An efficient catalytic synthesis of flavanones under green conditions

Article abstract of DOI:10.3184/174751911X13014075196818

An efficient and "green" catalytic conversion of 2′-hydroxychalcones to flavanones in 15 min in the presence of a simple amino acid and a base at room temperature is reported. Liquiritigenin was also efficiently synthesised under these conditions.

Full text of DOI:10.3184/174751911X13014075196818

220 RESEARCH PAPER
APRIL, 220–221
JOURNAL OF CHEMICAL RESEARCH 2011
An efficient catalytic synthesis of flavanones under green conditions
Heyan Jiang, Xuxu Zheng*, Zhongyi Yin and Jingjing Xie
Medicinal Chemistry and Chemical Biology Research Center, School of Environmental and Biological Engineering, ChongqingTechnology
and Business University, Chongqing 400067, P. R. China
An efficient and “green” catalytic conversion of 2’-hydroxychalcones to flavanones in 15 min in the presence of a
simple amino acid and a base at room temperature is reported. Liquiritigenin was also efficiently synthesised under
these conditions.
Keywords: green chemistry, 2′-hydroxychalcone, flavanone, amino acid, liquiritigenin
Table 1 Effect of different bases in the catalytic cyclisationa
Flavanones are pharmacologically important naturally occur-
ring compounds.1 showing biological activity as hypertensive,
antibacterial, antitumor, antifungal, and anti-inflammatory
agents. The synthesis of these compounds has generated sig-
nificant interest among chemists and biologists.2,3 The pre-
paration of flavanones has been carried out by intramolecular
cyclisation of 2′-hydroxychalcone under various conditions
Yield/%b
using acids,4 bases,5 thermolysis,6 electrolysis,7 photolysis8 and
microwave irradiation.9 However, the yields of these reactions
are often moderate, the reaction times are long and the separa-
tion of these products requires a lot of organic solvent such as
benzene. Tanaka has shown that 2′-hydroxychalcones can be
converted into flavanones under mild conditions in an hour.
However, the reaction time is still long when compared to
microwave irradiation assisted catalysis.9 We report here that
2′-hydroxychalcones can be converted into flavanones very
efficiently under mild green conditions, within a reaction time
that is comparable to microwave irradiation assisted catalysis.9
Furthermore, an efficient catalytic synthesis of Liquiritigenin
is also reported under these conditions.
Entry
Base
1
2
3
4
5
6
LiOH
55
98
>99
21
1
NaOH
KOH
Ca(OH)2
Na2CO3
Triethylamine
63
a All other conditions are the same with ref. 5.
b No optical rotation was observed during optical rotation test.
Table 2 Effect of different amino acids in the catalytic
cyclisationa
Result and discussion
L-Alanine, the best amino acid additive in the presence of
NaOH described previously,5 was employed as the first addi-
tive to test different kinds of bases in the catalytic conversion
of 2′-hydroxychalcones to flavanones. Table 1 shows that 1a
can be converted to 2a efficiently at room temperature within
1h in the presence of NaOH or KOH. Comparison of the alkali
hydroxides as bases showed that catalytic activities increase in
the order of KOH > NaOH > LiOH. When other bases were
introduced, poor to moderate activities are obtained. The
conclusion was that a strong base was associated with high
cyclisation activity.
Different amino acid additives were examined to further
enhance the catalytic activities in the presence of KOH.
Table 2 shows that 1a can be converted to 2a in just 6% yield
in 15 min in the absence of amino acid. However, 1a can be
completely converted to 2a very easily in the presence of most
amino acids in 15 min. This reaction time is comparable to
that of microwave irradiation assisted catalysis.9 The highest
activity is obtained in the presence of L-proline. There was no
Entry Amino acid
pKa b
Yield/%c
10 min
15 min
1
None
6
>99
>99
61
2
L-Alanine
9.69
9.13
9.62
9.13
9.67
10.40
9.15
9.17
9.60
9.60
9.68
84
93
54
68
87
92
76
77
75
66
78
3
L-Proline
L-Valine
4
5
L-Phenylalanine
L-Glutamic acid
L-Threonine
L-Serine
L-Histidine
L-Glycine
90
6
99
7
>99
>99
>99
93
8
9
10
11
12
L-Leucine
L-Isoleucine
85
93
a All other conditions are the same as Table 1.
b pKa of amino group in amino acid.
c No optical rotation was observed during optical rotation test.
Scheme 1 Catalytic cyclisation of Isoliquiritigenin. Conditions are the same with Table 1, no optical rotation of product was
observed during the optical rotation test.
* Correspondent. E-mail: xuxuzheng@ctbu.edu.cn

