Cleavage of methyl ethers of flavones by chloroaluminate ionic liquid

Article abstract of DOI:10.1081/SCC-200028625

A new o-demethylation method of a series of mono-, di-, trimethoxy-flavones using a chloroaluminate ionic liquid - [BMIM] [Al₂Cl₇] in dichloromethane is described. The desired products were obtained in moderate to good yields.

Full text of DOI:10.1081/SCC-200028625

SYNTHETIC COMMUNICATIONSw
Vol. 34, No. 17, pp. 3209–3218, 2004
Cleavage of Methyl Ethers of Flavones
by Chloroaluminate Ionic Liquid
*
Tao Liu and Yongzhou Hu
Zhejiang University, Department of Medicinal Chemistry,
School of Pharmaceutical Science, Hangzhou, P.R. China
ABSTRACT
A new o-demethylation method of a series of mono-, di-, trimethoxy-flavones
using a chloroaluminate ionic liquid—[BMIM] [Al2Cl7] in dichloromethane
is described. The desired products were obtained in moderate to good yields.
Key Words: Flavones; o-Demethylation; Ionic liquid.
INTRODUCTION
Flavones were among the most ubiquitous groups of polyphenolic com-
pounds. They might exert a wide range of beneficial effects on human
health, including protection against cardiovascular diseases.[1] Flavones
*
Correspondence: Yongzhou Hu, Zhejiang University, Department of Medicinal
Chemistry, School of Pharmaceutical Science, Hangzhou 310031, P.R. China;
E-mail: huyz@zjuem.zju.edu.cn.
3209
DOI: 10.1081/SCC-200028625
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com
Copyright # 2004 by Marcel Dekker, Inc.

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likely produced such biological effects through their free radical-scavenging
antioxidant activities and metal ion-chelating abilities.[2] In particular, many
compounds exhibited antitumor[3,4] or related activities, such as antimitotic
activity, through inhibition of aromatase[5] or topoisomerase.[6] Antiviral
activities have been also reported.[7]
The structure-activity relationship studies revealed that most activities
of flavones were closely related to the free hydroxyl group on aromatic ring.
A number of synthetic methods for the preparation of flavones had been devel-
oped, but these often required protection for the free hydroxyl group during
preparation. Among the most protective methods, the o-methyl group had
many desirable properties for hydroxyl protection. The reagents previously
employed for the o-demethylation of methyl ethers of flavones were pyridinium
hydrochloride and boron tribromide.[8,9] The former was a conventional o-
demethylation reagent; however, fairly high temperature was required. The
latter, as a fairly powerful Lewis acid, was easily decomposed on exposure to
light and rapidly hydrolyzed to boric acid in air. In connection with our work
on synthesis of flavone derivatives as an anticarcinogen, we required an efficient
method for the o-demethylation of methyl ethers of flavones.
Ionic liquids are usually composed of organic cations and either organic or
inorganic anions. They show a unique combination of properties including high
polarity, low viscosity, high liquid temperature range, high thermal stability,
wild tunability, immiscibility with certain organic solvents, and no effective
vapor pressure.[10] Recently, many organic reactions, including alkylation, epoxi-
dation, and hydrogenation, have been reported to proceed in ionic liquids with
excellent yields and selectivities.[11] It is known that ionic liquids containing
chloroaluminate (AlCl24 , Al2Cl7) anion could be strong Lewis acids and there-
fore could act as either catalysts or reaction medium for acid-catalyzed pro-
cesses. Lange also reported vanillin could be o-demethylated using AlCl3.[12]
Taking into account these results, we tried using [N-butyl-N-methylimidazo-
lium] [Al2Cl7] ([BMIM] [Al2Cl7]), a commonly used and easily prepared
Scheme 1.

