Facile one-pot synthesis of flavanones using tetramethylguanidinum-based ionic liquids as catalysts

Article abstract of DOI:10.1007/s10562-015-1581-9

Several tetramethylguanidinum-based ionic liquids (TMGILs) were prepared, characterized and used as catalysts in one-pot synthesis of flavanones. The results indicated that TMGILs composed of phenolate anion was beneficial for one-pot synthesis of flavanones, and [TMG][4-MeO-PhO] induced the good yields of flavanones owing to the electron-donating effect of methoxy substituent on phenolate anion. Furthermore, [TMG][4-MeO-PhO] was found to be used repetitively at least five times without obvious decrease in activity and quantity.

Full text of DOI:10.1007/s10562-015-1581-9

Catal Lett
DOI 10.1007/s10562-015-1581-9
Facile One-Pot Synthesis of Flavanones Using
Tetramethylguanidinum-Based Ionic Liquids as Catalysts
Yan Zhou1 Wei Huang1 Xiang-Shu Chen1 Zhi-Bin Song1 Duan-Jian Tao1
•
•
•
•
Received: 6 May 2015 / Accepted: 5 July 2015
Ó Springer Science+Business Media New York 2015
Abstract Several tetramethylguanidinum-based ionic
liquids (TMGILs) were prepared, characterized and used as
catalysts in one-pot synthesis of flavanones. The results
indicated that TMGILs composed of phenolate anion was
beneficial for one-pot synthesis of flavanones, and
[TMG][4-MeO–PhO] induced the good yields of
flavanones owing to the electron-donating effect of meth-
oxy substituent on phenolate anion. Furthermore,
[TMG][4-MeO–PhO] was found to be used repetitively at
least five times without obvious decrease in activity and
quantity.
Graphical Abstract
Keywords Ionic liquid Á Flavanones Á One-Pot synthesis Á
Phenolate anion
Electronic supplementary material The online version of this
article (doi:10.1007/s10562-015-1581-9) contains supplementary
material, which is available to authorized users.
1 Introduction
& Xiang-Shu Chen
cxs66cn@jxnu.edu.cn
As being the secondary metabolites in plant, flavanones are
the important precursors for the production of many valu-
able-added flavanone derivatives such as flavones, iso-
flavones, flavonols and dihydroflavonols [1]. Thus, over the
past decade, significant efforts have been put into devel-
oping efficient synthetic strategies to prepare flavanones,
& Zhi-Bin Song
zbsong@jxnu.edu.cn
1
Key Laboratory of Functional Small Organic Molecules,
Ministry of Education, College of Chemistry and Chemical
Engineering, Center of Analysis and Testing, Jiangxi Normal
University, Nanchang 330022, People’s Republic of China
123