JOURNAL OF CHEMICAL RESEARCH 2011 221
Table 3 Cyclisation of different 2’-hydroxychalcones in the
collected by filtration, washed with water and dried in a desiccator
presence of proline and KOHa
to give flavanone 2a. All prepared products are known compounds
1
and were identified by m.p., IR and H NMR. The products did not
show any optical rotation.
2a: M.p. 74–75 °C (lit.5 75–76 °C); IR(KBr): v(C=O) 1715cm−1;
δH(300 MHz, CDCl3) 7.04–7.94 (m, 9H), 5.50 (dd, J = 3.0, 13.0 Hz,
1H), 3.12 (dd, J = 12.9, 16.2, 1H), 2.88 (dd, J = 2.7, 16.2, 1H).
2b: M.p. 96–97 °C (lit.12 95–97 °C); IR(KBr): v(C=O) 1685cm−1;
δH(300 MHz, CDCl3) 7.09–7.89 (m, 8H), 5.66 (dd, J = 2.7, 10.2 Hz,
1H), 2.70–3.15 (m, 2H).
Substrate
Ar
Yield (%)b
2c: M.p. 97–99 °C (lit.13 98–99 °C); IR(KBr): v(C=O) 1695cm−1;
δH(300 MHz, CDCl3) 7.10–7.90 (m, 8H), 5. 44–5.47 (m, 1H), 2.83–
3. 15 (m, 2H).
1a
1b
1c
1d
1e
1f
C6H4
o-ClC6H4
>99
89
94
95
75
95
50
85
m-ClC6H4
p-ClC6H4
o-MeOC6H4
m-MeOC6H4
p-MeOC6H4
p-NO2C6H4
2d: M.p. 94–96 °C (lit.9 95–96 °C); IR(KBr): v(C=O) 1690cm−1;
δH(300 MHz, CDCl3) 7.03–7.65 (m, 8H), 5.43–5.46 (m, 1H), 2.82–
3.06 (m, 2H).
2e: M.p. 81–82 °C (lit.12 80–82 °C); IR(KBr): v(C=O) 1685cm−1;
δH(300 MHz, CDCl3) 6.84–8.60 (m, 8H), 5.75 (dd, J = 12.5, 3.0 Hz,
1H), 3.72 (s, 3H), 2.91 (dd, J = 17.0, 3.0, 1H), 2.83 (dd, J = 17.0, 12.6,
1H).
1g
1h
a All other conditions are the same with Table 1.
b No optical rotation was observed during optical rotation test.
2f: M.p. 79–80 °C (lit.14 78–79 °C); IR(KBr): v(C=O) 1685cm−1;
δH(300 MHz, CDCl3) 6.93–8.55 (m, 8H), 5.75 (dd, J = 12.0, 3.6 Hz,
1H), 3.70 (s, 3H), 2.82–3.12 (m, 2H).
2g: M.p. 86–88 °C (lit.9 87–88 °C); IR(KBr): v(C=O) 1690cm−1;
δH(300 MHz, CDCl3) 6.96–7.91 (m, 8H), 5.40 (dd, J = 2.7, 13.5 Hz,
1H), 3.80 (s, 3H), 2.86–3.15 (m, 2H).
clear relationship between the pKa of the amino group in
amino acid additives and the cyclisation activity. We speculate
that both this property of amino group and steric hinderance of
amino acid additives affect the cyclisation activity.
Some representative examples are listed in Table 3 for the
cyclisation of different 2′-hydroxychalcones in the presence
of L-proline and KOH. The extent of activities appears to be
delicately influenced by the structure and the electron proper-
ties of substrates. Cyclisation of 2′-hydroxychalcone 1a gave
the best activity. When comparing the chloro-substituents,
the steric hinderance clearly influences the catalytic activity,
in the order of p-Cl > m-Cl > o-Cl. However, as in the previous
report,5 electronic properties may play the main role in
substrates possessing a methoxy substituent.
Liquiritigenin 4 is wildly used as an anti-ulcer agent, in the
prevention of atherosclerosis, in the inhibition of monoamine
oxidase, in the treatment of mental depression, anti-virus,
and as an anti-viral agent. However, liquiritigenin has been
prepared in moderate yield at high temperature over a long
time.10,11 Purification of the product in these reports requires
a lot of organic solvent. We applied our optimized catalytic
conditionstothepreparationofliquiritigenin4fromisoliquiriti-
genin 3 (Scheme 1). Liquiritigenin was obtained in high yield
under mild green conditions with simple work-up procedure.
In conclusion, we have shown that different flavanones can
be prepared from 2′-hydroxychalcones very efficiently under
mild green condition. Further work on the mechanism and on
the asymmetric cyclisation employing amino acids and their
derivatives as catalysts is in progress.
2h: M.p. 140–142 °C (Authentic product from TCI 141–142 °C);
IR(KBr): v(C=O) 1685cm−1; δH(300 MHz, CDCl3) 7.02–7.56 (m, 8H),
5.44–5.47 (m, 1H), 2.82–3.12 (m, 2H).
4: M.p. 196–197 °C (lit.10 195–197 °C); IR(KBr): v(C=O) 1660cm−1;
δH(300 MHz, acetone-d6) 9.20 (br, 1H), 8.40 (br, 1H), 7.71 (d, J =
8.5 Hz, 1H), 7.38 (d, J = 8.7 Hz, 2H), 6.84 (d, J = 8.6 Hz, 2H),
6.51 (dd, J = 2.3, 8.8 Hz, 1H), 6.41 (d, J = 2.3 Hz, 1H), 5.44 (dd, J =
3, 12.9 Hz, 1H), 3.06 (dd, J = 12.0, 16.2 Hz, 1H), 2.66 (dd, J = 3,
10.8 Hz, 1H).
This work was supported by grants from Ministry of Educa-
tion of the People’s Republic of China (No. 208119), Innova-
tive Research Team Development Program in University of
Chongqing (No. KJTD201020) and Chongqing Technology
and Business University (No. yjscxx2009-07).
Received 22 January 2011; accepted 11 March 2011
Paper 1100544 doi:10.3184/174751911X13014075196818
Published online: 3 May 2011
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