Clevage of Methyl Ethers of Flavones
3211
ionic liquid, to cleave methyl ethers of flavones. We found it was a useful
reagent for cleavage of methyl ether of flavones (Sch. 1).
RESULTS AND DISCUSSION
The flavones investigated were mono-, di-, trimethoxy-flavones. When
methyl ethers of flavones were treated with [BMIM] [Al2Cl7] in dichloro-
methane under reflux, the corresponding o-demethylated flavones were
obtained in moderate to good yields. The physical data of these products
appear in Table 1.
As is evident from Table 1, if there were a methoxy group on the B
ring of flavones, the yields of the desired products were relatively low,
ranging from 49%to 57%. The reason for the lower yields was that other
products, i.e., flavone derivatives that kept a methoxy group on B ring,
were found in these o-demethylation experiments. The yields ranged from
14% to 39% (It wouldn’t disappear even if the reaction time were pro-
longed). The structures of these products were confirmed by 1H-NMR
(nuclear magnetic resonance) and ultraviolet (UV) spectra. As shown by
entry 4 in Table 1, another product was 2-(30-methoxyphenyl)-5,7-dihy-
droxyl-flavone (3d) (Sch. 2). It was isolated as a pale yellow solid. The
1H-NMR spectra revealed the signal at d 12.91 assignable to a chelated
hydroxyl group at C-5; chelated hydroxyl group at C-5; the signal at d
11.03 was assigned to a hydroxyl group at C-7 position; and the signal
at d 3.93 was assigned to a methoxyl group at C-30 position. Furthermore,
UV spectra in MeOH showed absorption maxima at 235 nm and 308 nm,
typical of a flavone derivative. A hypsochromic shift of 19 nm in its UV
absorption maxima on addition of NaOAc suggested the presence of a
hydroxyl group at C-7 position, as described in Ref.[19]
.
When a methyl ether of flavanone (2-phenyl-5,7-dimethoxyl-flavanone)
was reacted with [BMIM] [Al2Cl7] in the same reaction condition, an
unexpected result was obtained. We obtained only a small amount of
the intended product, 2-phenyl-5,7-dihydroxyl-flavanone (20%); ring-
opening product, 2,6-dihydroxyl-4-methoxyl-chalcone, was obtained in
large amounts (46%) (Sch. 3). It revealed that o-demethylation proceeds
and ring opening reaction took place at the same time in such a Lewis
acidic condition.
In order to evaluate the o-demethylation of [BMIM] [Al2Cl7] and conven-
tional o-demethylation reagents, pyridinium hydrochloride and boron tribromide,
we adopted 8-(1-methyl-4-piperidinyl)-2-phenyl-5,7-dimenthoxyl-flavone 1a as
the substrate. The results of three o-demethylation methods are illustrated in
Table 2. As shown in Table 2, almost the same yields were obtained. The

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Clevage of Methyl Ethers of Flavones
3213

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Liu and Hu

Clevage of Methyl Ethers of Flavones
3215
Scheme 2.
Scheme 3.
result means that [BMIM] [Al2Cl7] is a more mild, nontoxic o-demethylation
reagent.
In conclusion, the cleavage of the methyl ethers of flavones by nontoxic
chloroaluminate ionic liquid—[BMIM] [Al2Cl7]—was reported. It could
exhibit the same o-demethylation as the conventional o-demethylation
reagents. The method adopted here provided a facile and efficient method-
ology useful for the preparation of polyhydroxyl flavone derivatives.
EXPERIMENTAL
1
The H-NMR spectra were recorded on a Bruker 400 MHz instrument
(Germany) as DMSO-d6 solutions using tetramethylsilane as the internal
standard. Melting points were determined on BUCHI Melting Point B-540
(Switzerland) apparatus and were uncorrected. The UV spectra were
Table 2. o-Demethylation of 1a with different cleavage reagents.
Reaction
temperature (8C)
Entry
1
Reagent
Yield (%)
69
Pyridinium
180
Hydrochloride
Boron tribomide
[BMIM] [Al2Cl7]
2
3
83
40
68
66

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Liu and Hu
determined using Beckman DU-640 (USA). Infrared spectra were recorded on
a Bruck Vector 200 spectrophotometer (Brucker Optic GmbH, Germany); ESI
were measured on a Esquire-LC-00075 spectrometer (Germany); and elemen-
tal analyses were performed on a EA-1110 instrument (Carlo Erba, Italy).
General Procedure
A solution of [BMIM] [Al2Cl7] (5.3 g, 0.012 mol) in dichloromethane
(6 mL) was added drop-wise to a solution of flavone 1a (0.76 g, 0.002 mol)
in dichloromethane (10 mL). The reaction mixture was stirred for 4 hr at
408C. The reaction mixture was poured into a mixture of water (8 mL) and
concentrated hydrochloric acid (1.2 mL). The aqueous layer was extracted
three times with chloroform. The solvents were removed to obtain the crude
product, which was purified by silica gel column chromatography using
dichloromethane and ethanol (200 ꢀ 1) as eluent. The products were charac-
1
terized by IR, H-NMR, ESI, and elemental analysis.a
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Received in Japan March 9, 2004