Y. Zhou et al.
CHO
O
O
Claisen-Schmidt
condensation
OH
O
OH
O
Cyclization
R1
R1
R2
+
R1
R2
R2
H
2O
Scheme 1 Two-step routes for the synthesis of flavanones
including condensation of phenylpropiolic acid with phe-
nols [2, 3], microwave-irradiation of phloroglucinol and b-
ketoesters [4], intramolecular cyclization of 20-hydroxy-
chalcones [5].
purity C99.5 %), 4-fluorophenol
(4-F-PhOH,
pur-
ity C99 %), and 4-methoxyphenol (4-MeO–PhOH, pur-
ity C99 %) were purchased from Aladdin (Shanghai,
China), and other reagents such as aromatic aldehydes,
ethanol, and ethyl acetate were of analytical grade and used
without any further purification.
In terms of economic and environmental points of view,
the synthesis of flavanones using 20-hydroxychalcones as
raw materials has received significant attention. As shown in
Scheme 1, the two-step protocol for the preparation of fla-
vanones involves the Claisen–Schmidt condensation of
20-hydroxyacetophenone with aldehydes to form 20-hy-
droxychalcones, and follows a cyclization to flavanones. Till
now, various catalysts have been reported for this synthetic
route to preparation of flavanones and their derivatives [6, 7].
For example, silicotungstic acid [8] and animal bone meal
catalysts [9] were used as efficient catalyst for the synthesis
of 20-hydroxychalcones. Silica supported-double metal cya-
nides [10], N-methyl imidazole [11] displayed excellent cat-
alytic performance for isomerisation of 20-hydroxychalcones
to flavanones. Despite the great yields and selectivities, there
has been little mention paid to the one-pot synthesis of fla-
vanones. A facile and efficient one-pot chemosynthesis of
flavanones thus continues to be appealing.
2.2 Catalyst Preparation and Characterization
Five TMGILs were prepared by the neutralization reactions
of tetramethylguanidine with acetic acid, glycine, phenol,
4-fluorophenol, and 4-methoxyphenol, respectively
(Scheme 2). The preparation process was similar to the
procedure described in our previous work [15]. All the
yields of these TMGILs were more than 90 %, and the
structures of TMGILs were then confirmed by 1H, 13C
NMR and FT-IR spectroscopy (available as the supple-
mentary data).
2.3 Evaluation of Catalysts
In a typical run, the one-pot reaction was carried out in a
25 mL stainless round-bottomed flask equipped with a
magnetic stirrer and reflux condenser. Weighed amounts of
20-hydroxyacetophenone, aldehyde, solvent and TMGIL
catalyst were mixed and allowed to proceed for 2–9 h with
the vigorous stirring and heating at the designed tempera-
ture. Qualitative analyses of products were examined by a
Thermo Trace 1300 GC-ISQ. For ingredient of products
analysis, the reaction samples were collected and analyzed
periodically by a gas chromatography-flame ionization
detector (GC-FID) (Agilent 7890B, HP-5 column,
30 m 9 0.32 mm 9 0.25 lm). Nitrogen was used as the
carrier gas at a flow rate of 1.5 mL/min. The detailed
temperature conditions were described as follows: the
injector and detector temperatures were set as 250 and
Recently, ionic liquids (ILs) have been attracting attention
in the synthesis of heterocyclic compounds due to their
specific properties such as designable structure, low volatility,
high thermal and chemical stability [12, 13]. As our continu-
ous work on the synthesis and utilization of ILs in green and
sustainable catalysis [14], five tetramethylguanidinum-based
ionic liquids (TMGILs) were prepared, characterized, and
used as catalysts for one-pot synthesis of flavanones in this
work. The reaction parameters such as reaction time, solvent,
temperature, catalystdosage, andmolarratioofreactantswere
studied in detail to obtain the optimum conditions. In addition,
the reusability of TMGILs was explored, and a plausible
reaction mechanism involving the catalytic role of phenolate
anion of TMGILs was then proposed.
2 Experimental
2.1 Materials
NH2
N
NH
r.t.
R
H R
+
N
N
N
Tetrahydrofurfuryl alcohol (THFA, purity C99 %), 20-hy-
droxyacetophenone (HAC, purity C99 %), 1,1,3,3,-te-
tramethylguanidine (TMG, purity C98 %), phenol (PhOH,
Gly, Ac, PhO, 4-F-PhO, 4-MeO-PhO
=
R
Scheme 2 Structures of TMGILs
123

