Efficient and mild one-pot three-component reaction to synthesize pyrano[3,2-b]pyran derivatives in ionic liquid

Article abstract of DOI:10.1016/j.tetlet.2012.11.006

A series of 2-amino-4-aryl-4H,8H-6-methyl-8-oxo-pyrano[3,2-b]pyran derivatives have been synthesized efficiently from aromatic aldehyde, malononitrile or cyanoacetate, and 5-hydroxy-2-methyl-4H-pyran-4-one via an one-pot three-component reaction catalyzed by Et₃N in ionic liquid [bmim]BF₄. The present approach offers the advantages of short reaction time, mild reaction conditions, high yields, convenient operation, and reuse of ionic liquid.

Full text of DOI:10.1016/j.tetlet.2012.11.006

Tetrahedron Letters 54 (2013) 227–230
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Efficient and mild one-pot three-component reaction to synthesize
pyrano[3,2-b]pyran derivatives in ionic liquid
⇑
Yuling Li , Bo Zhao, Baixiang Du, Qiushi Jiang, Xiangshan Wang, Changsheng Cao
School of Chemistry and Chemical Engineering, Jiangsu Key Laboratory of Green Synthetic Chemistry for Functional Materials, Jiangsu Normal University, Xuzhou 221116, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 2 July 2012
Revised 23 October 2012
Accepted 2 November 2012
Available online 9 November 2012
A series of 2-amino-4-aryl-4H,8H-6-methyl-8-oxo-pyrano[3,2-b]pyran derivatives have been synthesized
efficiently from aromatic aldehyde, malononitrile or cyanoacetate, and 5-hydroxy-2-methyl-4H-pyran-4-
one via an one-pot three-component reaction catalyzed by Et3N in ionic liquid [bmim]BF4. The present
approach offers the advantages of short reaction time, mild reaction conditions, high yields, convenient
operation, and reuse of ionic liquid.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Multi-component reactions
Synthesis
Ionic liquid
Pyrano[3,2-b]pyran
Introduction
in the presence of triethylbenzylammonium chloride (TEBA),15
Wang et al. developed a rapid and efficient method to synthesize
In recent years, multi-component reactions (MCRs) have been
used as an efficient tool to synthesize biologically active com-
pounds.1,2 MCRs have the advantages such as convergence, produc-
tivity, facile execution, and generally high yields of products.
Besides, ionic liquids (IL) have attracted extensive interest as be-
nign reaction media in organic synthesis in recent years because
of their unique properties of non-volatility, non-flammability,
recyclability, and ability to dissolve a wide range of materials. As
a result of their green credentials and potential to enhance reaction
rates and selectivity, ionic liquids have been found to have increas-
ing applications to organic synthesis, including many MCRs.3
Pyrans and fused pyran derivatives are an important class of
structural motif of many natural and synthetic compounds which
possess a high activity profile due to their wide range of biological
activities such as anticancer,4,5 anti-tuberculosis,6 anti-HIV,7 cal-
cium channel antagonist activity,8 antifungal,9 antimicrobial,10
antiproliferative,11 antidiabetic,12 anti-inflammatory, and antivi-
ral.13 On the other hand, pyranopyranones are also known for their
biological properties including antioxidant and cytotoxic activi-
ties.14 Therefore, the synthesis of pyranopyranone structure is of
great importance in organic synthesis. Recently, some synthetic
approaches have been developed for the synthesis of pyranopyra-
nones. Shi et al. synthesized pyrano[3,2-c]pyran-5-one derivatives
via substituted cinnamonitriles and active methylene carbonyl
compound 4-hydroxy-6-methylpyran-2-one at 90 °C in aqueous
a series of pyrano[3,2-c]pyrans by the reaction of aromatic alde-
hydes, malononitrile or cyanoacetate, and 4-hydroxy-6-methyl-
pyran-2-one in EtOH at room temperature and in the presence of
KF-Al2O3.16 Piao prepared pyrano[3,2-b]pyran-4-one derivatives
by the reaction of substituted cinnamonitriles and kojic acid in
an organic solvent (e.g., absolute ethanol) in the presence of organ-
ic bases like piperidine.17 However, these methods suffer from dis-
advantages such as the use of organic solvents and long reaction
time. The development of a synthetic protocol that is devoid of
the above-mentioned problems and yet environmentally benign,
simple, and efficient for the synthesis of pyranopyranone structure
is in great demand.
Based on our previous studies on the use of ionic liquid as sol-
vent and as part of our continuing interest in the development of
new synthetic methods in heterocyclic chemistry,18–20 we now re-
port the synthesis of 2-amino-4-aryl-4H,8H-pyrano[3,2-b]pyran-8-
ones by the reactions of aromatic aldehyde, malononitrile or
O
Ar
O
OH
CN
R
O
O
R
Et3N
IL
+
+
Ar CHO
O
NH2
4
3
2
1
R= CN, COOMe, COOEt
Scheme 1. Preparation of pyrano[3,2-b]pyrans via three-component reaction.
⇑
Corresponding author. Tel./fax: +86 (516) 83403165.
E-mail address: ylli19722@163.com (Y. Li).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.11.006

