Silica-gel-supported Ce(SO4)2·4H2O-mediated cyclization of 2′-amino and 2′-hydroxychalcones under solvent-free conditions

Article abstract of DOI:10.1080/00397911.2016.1230217

A simple, efficient, and environmentally friendly approach for the synthesis of flavones, aza-flavones, and aza-flavanones from corresponding 2′-hydroxy or 2′-aminochalcones has been developed. The reactions are successfully conducted in presence of silica-gel-supported Ce(SO₄)₂·4H₂O under solvent-free conditions.

Full text of DOI:10.1080/00397911.2016.1230217

Silica gel supported-Ce(SO4)2·4H2O mediated cyclization of 2′-amino and
2′-hydroxychalcones under solvent-free conditions
Ruihuan Liu1,2, Yan Zhang2, Kangpin Xu2, Guishan Tan1,2
1Xiangya hospital, Central South University, Changsha, PR China, 2School of
Pharmaceutical Sciences, Central South University, Changsha, PR China
Corresponding author Guishan Tan, . E-mail: tgs395@csu.edu.cn
Abstract
A simple, efficient and environmentally friendly approach for the synthesis of flavones,
aza-flavones, and aza-flavanones from corresponding 2′-hydroxy or 2′-aminochalcones
has been developed. The reactions are successfully conducted in presence of silica gel
supported- Ce(SO4)2•4H2O under solvent free conditions.
GRAPHICALABSTRACT
KEYWORDS: 2′-hydroxychalcones; 2′-aminochalcones; Silica gel
supported-Ce(SO4)2•4H2O; flavones; aza-flavonoids
INTRODUCTION
Substituted flavonoids and aza-flavonoids are important naturally occurring compounds
isolated from various plants, and show a wide range of biological activities such as
1

antibacterial [1-4], anticancer [5,6], and anti-inflammatory [7,8], etc. [9-12]. Generally, their
synthesis is of considerable interest. Most of the existing procedures were carried out via
Michael reaction of 2′-hydroxy and 2′-aminochalcone in presence of various catalysts such
[19]
as NH4I[13], oxalic acid [14], Na2SeO3 [15], I2 [16], SPB [17], FeCl3 [18], NaHSO4-SiO2
,
[bmin][BF4] [20], etc. [21-31]
.
Generally, the cyclization of 2′-hydroxy and 2′-aminochalcone were carried out using
different adducts. Although all of these procedures are effective, many of them involve
toxic or expensive reagents [21-24], long reaction time [25], low yield [26], and use of excess of
organic solvent [27]. Thus, there remains a need to develop a practical, mild and
environmentally friendly protocol for the synthesis of flavones and aza-flavonoid.
Recently, organic reactions under solventless conditions have been increasingly attractive
to synthetic organic chemists because of their simplicity and synthetic value. Moreover,
solventless reactions have many advantages, including commercial viability,
ecofriendliness, and operational simplicity. In the last decades, applications of lanthanide
reagents cover almost every aspect of organic transformations, and they represent ideal
promoters for being applied widely. And some lanthanide reagents have been developed
as good catalysts for the synthesis of flavones or aza-flavonoids [23, 28-30]. Cerium, which
is the most abundant element in the lanthanide series, is more inexpensive and abundant
than other lanthanides. Cerium compounds have been widely used in variety of
2

transformations. Particularly, alumina supported CeCl3•7H2O-NaI have emerged as an
efficient catalyst for the isomerization of 2′-aminochalcones to the corresponding
aza-flavonones [30], which failed to promote the cyclization of 2′-hydroxychalcones.
Herein, we wish to report a mild and efficient method for the synthesis of flavones and
aza-flavonoids via the oxidative cyclization of the corresponding chalcones mediated by
silica supported-Ce(SO4)2•4H2O. This stable catalyst is easily prepared, safely handled,
active under solvent-free conditions and employed under environmentally friendly
conditions.
RESULTS AND DISCUSSION
Initial study was performed by absorbing 2′-hydroxychalcone (1a) on silica gel
supported-Ce(SO4)2•4H2O (1 equiv Ce(SO4)2•4H2O), heating the reaction mixture at 100
°C. The crude product was obtained along with largely starting material. Inspired by this
result, the cyclization of 2′-hydroxychalcone (1a) was chosen as a model reaction. In
order to optimize the reaction conditions, various factors including amounts of oxidant,
reaction time, and reaction temperature were investigated. The results are shown in Fig.
1.
In order to investigate the appropriate amount of silica gel supported-Ce(SO4)2•4H2O, the
influence of the amount of silica gel supported-Ce(SO4)2•4H2O on oxidation of 1a into 2a
was examined at 100 °C with a reaction time of 4h, and the results are given in Fig. 1(a).
3