Facile One-Pot Synthesis of Flavanones Using Tetramethylguanidinum-Based Ionic Liquids as…
250 °C, respectively; the column temperature was
increased stepwise to 220 °C, holding at 80 °C for 3 min,
increasing to 220 °C at 30 °C min-1, holding at 220 °C for
5 min. Then the conversion of 20-hydroxyacetophenone
and selectivity of flavanone were calculated according to
the area of chromatograph peaks using flavone as an
internal standard.
employed. It was demonstrated that these basic catalysts
induced high conversions of 20-hydroxyacetophenone but
their selectivities of flavanone were relatively low (Entries
6–9). This shows that the Claisen–Schmidt condensation
reaction is easily performed in the presence of strong
basic catalysts [16], but the second step of the intercon-
version of 20-hydroxychalcone to flavanone is hard to
carry out.
Moreover, it was indicated that the substituent on phe-
nolate anion had an obvious impact on reaction selectivity.
The electron-donating methoxyl group could improve the
yield of flavanone. With an electron-donating substituent on
phenyl ring, the pKb value of 4-methoxyphenol decreases
(e.g. the pKb of phenol and 4-methoxyphenol is 4.02 and
3.79), and the basicity thus is strengthened [17]. This
implies that 4-methoxyphenate anion could weaken the
intramolecular hydrogen bond interaction of 20-hydroxy-
chalcone effectively, and then 20-hydroxychalcone was
converted to flavanone with a considerable yield (see the
below section of Reaction Mechanism).
3 Results and Discussion
3.1 Catalyst Selection
In order to get the catalytic activity of TMGILs, the
reaction of benzaldehyde and 20-hydroxyacetophenone
was selected as a model reaction, and the results are listed
in Table 1. It was found that TMGILs exhibited various
catalytic activities and the catalytic performances of
TMGILs were closely relevance to the structures of their
anions. For example, [TMG][4-MeO–PhO], [TMG][4-F–
PhO], and [TMG][PhO] catalyzed this reaction to have
excellent conversions of 20-hydroxyacetophenone and
considerable selectivities of flavanone, whereas [TMG]
[Gly] and [TMG][Ac] led to very poor conversions
(Entries 1–5). This implies that TMGILs composed of
phenolate anions are favorable to the one-pot synthesis of
flavanone. For comparison, several conventional basic
catalysts such as TMG, NaOH, K2CO3, and DBU were
In addition, we compared the catalytic performance of
[TMG][4-MeO–PhO] with the results of other catalysts in
the previous literatures [18–25] (Table 2). It was found that
over-high temperature and too long reaction time were
often taken to achieve a moderate catalytic performance.
By contrast, TMGILs composed of phenolate anions
showed better catalytic activities for one-pot synthesis of
flavanone under mild conditions.
Table 1 Catalyst screening for one-pot synthesis of flavanonea
Entry
Catalyst
Conversion of A (%)
Yield (%)b
C
D
1
2
3
4
5
6
7
8
9
a
[TMG][Ac]
[TMG][Gly]
[TMG][PhO]
[TMG][4-F–PhO]
[TMG][4-MeO–PhO]
TMG
8
25
90
86
97
97
94
96
91
4
11
35
27
20
46
46
42
44
4
14
55
59
77
51
48
54
47
NaOH
K2CO3
DBU
Reaction conditions: 70 °C, 8 h, 5 mmol B, molar ratio of A:B = 1:1.3, catalyst (0.3 mol/mol B), 2 mL THFA
Determined by GC
b
123