228
Y. Li et al. / Tetrahedron Letters 54 (2013) 227–230
Table 2
cyanoacetate, and 5-hydroxy-2-methyl-4H-pyran-4-one (allomal-
tol) in ionic liquid [bmim]BF4 catalyzed by Et3N at room tempera-
ture (Scheme 1), and [bmim]BF4 here is used as solvent, which can
be recycled and reused. To the best of our knowledge, this method-
ology has not been reported in the literature.
a
Synthesis of 4 in ionic liquid [bmim]BF4
Entry
Ar
R
Product
Time/min
Yieldsb/%
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
4-ClC6H4
4-BrC6H4
3,4-Cl2C6H3
3-F3CC6H4
3-BrC6H4
3-O2NC6H4
2-CH3OC6H4
4-FC6H4
3-FC6H4
3-ClC6H4
3-CH3O-4-HOC6H3
4-CH3OC6H4
2,3-(CH3O)2C6H3
3,4-(CH3O)2C6H3
4-H3CC6H4
3,4-(H3C)2C6H3
2,3-(CH3O)2C6H3
3,4-(CH3O)2C6H3
4-ClC6H4
3,4-Cl2C6H3
2-ClC6H4
3-ClC6H4
4-ClC6H4
4-BrC6H4
CN
CN
CN
CN
CN
CN
CN
CN
CN
CN
CN
CN
CN
CN
CN
CN
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
4q
4r
20
35
24
22
20
25
32
29
8
18
120
120
45
30
33
30
40
35
25
20
40
24
35
35
38
180
90
89
91
86
85
87
91
75
97
99
90
82
88
81
77
73
70
75
81
77
85
80
70
77
85
69
The study was initiated by using 4-chloroaldehyde, malononit-
rile, and allomaltol as model substrates for the preparation of 4a.
There was no reaction without Et3N in ionic liquid [bmim]BF4 at
room temperature (Table 1, entry 12). The transformation of 4-
chlorobenzaldehyde with malononitrile and allomaltol proceeded
smoothly with Et3N (1 equiv) in ionic liquid [bmim]BF4 (2 mL),
and at the end of the reaction (about 20 min later, monitored by
TLC), the product was collected by filtration and recrystallized
from ethanol, affording the nicely crystalline 4a in good yield
(90%, Table 1, entry 1). Different solvents and catalysts were
screened in the model reaction, and the results are collected in Ta-
ble 1. In the presence of piperidine, pyridine, NH4OAc, KOH, NaOH,
and Na2CO3 in [bmim]BF4, the reactions became sluggish (Table 1,
entries 2–7). Different solvents, for example, DMF, CH3CN, EtOH,
and H2O, were tested in the presence of Et3N as catalyst, but unfor-
tunately they resulted in low yields or no reaction (Table 1, entries
8–11). The reasons for this are probably related to their composi-
tion that they are in the form of molecules. While Ionic liquids
are quite simply liquids that are composed entirely of ions, which
can stabilize the intermediates and promote the reaction. The
yields of 4a were not further improved with increased or decreased
amount of the catalyst (Table 1, entries 12–14). An increase in the
quantity of Et3N from 2.0 to 1.0 equiv lowers the yield of the prod-