It can be found that the yield of 2a reached a maximum when the amount of silica gel
supported-Ce(SO4)2•4H2O was 2.5 equiv. The yield of 2a was almost unchanged as the
loading of silica gel supported-Ce(SO4)2•4H2O increased from 2.5 equiv to 3.0 equiv.
Thus, a dosage of 2.5 equiv was adopted to obtain acceptable reaction rate and yield. We
also investigated the effect of reaction temperature on the cyclization of 1a. In the low
temperature range (<75 °C), the reaction processed slowly with a flavone yield less than
30% with 4h, and no flavanone was detected. Increasing the temperature could enhance
the yield significantly. The yield of flavone reached 94% when the temperature increased
from 70°C to 100 °C and then slowly decreased to 85% when the reaction temperature
increased to 130°C. In the reaction system, the oxidative cyclization of chalcone was
accelerated by increasing temperature, but chalcone or the desired product may be
decomposed at higher temperature. Thus, 100°C is high enough to obtain satisfactory
reaction rate and flavone yield. Based on the results above, we studied the influence of
reaction time at 100 °C. From Fig. 1(c), we can see that when the reaction was conducted
at 100 °C, the yield increased gradually with time at the beginning, and reached the
maximum 94% at 4 h. With these preliminary results, in order to demonstrate the general
applicability of silica gel supported-Ce(SO4)2•4H2O as an oxidizing agent for
2′-hydroxychalcone cyclization, a wide range of substrates were treated as described
above and the results are summarized in Table 1. As shown in Table 1, the substrates
with electron-withdrawing or electron-donating groups were well tolerated and the
products were obtained in excellent yields; the assigned structures were confirmed by
4

their spectral properties (1H NMR, 13C NMR and HRMS) and by comparison with
literature data.
The success encountered in the synthesis of flavones prompted us to study the action of
silica gel supported-Ce(SO4)2•4H2O on 2′-aminochalcones. 2′-aminochalcone (3a) was
subjected to the similar reaction conditions afforded to a complex mixture of
aza-flavanone (4a) and aza-flavone (5a), together with unknown byproducts. In order to
optimize the reaction temperature, the cyclization of 2′-aminochalcone (3a) was carried
out at various temperatures (Fig. 1(d)). The reaction gave a mixture of aza-flavanone (4a)
and aza-flavone (5a) when the reactions were carried out at 70-110°C. With increasing
the temperature from 70 °C to 110°C, the yield of aza-flavanone (4a) was decreased and
the yield of aza-flavone (5a) was increased. These results indicated that aza-flavanones
maybe the intermediate for further be oxidized to the final product, aza-flavone. As
shown in Fig. 1(d), it could be found that 70 °C is the optimum temperature to get
satisfactory yield of aza-flavanone, as well as aza-flavone was obtained in 91% yield
under 110 °C. Hence, we attempted to subject a wide range of substituted
2′-aminochalcones to the similar reaction conditions, with the exception of reaction
temperature. To our delight, the reaction proceeded in a similar fashion, and substituted
aza-flavanones and aza-flavones were yielded in moderate yields (Table 2).
5

Although the oxidative cyclization of chalcones with silica gel supported-Ce(SO4)2•4H2O
required higher catalyst loading, a wider range of substrates (2′-hydroxychalcones and
2′-aminochalcones) was tolerated. Under above conditions, a number of substituted
2′-hydroxy and 2′-aminochalcone derivatives were found to give the corresponding
flavones, aza-flavanones, and aza-flavones, respectively. Compared to previously
reported methods (listed in Table 3), which still have some limitations, such as need of
aqueous workup, high cost, or removal of metal ions as a water-soluble complex, the use
of silica gel supported-Ce(SO4)2•4H2O as oxidizing agent in these reactions have
advantages of high yields, simple work-up and low cost. According to literature, the
plausible mechanism for the cyclization of 2′-hydroxychalcones and 2′-aminochalcones
were performed in Scheme 1.
Finally, we also tried to cyclize chalcones (1a and 2a) to their corresponding flavonoids
under the same reaction conditions as described above, except using the recovered
catalyst. The recovered catalyst was isolated from the reaction mixture at the end of the
reaction, washed with methanol, and then dried at 50 °C under vacuum. Unfortunately,
no appreciable conversion of chalcones was observed.
EXPERIMENTAL SECTIONS
Starting materials were purchased from commercial sources and all solvents were used
without further purification. Melting points were recorded on a YRT-3 melting point
6