Y. Zhou et al.
Reference
Table 2 Catalytic performance of various catalysts
Catalyst
Reaction condition
Yield (%)
MgO
160 °C, 90 min, 0.1 wt%, DMSO/4-nitrobenzene
150 °C, 8 h, 0.15 g, free-solvent
60 °C, 8 h, 4.43 mmol, free-solvent
140 °C, 10 h, 0.15 g, free-solvent
80 °C, 18 h, 30 mol%, DMF
140 °C, 6 h, 35 mol%, free-solvent
160 °C, 60 min, 0.1 wt%, DMSO
140 °C, 20 min, 5 wt%, DMF
62
64
58
61
70
68
59
73
77
[18]
SBA-15-NH2
[19]
CHMgO
[20]
Aminopropylated Silica
L-Proline
[21]
[22]
TESP-[MIm]Cl/Zn–Al
[LiAl2(OH)6](CO3)0.5ÁnH2O
Cs-MgO
[23]
[24]
[25]
[TMG][4-MeO–PhO]
70 °C, 8 h, 30 mol%, THFA
This work
Table 3 Effect of solvent on the synthesis of flavanonea
3.2 Optimization of Reaction Conditions
Entry
Solvent
Conversion
of A (%)
Yield(%)b
Firstly, the effect of solvents on the synthesis of flavanone
was investigated and the results are listed in Table 3. It was
indicated that alcohol solvents were better than other sol-
vents in the conversion of 20-hydroxyacetophenone and the
selectivity of flavanone (Entries 1–3). It may be due to the
better solubility of alcohols in this reaction mixture com-
pared with other solvents. THFA was then chosen as sol-
vent for further experiments. Reaction temperature is
essential to the isomerization of 20-hydroxychalcone to
flavanone. As seen from Table 4, flavanone could be
effectively synthesized at a relatively high temperature. For
example, the conversion of 20-hydroxyacetophenone and
selectivity of flavanone increased obviously from 50 °C to
70 °C (Entries 1, 2). However, when the temperature
increased to 100 °C and 130 °C (Entries 3, 4), the con-
version of 20-hydroxyacetophenone and selectivity of fla-
vanone only improved with a limited extent. Therefore, an
optimized reaction temperature would choose at 70 °C.
C
D
1
THFA
94
94
87
81
80
82
85
71
55
66
33
27
31
32
32
34
36
29
27
19
24
10
67
63
55
49
46
46
56
44
36
42
23
2
MeOH
3
EtOH
4
THF
5
DMSO
6
DMF
7
Cyclohexanemethanol
Dimethylacetamide
Dichloromethane
Ethyl acetate
Ethyl lactate
8
9
10
11
a
Reaction conditions: 70 °C, 6 h, 5 mmol B, molar ratio of
A:B = 1:1, [TMG][4-MeO–PhO] catalyst (0.3 mol/mol B), 2 mL
solvent
b
Determined by GC
Table 4 Optimization of other parametersa
Entry
Temperature (°C)
Molar ratio
Catalyst loading (mol/mol B)
Time(h)
Conversion of A (%)
Yield(%)b
C
D
1
2
3
4
5
6
7
8
9
10
a
50
70
1:1
0.3
0.3
0.3
0.3
0.3
0.3
0.3
0.1
0.5
0.7
9
6
4
2
8
5
6
9
5
4
88
94
97
98
97
94
90
42
97
97
29
26
27
27
20
19
18
13
30
31
59
68
70
70
77
75
72
29
67
66
1:1
100
130
70
1:1
1:1
1:1.3
1:1.5
1:2
70
70
70
1:1.3
1:1.3
1:1.3
70
70
Reaction conditions: [TMG][4-MeO–PhO] as catalyst, 5 mmol B, 2 mL THFA
b
Determined by GC
123

