An efficient and facile synthesis of flavanones catalyzed by N-methylimidazole

Article abstract of DOI:10.2298/JSC120629157W

The use of N-methylimidazole as an efficient catalyst for the cyclization of 2'-hydroxychalcones to the corresponding flavanones in DMSO was investigated. The scope of this process was studied and various flavanones were obtained exclusively in good yields. Copyright

Full text of DOI:10.2298/JSC120629157W

J. Serb. Chem. Soc. 78 (7) 917–920 (2013)
UDC 547.814.5+544.478+547.781/.783+542.913
JSCS–4469
Short communication
SHORT COMMUNICATION
An efficient and facile synthesis of flavanones catalyzed by
N-methylimidazole
PENG WANG1, JIABIN YANG1, JIN CAI2, CHUNLONG SUN2, LUSHEN LI1
2
∗
and MIN JI
1School of Biological Science & Medical Engineering, Southeast University, Nanjing 210096,
China and 2 School of Chemistry & Chemical Engineering, Southeast University,
Nanjing 210096, China
(Received 29 June 2012)
Abstract: The use of N-methylimidazole as an efficient catalyst for the cyc-
lization of 2′-hydroxychalcones to the corresponding flavanones in DMSO was
investigated. The scope of this process was studied and various flavanones
were obtained exclusively in good yields.
Keywords: 2′-hydroxychalcones; flavanones; N-methylimidazole.
INTRODUCTION
The flavanone structure is abundant in natural products that possess a broad
1
array of biological activity. Due to their favorable anti-cancer, anti-estrogen and
anti-inflammatory properties, flavanones have been investigated as selective
2
estrogen receptor modulators and tumor necrosis factor (TNF)-α inhibitors.
Moreover, these kinds of compounds are important intermediates in the synthesis
of flavanone glycosides and 2-aryl chromans. These compounds have been syn-
3
thesized by the cyclization of 2′-hydroxychalcones, that is, by an intramolecular
oxa-Michael addition (Scheme 1) using various reagents, such as potassium ferri-
4
5
6
7
cyanide, iodine, alkali metal carbonates and trifluoroacetic acid. Despite
these impressive contributions, more efficient and practical catalytic systems for
the synthesis of flavanones are still in high demand.
Recently, several reports referred to N-methylimidazole as a co-catalyst for
aldol, Claisen and other reactions. Moreover, Lin reported an aza-Michael addi-
8
tion catalyzed by N-methylimidazole. Inspired by these findings, herein the use
of N-methylimidazole as an efficient catalyst that facilitates the cyclization of 2′-
hydroxychalcones in high yields is presented.
∗Corresponding author. E-mail: jimin@seu.edu.cn
doi: 10.2298/JSC120629157W
917
Available online at www.shd.org.rs/JSCS/
___________________________________________________________________________________________________________________
Copyright (C)2013 SCS

918
WANG et al.
Scheme 1. N-Methylimidazole catalyzed cyclization of 2′-hydroxychalcones.
RESULTS AND DISCUSSION
First, optimization experiments involving 2′-hydroxychalcone (1a) as the test
substrate were performed, these focused on the determination of the effect of the
solvent and the amount of N-methylimidazole. The results are summarized in
Table I. The reaction was realized in three different solvents, viz., dichlorome-
thane, acetonitrile, and DMSO (Table I, entries 1–3). It was observed that a
higher yield of the flavanone 2a was achieved in DMSO compared with those in
the other two solvents, which led DMSO to be chosen for all further studies. The
importance of the N-methylimidazole was confirmed by the fact that no product
2a was obtained in the absence of N-methylimidazole (Table I, entry 4).
Subsequent studies indicated that 20 mol % N-methylimidazole was the optimal
amount. The product 2a was obtained in 90 % yield after 6 h in DMSO at 80 °C,
while only trace amounts of 2a were observed at room temperature (Table I,
entry 7).
TABLE I. Optimization of the solvent and the amount of N-methylimidazole
Entry
Solvent
N-methylimidazole (equiv.)
Time, h
Yielda, %
1
2
3
4
CH2Cl2
CH3CN
DMSO
DMSO
DMSO
DMSO
DMSO
0.2
0.2
0.2
–
0.1
0.5
0.2
6
6
6
6
12
6
30
75
90
N.R.
85
90
5
6
7b
12
trace
aIsolated yield after column chromatography; bat room temperature
To evaluate the scope of the substrate of this methodology, a variety of
2′-hydroxychalcones were examined in the reaction, and the results are sum-
marized in Table II. In all cases, the optimized conditions described previously
Available online at www.shd.org.rs/JSCS/
___________________________________________________________________________________________________________________
Copyright (C)2013 SCS