apparatus and are uncorrected. NMR spectra were recorded on Avance III 400 MHz and
Avance III 500 MHz Bruker spectrometers [DMSO-d6 as solvent and TMS as internal
standard, chemical shifts (δ scale) are reported in parts per million (ppm). High resolution
electrospray ionization mass spectroscopy (HRESIMS) was performed in an Agilent
Technologies liquid chromatograph connected to Q-TOF mass spectra. Silica gel (200–300
mesh) was purchased from the Qingdao Marine Chemical Factory (Qingdao, China).
Typical Procedure for the Synthesis of 2-Aryl-4H-Chromen-4-Ones (2)
Silica gel (5.05 g, Qingdao Haiyang China, 200-300 mesh) was added to a stirred mixture
of Ce(SO4)2•4H2O (5.05 g, 12.5 mmol) and H2O, and further stirred overnight. After
removing solvent in vacuo, the resulting powdered mixture was added to
2′-hydroxychalcones (1, 5.0 mmol, dissolved in a minimum amount of ethyl acetate). The
solvent was removed by heating and the dry mixture is stirred at 100 ℃. After the
completion of reaction (by TLC monitoring), the mixture was cooled to room
temperature. The crude products were obtained by washing with ethyl acetate and solvent
evaporation. The crude products were purified by recrystallization or column
chromatography to give the desired product.
Typical Procedure for the Synthesis of 2-Aryl-2,3-Dihydroquinoline-4(1H)-Ones (4)
Silica gel (5.05 g, Qingdao Haiyang China, 200-300 mesh) was added to a stirred mixture
of Ce(SO4)2•4H2O (5.05 g, 12.5 mmol) and H2O, and further stirred overnight. After
7

removing solvent in vacuo, the resulting powdered mixture was added to
2′-aminochalcones (3, 5.0 mmol, dissolved in a minimum amount of ethyl acetate). The
solvent was removed by heating and the dry mixture is stirred at 60 ℃. After the
completion of reaction (by TLC monitoring), the mixture was cooled to room
temperature. The crude products were obtained by washing with ethyl acetate and solvent
evaporation. The crude products were purified by recrystallization or column
chromatography to give the desired product.
Typical Procedure for the Synthesis of 2-Aryl-Quinolin-4(1H)-Ones (5)
Silica gel (5.05 g, Qingdao Haiyang China, 200-300 mesh) was added to a stirred mixture
of Ce(SO4)2•4H2O (5.05 g, 12.5 mmol) and H2O, and further stirred overnight. After
removing solvent in vacuo, the resulting powdered mixture was added to
2′-hydroxychalcones (3, 5.0 mmol, dissolved in a minimum amount of ethyl acetate). The
solvent was removed by heating and the dry mixture is stirred at 110 ℃. After the
completion of reaction (by TLC monitoring), the mixture was cooled to room
temperature. The crude products were obtained by washing with ethyl acetate and solvent
evaporation. The crude products were purified by recrystallization or column
chromatography to give the desired product.
Spectral Data for Selected Compounds
8

Compounds 2a-l, 4a-g, and 5b-f are known compounds, compounds 5a and 5g are novel
compounds.
2-Phenyl-4H-Chromen-4-One (2a) [32]
Purification by recrystallization frome 95% ethanol gave 2a as pale white solid; yield: 1.04
g (94%). 1H NMR (500 MHz, DMSO-d6): δ = 8.13 (dd, J = 7.9, 1.4 Hz, 2 H), 8.07 (dd, J =
7.9, 1.4 Hz, 1H), 7.85 (td, J = 7.7, 1.6 Hz, 1H), 7.81 (d, J = 7.9 Hz, 1H), 7.65 – 7.58 (m, 3H),
7. 52 (td, J = 7.4, 1.0 Hz, 1H), 7.07 (s, 1H). 13C NMR (125 MHz, DMSO-d6): δ = 177.6,
163.1, 156.2, 134.8, 132.3, 131.6, 129.6, 126.8, 126.0, 125.3, 123.8, 119.1, 107.4. MS
(ESI): m/z [M+H]+ 223.08.
2-(2-Methylphenyl)-2,3-Dihydroquinoline-4(1H)-One (4a) [6]
Purification by recrystallized from ethyl acetate gave 4a as yellow solid; yield: 0.95 g
(80%). 1H NMR (500 MHz, DMSO-d6): δ = 7.62 (dd, J = 8.0, 1.7 Hz, 1H), 7.60 (d, J = 6.5
Hz, 1H), 7.32 (td, J = 7.0, 1.7 Hz, 1H), 7.28 – 7.20 (m, 3H), 7.00 (s, 1H), 6.89 (dd, J = 8.4,
1.0 Hz, 1H), 6.65 (td, J = 7.0, 1.0 Hz, 1H), 4.95 (dd, J = 13.2, 4.0 Hz, 1H), 2.74 (dd, J =
16.1, 13.2 Hz, 1H), 2.61 (dd, J = 16.1, 4.0 Hz, 1H), 2.36 (s, 3H). 13C NMR (125 MHz,
DMSO-d6): δ = 193.0, 153.4, 134.0, 135.6, 135.4, 131.0, 127.9, 126.8, 126.7, 126.7, 118.0,
116.9, 116.8, 53.4, 44.6, 19.2. MS(ESI): m/z [M+H]+ 238.13.
2-(2-Methylphenyl)Quinolin-4(1H)-One (5a)
9

