Formation of the unexpected 3-alkylated flavonoids in the alkylation of B-ring substituted 5,7-dihydroxy flavones

Article abstract of DOI:10.1016/j.tetlet.2005.05.144

Treatment of B-ring substituted 5,7-dihydroxy flavones with alkyl halides in the presence of potassium carbonate gave unexpected 3-alkylated flavonoids. Related experiments were carried out to explain the formation of 3-alkylated flavonoids and a ring opening followed by alkylation and ring closure mechanism was proposed.

Full text of DOI:10.1016/j.tetlet.2005.05.144

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 5399–5402
Formation of the unexpected 3-alkylated flavonoids in
the alkylation of B-ring substituted 5,7-dihydroxy flavones
Cai-Ling Wang,a Xing Zheng,a Wei-Dong Meng,a Hong-Qi Lia and Feng-Ling Qinga,b,
*
aInstitute of Biological Sciences and Biotechnology, Donghua University, 1882 West Yanan Road, Shanghai 200051, China
bKey Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
354 Fenglin Lu, Shanghai 200032, China
Received 19 April 2005; revised 27 May 2005; accepted 30 May 2005
Available online 22 June 2005
Abstract—Treatment of B-ring substituted 5,7-dihydroxy flavones with alkyl halides in the presence of potassium carbonate gave
unexpected 3-alkylated flavonoids. Related experiments were carried out to explain the formation of 3-alkylated flavonoids and
a ring opening followed by alkylation and ring closure mechanism was proposed.
Ó 2005 Elsevier Ltd. All rights reserved.
Flavonoids have been found to exhibit a broad range of
pharmacological properties.1 In recent years, there has
been a growing interest in the search for anti-tumor
flavonoids with high efficacy and low toxicity.2 It is
known that fluorine is the most electronegative element
and the van der Waals radius of fluorine is close to that
of hydrogen. The introduction of the trifluoromethyl
(CF3) or gem-difluoromethylene (CF2) group into organic
molecules often changes their physiological, physical and
chemical properties dramatically, without extra steric
demand.3 We have recently reported that introduction
of CF3 group into the A- and B-ring of flavonoids mole-
cule can enhance their anti-cancer activities.4,5 When
CH3I, CH3CH2Br and CH3CH2CH2Br were used as
alkylating agents for the alkylation of B-ring trifluoro-
methylated flavonoid 1, unexpected 3-alkylated products
2 were formed along with the expected compounds 3
(Scheme 1).5 This result aroused our interest. So a series
of experiments have been carried out to explain the for-
mation of 3-alkylated flavonoids.
Under the same reaction conditions, when bulky alkyl
halides such as benzyl chloride and heptyl chloride were
used, only compounds 3 were obtained, no 3-alkylated
flavonoids were found (Scheme 2).
Treatment of compounds
CH3CH2CH2)
3
(R = CH3, C2H5,
CH3CH2Br
with
CH3I,
and
CF3
CF3
CF3
HO
O
O
RX / K2CO3
RO
O
RO
O
O
+
R
O
OH
OR
OR
1
2
3
2a R = CH3, 41%
3a R = CH3, 49%
3b R = CH3CH2, 43%
3c R = CH3CH2CH2, 41%
RX: CH3I; CH3CH2Br; CH3CH2CH2Br
2b R = CH3CH2, 23%
2c R = CH3CH2CH2, 22%
Scheme 1.
Keywords: Flavonoids; Fluorinated compounds.
*
Corresponding author. Fax: +86 21 64166128; e-mail: flq@mail.sioc.ac.cn
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.05.144

5400
C.-L. Wang et al. / Tetrahedron Letters 46 (2005) 5399–5402
CF3
CF3
HO
O
O
RO
O
O
RX / K2CO3
OH
OR
3
1
3d R = C6H5CH2, 96%
3e R = n-C7H15, 82%
RX: C6H5CH2Cl; n-C7H15Cl
Scheme 2.
CF3
CF3
RX / K2CO3
RO
O
RO
O
O
R
OR
O
OR
2a R = CH3
3a R = CH3
2b R = CH3CH2
3b R = CH3CH2
3c R = CH3CH2CH2
2c R = CH3CH2CH2
Scheme 3.
CH3CH2CH2Br, respectively, in the presence of K2CO3
failed to give 3-alkylated products 2 (Scheme 3). These
results showed that compounds 2 were not formed from
the further alkylation of compounds 3.
alkylation of compound 4 with CH3I in the presence
of K2CO3 gave compounds 2f and 3f. Compound 5
was treated under the same conditions to give com-
pounds 2g and 3g. However, compound 6 only yielded
compound 3h in nearly quantitative yield, no 3-alkyl-
ated product was detected (Scheme 4). It was evident
that the substituted B-ring was an important factor for
the formation of 3-alkylated product, whereas the
To explain the formation of unexpected compound 2 in
the alkylation of compound 1, the effect of other substi-
tutes on the B-ring of flavonoids was investigated. The
OCF2H
OCF2H
OCF2H
HO
O
O
H3CO
O
H3CO
O
CH3I / K2CO3
+
CH3
OH
OCH3O
OCH3O
2f 43%
3f 41%
4
OCH3
CH3I / K2CO3
OCH3
OCH3
HO
O
H3CO
O
H3CO
O
+
CH3
OH
O
OCH3O
2g 41%
OCH3O
3g 47%
5
HO
O
O
CH3I / K2CO3
H3CO
O
OH
OCH3O
3h 99%
6
Scheme 4.