SYNTHESIS OF FLAVANONES
919
proved to be applicable. Good to excellent results were achieved for 4-chloro and
4-methyl substituents (Table II, entries 8 and 10). However, the 4-fluoro group
significantly decreased the yield (Table II, entry 9). 4-Methoxyl and 3-nitro sub-
stitutes afforded the corresponding flavanones in good yields (Table II, entries 7
and 11). Additionally, substitutions at the R or R positions were also tolerated
1
2
(Table II, entries 2–6).
TABLE II. Scope of the cyclization of 2′-hydroxychalcones; the reactions were carried out
with 1 mmol 2′-hydroxychalcones and 0.2 mmol N-methylimidazole in DMSO (1 mL) at 80
°C, 6h
Entry
R1
R2
R3
R4
Product
Yield, %
1
2
3
4
5
6
7
8
H
CH3
CH3
CH3O
H
H
H
H
H
H
H
H
H
H
H
H
H
H
NO2
H
H
H
H
H
CH3
H
H
CH3O
H
Cl
F
CH3
CH3O
2a
2b
2c
2d
2e
2f
2g
2h
2i
90
87
76
H
89
CH3O
CH3O
H
H
H
90
79a
86
87
9
10
11
65a
87
H
H
H
H
2j
2k
H
90a
aAt 100 °C, 8 h
EXPERIMENTAL
Commercial reagents were used as received. Analytical-grade solvents and commercially
available reagents were used without further purification. For product purification by flash
column chromatography, silica gel (200–300 mesh) and light petroleum ether (PE, b.p. 60–90
°C) are used. The IR spectra were recorded on a Bruker Tensor 37 spectrophotometer as liquid
film. The 1H- and 13C-NMR spectra were taken on a Bruker AM-300 spectrophotometer with
tetramethylsilane (TMS) as an internal standard and CDCl3 as the solvent. Melting points
were measured on a WRS-2A melting point apparatus and are uncorrected. Electron impact-
mass spectrometry (EI-MS) was realized on a HP-5988 spectrometer. Elementary analyses
were performed on a Vario EL III elementary analysis instrument.
General procedure for the synthesis of flavanones
N-Methylimidazole (0.2 mmol) was added to a solution of 2′-hydroxychalcone 1a (224
mg, 1 mmol) in DMSO (1 mL). After stirring the reaction mixture at 80 °C for 6 h, it was
quenched by adding water and the resulting mixture was extracted with AcOEt, washed with
water and brine, and dried over MgSO4. The crude product was purified by flash chroma-
tography on silica gel to afford the desired product. The other flavanones were synthesized in
a similar manner.
Characterization of the flavanones
The structures of the synthesized flavanones were confirmed by elemental analysis and
spectroscopic methods. The results are given in the Supplementary material to this paper.
Available online at www.shd.org.rs/JSCS/
___________________________________________________________________________________________________________________
Copyright (C)2013 SCS

920
WANG et al.
CONCLUSIONS
In summary, a facile and efficient cyclization of 2′-hydroxychalcones using
N-methylimidazole as a catalyst in DMSO is reported. Good yields of flavanones
were obtained for a variety of 2′-hydroxychalcones. Extension of this
methodology is presently under active study.
SUPPLEMENTARY MATERIAL
Analytic and spectral data for the synthesized flavanones are available electronically
from http://www.shd.org.rs/JSCS/, or from the corresponding author on request.
И З В О Д
ЕФИКАСНА И ЛАКА СИНТЕЗА ФЛАВАНОНА КАТАЛИЗОВАНА
N-МЕТИЛИМИДАЗОЛОМ
PENG WANG1, JIABIN YANG1, JIN CAI2, CHUNLONG SUN2, LUSHEN LI1 и MIN JI2
1
School of Biological Science & Medical Engineering, Southeast University, Nanjing 210096, China и
2
School of Chemistry & Chemical Engineering, Southeast University, Nanjing, 210096, China
Испитана је употреба N-метил-имидазола као катализатора у реакцији циклизације
2′-хидроксихалкона до одговарајућих флавона у ДМСО-у као растварачу. Изучаван је
домет и опсег реакција и добијени су различити флавони у одличном приносу.
(Примљено 29. јуна 2012)
REFERENCES
1. a) L. C. Chang, A. D. Kinghorn, Bioactive Compounds from Natural Sources: Isolation
Characterisation and Biological Properties, Taylor & Francis, London, 2001; b) Ø. M.
Andersen, K. R. Markham, Flavonoids: Chemistry, Biochemistry and Applications,
Taylor & Francis, London, 2006
2. M. M. Biddle, M. Lin, K. A. Scheidt, J. Am. Chem. Soc. 129 (2007) 3830
3. a) K. Oyama, T. Kondo, J. Org. Chem. 69 (2004) 5240; b) J, H. Kevin Tetrahedron 61
(2005) 6860
4. J. K. Makrandi, S. Bala, Synth. Commun. 30 (2000) 3555
5. P. D. Lokhande, S. S. Sakate, K. N. Taksande, B. Navghare, Tetrahedron Lett. 46 (2005)
1573
6. R. Mondal, A. D. Gupta, A. K. Mallik, Tetrahedron Lett. 52 (2011) 5020
7. G. J. Sagrera, G. A. Seoane, J. Braz. Chem. Soc. 16 (2005) 851
8. B. K. Liu, Q. Wu, X. Q. Qian, D. S. Lv, X. F. Lin, Synthesis (2007) 2653.
Available online at www.shd.org.rs/JSCS/
___________________________________________________________________________________________________________________
Copyright (C)2013 SCS

Copyright of Journal of the Serbian Chemical Society is the property of National Library of
Serbia and its content may not be copied or emailed to multiple sites or posted to a listserv
without the copyright holder's express written permission. However, users may print,
download, or email articles for individual use.