Purification by recrystallized from ethyl acetate gave 5a as yellow solid; yield: 1.07 g
(91%). 1H NMR (500 MHz, DMSO-d6): δ = 11.81 (s, 1H), 8.13 (dd, J = 8.1, 1.4 Hz, 1H),
7.67 (ddd, J = 8.4, 6.8, 1.6 Hz, 1H), 7.62 (dd, J = 8.4, 1.2 Hz, 1H), 7.48 – 7.42 (m, 2H), 7.41
(d, J = 7.4 Hz, 1H), 7.39 – 7.36 (m, 1H), 7.36 – 7.32 (m, 1H), 5.97 (d, J = 1.7 Hz, 1H), 2.32
(s, 3H). 13C NMR (125 MHz, DMSO-d6): δ = 177.2, 151.1, 140.7, 136.1, 135.5, 132.2,
131.0, 130.1, 129.5, 126.5, 125.3, 125.1,123.7, 118.9, 109.8, 21.5. HRMS (ESI): m/z
[M+H]+ calcd for C16H13NO 236.1070, found 236.1076.
2-(3-Nitrophenyl)Quinolin-4(1H)-One (5g)
Purification by recrystallized from ethyl acetate gave 5a as yellow solid; yield: 1.25 g
(94%). m.p. >365°C; 1H NMR (500 MHz, DMSO-d6): δ = 11.96 (s, 1H), 8.69 (t, J = 2.1 Hz,
1H), 8.43 – 8.38 (m, 1H), 8.33 (d, J = 7.7 Hz, 1H), 8.12 (dd, J = 8.1, 1.5 Hz, 1H), 7.87 (t, J
= 8.0 Hz, 1H), 7.79 (d, J = 8.4 Hz, 1H), 7.72 (ddd, J = 8.5, 6.9, 1.6 Hz, 1H), 7.41 – 7.35 (m,
1H), 6.54 (s, 1H). 13C NMR (125 MHz, DMSO-d6): δ = 177.5, 148.5, 146.5, 142.5, 136.6,
134.5, 132.4, 131.1, 127.7, 125.4, 125.0, 124.2, 123.7, 122.6, 119.0, 108.2. HRMS (ESI):
m/z [M+H]+ calcd for C15H10N2O3 267.0764, found 267.0762.
CONCLUSION
In summary, the present procedure mediated by Ce(SO4)2•4H2O supported by silica gel
provides an operationally simple and environmentally friendly procedure for the
preparation of flavones and aza-flavonoids by the cyclization of the corresponding
10