C.-L. Wang et al. / Tetrahedron Letters 46 (2005) 5399–5402
5401
R
R
CH3I / K2CO3
HO
O
O
H3CO
O
O
7a R = H
8a R = H, 87%
7b R = CF3
7c R = OCH3
8b R = CF3, 60%
8c R = OCH3, 89%
Scheme 5.
electron-withdrawing group (CF3, OCF2H) and elec-
tron-donating group (OCH3) of B-ring had no profound
effect on the outcome of the alkylation.
Based on the above facts, we presumed that the un-
expected 3-alkylated compounds 2a–g were formed via
a proposed mechanism (Scheme 6). The flavoniods were
deprotonated with K2CO3 to give anion 9. When a
strong electron-withdrawing group such as trifluoro-
methyl or difluoromethoxy group was presented at 40-
position such as compound 1 or 4, the electron density
on the oxygen atom at the C-ring decreased, and anion
9 (R=CF3, OCF2H) tended to tautomerize to 10 via a
resonance of the lone pair of electrons of oxygen atom
and a hydrogen-transfer between 5-hydroxy and 4-
carbonyl groups. Under the basic condition, 10 was
attacked by a hydroxy anion to form an intermediate
Then, we examined the effect of hydroxy groups of A-
ring on the formation of 3-alkylated flavonoids. Thus,
a series of B-ring substituted 7-hydroxy flavones 7a–c
were prepared. The reaction of 7a–c with CH3I in the
presence of K2CO3 produced compounds 8a–c, respec-
tively, without the formation of 3-methyl flavonoids
(Scheme 5). These results implied that 5-hydroxy group
of A-ring played a key role in the formation of 3-alkyl-
ated product.
R'
K2CO3
R'
R'
_
HO
O
O
_
+
O
O
O
O
O
_
OH
O
O
_
H
O
O
H
10
H
R' = CF3, OCF2H, OCH3
9
R' = CF3, OCF2H
_
+
OH
OMe
R'
_
O
O
O
_
O
O
_
_
OH
OH
O
H
_
O
_
O
O
H
H
R' = OCH3
11
12
R'
R'
R'
_
_
_
_
O
O
_
O
O
O
O
O
RX
O
OH
H
O
H
R
X
R
_
O
O
R
O
O
O
H
H
14
H
13
_
H2O
R'
R'
_
O
O
RO
O
K2CO3
RX
R
R
O
O
OR
2a-e
O
H
15
Scheme 6.

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C.-L. Wang et al. / Tetrahedron Letters 46 (2005) 5399–5402
11. On the other hand, when a strong electron-donating
methoxy group was presented at 40-position, the inter-
mediate 12 was formed through a resonance of the lone
pair of electrons of oxygen atom of methoxy group and
the proton switch between 5-hydroxy and 4-carbonyl
groups. Under the basic condition, 12 was also attacked
by a hydroxy anion to form the intermediate 11. The
intermediate 11 was then ring-opened to give intermedi-
ate 13, which was then alkylated with CH3I, CH3CH2Br
or CH3CH2CH2Br to give intermediate 14, followed by
a ring closure and dehydration to give 3-alkylated inter-
mediate 15. The intermediate 15 was then deprotonated
by K2CO3 and alkylated with alkyl halides to give 3-
alkylated compounds 2a–g. The proton switch between
5-hydroxy and 4-carbonyl groups played an important
role in the reaction, and this was supported by the above
facts that flavonoids without 5-hydroxy group, such as
compounds 7a–c could not give 3-methylated products.
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We thank the National Natural Science Foundation of
China, Ministry of Education of China and Shanghai
Municipal Scientific Committee for funding this work.