Facile One-Pot Synthesis of Flavanones Using Tetramethylguanidinum-Based Ionic Liquids as…
Table 5 One-pot synthesis of various flavanonesa
Entry
R
Conversion of A (%)
Time (h)
Yield (%)c
C
D
1
H
97
99
99
94
95
94
8
20
22
21
29
31
27
77
77
78
65
64
67
2
4-Br
6
3
2-Cl
5
4
4-Me
4-OMe
3,4-OMe
8
5b
6b
a
1.5
2.5
Reaction conditions: 70 °C, 5 mmol B, molar ratio of A:B = 1:1.3, [TMG][4-MeO–PhO] catalyst (0.3 mol/mol B1), 2 mL THFA. Reaction
products were identified by GC–MS
b
Reaction temperature 130 °C
Determined by GC
c
In addition, the effect of molar ratio of benzaldehyde to
20-hydroxyacetophenone on the one-pot reaction was
studied (Table 4). It was showed that increasing the
amount of benzaldehyde was beneficial to the yield of
flavanone. Nevertheless, further increasing the amount of
benzaldehyde did not substantially improve the conversion
of 20-hydroxyacetophenone (Entries 5–7). So the optimal
molar ratio of 20-hydroxyacetophenone to benzaldehyde
suggests to be 1:1.3. The influence of catalyst loading was
also evaluated, and the results showed that catalyst loading
had an obvious effect on the conversion of 20-hydroxy-
acetophenone (Entries 5, 8–10). The conversion of
20-hydroxyacetophenone increased from 42 to 97 % with
the rise of catalyst loading from 0.1 to 0.3 mol/mol.
However, when the catalyst loading was further added to
0.5 and 0.7 mol/mol, the conversion of 20-hydroxyace-
tophenone improved limitedly. This means that too large
catalyst loading is not necessary and 0.3 mol/mol of cata-
lyst was taken as the optimum catalyst loading.
favorable for this one-pot reaction (Entries 2, 3). However,
the electron-donating substituents decrease the reactivities
of benzaldehyde (Entries 4–6).
3.4 Reaction Mechanism
On the basis of the above-mentioned results and the
previous literatures [8, 16], we proposed a plausible
mechanism for the one-pot synthesis of flavanone (Fig. 1).
Firstly, chalcone 1 is formed from 20-hydroxyacetophe-
none and benzaldehyde through a typical Claisen–Sch-
midt condensation pathway. Subsequently, [4-MeO–PhO]
anion could make an effective contaction with chalcone 1
to weaken its intramolecular hydrogen bond interaction.
Then the activated hydroxyl group undergoes an
intramolecular cyclization smoothly to give intermediate
2. After the catalyst [TMG][4-MeO–PhO] is regenerated,
intermediate 3 can be formed. Finally, flavanone is pro-
duced from intermediate 3 via a keto-enol tautomerism
pathway.
3.3 One-Pot Reaction of Various Benzaldehydes
3.5 Recycling of Catalyst
With the optimized reaction condition, the reactions of 20-
hydroxyacetophenone with various benzaldehydes were
further examined. The results are summarized in Table 5. It
was observed that most of these flavanones could be
obtained with good yields, and the electronic nature of the
substituents on benzaldehydes had an obvious impact on
the selectivities of flavanones. The chloro- and bromo-
substituents, as being electron-withdrawing groups, are
To test the activity and stability of TMGILs, the catalyst
[TMG][4-MeO–PhO] was recycled and reused for five
times. As shown in Fig. 2, it was indicated that no obvious
drop in either flavanone yield or selectivity was observed
during these five successive recycles, showing that the
catalyst [TMG][4-MeO–PhO] is stable enough for this one-
pot reaction.
123

Y. Zhou et al.
O
CHO
OH
O
Claisen-Schmidt condensation
O
MeO
OH
+
TMGH
O
O
O
O
H
1
3
+
OMe
¦ÄO
TMGH
H
¦ÄO
¦ÄO
O
MeO
H
O
TMGH
O
2
¦Ä
+
Note:
NH
2
+
TMGH
=
N
N
Fig. 1 Plausible reaction mechanism for [TMG][4-MeO–PhO] catalyzed one-pot synthesis of flavanone
Fig. 2 The recycle and reuse of [TMG][4-MeO–PhO]
123

Facile One-Pot Synthesis of Flavanones Using Tetramethylguanidinum-Based Ionic Liquids as…
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In this work, [TMG][4-MeO–PhO] was found to be an
efficient and reusable catalyst for the synthesis of fla-
vanones through one-pot reaction of various benzaldehydes
with 20-hydroxyacetophenone under mild conditions. And
[TMG][4-MeO–PhO] could be readily recovered and
reused up to five times without significant losses in cat-
alytic activity.
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Acknowledgments We thank the financial support by the National
Natural Science Foundations of China (No. 21206063), the Depart-
ment of Science and Technology of Jiangxi Province (Nos.
20151BAB213016, 20123BBE50081, 20132BDH80003), and the
Sponsored Program for Cultivating Youths of Outstanding Ability in
Jiangxi Normal University.
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JE, Tichit D, Coq B (2004) Chem Commun 9:1096
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