2′-hydroxychalcones and 2′-aminochalcones. In addition, low cost, easy availability, low
toxicity, excellent yields of products, and the fairly mild reaction conditions make this
protocol convenient for applications.
ACKNOWLEDGMENTS
This work was supported by National Natural Science Foundation of China for financial
support (No. NSFC 31370370); Science and technology planning project of Hunan
province, China (No. 2013SK5077, 2014SK2002), Key Researching and Transforming
Project of Science and Technology of strategic emerging industry of Hunan Province
(No. 2015GK1053).
SUPPLEMENTAL MATERIAL
Full experimental detail, 1H NMR and 13C NMR spectra for all the products. This
material can be found via the “Supplementary Content” section of this article’s webpage.
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Table 1. Synthesis of flavones catalyzed by silica supported-Ce(SO4)2•4H2O a
Entry 2′-hydroxychalcone R1
R2
Time [h] Product
Yield b
[%]
94
1
H
H
H
H
H
H
H
H
H
H
H
4
4
4
4
4
4
4
3
3
4
2
4
2a [32]
2b [32]
2c [32]
2d [32]
2e [33]
2f [33]
2g [32]
2h [34]
2i [35]
2j [36]
2k [37]
2l [38]
1a
1b
1c
1d
1e
1f
2
2′-OCH3
3′-OCH3
4′-OCH3
2′-CH3
3′-CH3
4′-CH3
3′-Cl
92
3
94
4
95
5
89
6
90
7
92
1g
1h
1i
8
88
9
2′-F
93
10
11
12
4′-OBn
94
1j
5,7-OCH3 4′-NO2
5,7-OCH3 4′-OBn
93
1k
1l
94
aReaction conditions: Substrate (5.0 mmol) and silica supported-Ce(SO4)2•4H2O (10.1 g)
were kept at 100 °C.
bIsolated yield.
15

Table 2. Synthesis of aza-flavonoids catalyzed by silica supported-Ce(SO4)2•4H2O a
Entry 2′-aminochalcone R
Temp
[°C]
70
Time [h] Product
Yield b
[%]
80
(4/5)
1
2′-CH3
1.5
2.5
1.5
2.5
2.0
2.5
2.0
2.5
1.5
2.5
2.5
3.0
2.0
1.5
4a [6]
5a
3a
3a
3b
3b
3c
3c
3d
3d
3e
3e
3f
2
2′-CH3
3′-CH3
3′-CH3
4′-CH3
4′-CH3
110
70
91
3
4b [6]
5b [39]
4c [19]
5c [40]
4d [6]
5d [41]
4e [23]
5e [42]
4f [23]
5f [43]
4g [23]
5g
86
4
110
70
87
5
85
6
110
90
7
2′-OCH3 70
2′-OCH3 110
3′-OCH3 70
3′-OCH3 110
83
8
88
9
85
10
11
12
13
14
91
4′-Cl
70
81
4′-Cl
110
70
91
3f
3-NO2
3-NO2
83
3g
3g
110
94
16

aReaction conditions: Substrate (5.0 mmol) and silica supported-Ce(SO4)2•4H2O (10.1 g)
were heated for 1-3h.
bIsolated yield.
17

Table 3. Comparison silica gel supported-Ce(SO4)2•4H2O with other catalysts for the
cyclization of 2′-hydroxy and 2′-aminochalcones
Entr Substra Adducts
Temp
[°C]
70
Time Produ Yield[
y
1
te
[h]
2
ct
%]
Alumina
98[30]
3a
4a
supported-CeCl3•7H2O-NaI a
a
2
3
4
5
6
Silica gel supported InBr3
140
150
65
0.75
0.17
10
3
96[44]
92[22]
55[18]
71[25]
94
1a
3a
1a
1a
1a
2a
4a
2a
2a
2a
a
silica gel supported TaBr5
FeCl3•6H2O a
CuI a
130
110
silica gel
4
supported-Ce(SO4)2•4H2O b
silica gel
7
8
70
1.5
2.5
80
91
3a
3a
4a
5a
supported-Ce(SO4)2•4H2O b
silica gel
110
supported-Ce(SO4)2•4H2O b
aReaction data were obtained from corresponding literatures.
bReaction data were obtained from our experiments.
18

Scheme 1. Postulated catalytic pathway for silica gel supported-Ce(SO4)2•4H2O mediated
reaction.
19

Figure 1. Optimized conditions of the cyclization of 2′-hydroxy and 2′-aminochalcones. a)
Influence of the amount of Ce(SO4)2•4H2O on 2a yield. Reaction conditions: 1a (5mmol),
silica gel-supported Ce(SO4)2•4H2O, stirring at 100 ℃for 4h; b) Influence of temperature
on 2a yield. Reaction conditions: 1a (5mmol), silica gel-supported Ce(SO4)2•4H2O (250
mol%), heating for 4h; c) Influence of reaction time on 2a yield. Reaction conditions: 1a
(5mmol), silica gel-supported Ce(SO4)2•4H2O (250 mol%), stirring at 110 ℃; d) Influence
of temperature on 4a and 5a yields. Reaction conditions: 3a (5mmol), silica gel-supported
Ce(SO4)2•4H2O (250 mol%), heating for 4h.
20