl, 99% )
1f ( R = 2-pyridinyl, 98%)
3d ( R = p-CH3(CH2)3C6H4, 80% )
3e ( R = 2,3-dimethylphenyl, 85% )
3f ( R = 2-pyridinyl, 82%)
3g ( R = p-CNC6H4, 45%)
1g ( R = p-CNC6H4, 95%)
3h (R = (CH2)4CH3, 90%)
1h (R = (CH2)4CH3, 95%)
Table 2.
O
O
O
X
Cl
R
additives, DMF
+
R
100oC, 2h
O
R
OMe
OMe
6
7
1
Entry
additive
yield (%)
1b (R = p-CH3C6H4)
1c (R = p-OCH3C6H4)
1d (R = p-CH3(CH2)3C6H4)
1e (R =2,3-dimethylphenyl)
1f (R = 2-pyridinyl)
NCS
NCS
NCS
NCS
NCS
NCS
6b (58%)
6c (60%)
6d (42%)
6e (50%)
7f (X = Cl, 40%)
7g (X = Cl, 40%)
1g (R = p-CNC6H4)
1h, R = (CH2)4CH3
NIS
7ha (X = I, 45%)
NBS
NCS
7hb (X = Br, 38%)
¾
Scheme III
O
O
N
O
N
O
Cl
Cl
+
+
Ar
Ar
OCH3
OCH3
O
O
5-exo
6-endo
O
O
Cl
Ar
O
O
Cl
Ar

186 J. Chin. Chem. Soc., Vol. 51, No. 1, 2004
Lin et al.
compound 8 was rational to undergo desilylation of 1j, fol-
lowed by a 5-exo cyclization.
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In conclusion, we have demonstrated a novel synthetic
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cyclization of 2-(3-aryl-2-propynonyl)anisoles. We found
that this cyclization reaction is sensitive to the substituent on
the alkyne terminus and the protecting group on the phenol
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We thank the National Science Council of the Republic
of China for financial support of this program.
Received June 13, 2003.