uct 4a. A possible explanation for the decrease in product yield is
that the reaction becomes more complicated and some side prod-
ucts are formed when excess amount of Et3N was used. Different
ionic liquids were also studied at room temperature as shown in
Table 1 (entries 15–17). The results showed that different ILs as
solvents exhibit a dramatic difference in the yield of 4a. This is
attributed to the tunable physical properties of ionic liquids. By
COOMe
COOMe
COOMe
COOMe
COOMe
COOMe
COOEt
COOEt
COOEt
COOEt
4s
4t
4u
4v
4w
4x
4y
4z
3,4-Cl2C6H3
4-HOC6H4
a
Reaction condition: 2 mL of ionic liquid, 1 mmol of aromatic aldehyde, 1 mmol
of allomaltol, 1 mmol of malononitrile (entries 1–16), or cyanoacetate (entries 17–
26), rt.
b
Isolated yields.
Table 1
Optimization of the reaction conditions for synthesis of 4aa
Cl
O
O
CN
CN
+
+
CHO
Cl
O
O
CN
NH
OH
O
2
Entry
Catalyst/equiv
Solvent
Time/h
Yieldb/%
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
Et3N(1.0)
Pyridine(1.0)
Piperidine(1.0)
NH4OAc(1.0)
KOH(1.0)
NaOH(1.0)
NaCO3(1.0)
Et3N(1.0)
Et3N(1.0)
Et3N(1.0)
Et3N(1.0)
Et3N(0)
Et3N(0.5)
Et3N(2.0)
Et3N((1.0)
Et3N(1.0)
Et3N(1.0)
[bmim]BF4
[bmim]BF4
[bmim]BF4
[bmim]BF4
[bmim]BF4
[bmim]BF4
[bmim]BF4
EtOH
CH3CN
DMF
H2O
[bmim]BF4
[bmim]BF4
[bmim]BF4
[bmim]Br
[emim]BF4
[bmim]PF6
0.3
0.3
0.3
0.3
0.3
0.3
0.3
24
24
0.3
24
0.3
0.3
0.3
0.3
0.3
0.3
90
11
6
45
18
19
22
0
0
6
0
0
41
40
30
32
56
Figure 1. X-Ray crystal structure of compound 4d.
varying the anion and cation, ionic liquids can be prepared that
vary in polarity, density, and solubility properties.21,22 These prop-
erties have an important effect on the reaction and result in differ-
ent yields of 4a. Thus, it is clear from the experiments that the best
condition for 4a could be entry 1, employing Et3N (1.0 equiv) as
base and [bmim]BF4 as solvent at room temperature.
After optimizing the reaction conditions, a variety of aromatic
aldehydes were employed under similar circumstances to evaluate
the substrate scope of this reaction. The results were summarized
in Table 2. Data from Table 2 demonstrated that aromatic alde-
hydes carrying both electron-withdrawing and electron-releasing
substituents were converted into their corresponding pyrano[3,2-
b]pyran derivatives in good yields under optimal conditions
a
Reaction condition: 2 mL of ionic liquid, 1 mmol of 4-chlorobenzaldehyde,
1 mmol of allomaltol, and 1 mmol of malononitrile, rt.
b
Isolated yields.

Y. Li et al. / Tetrahedron Letters 54 (2013) 227–230
229
100
90
90
87
85
84
80
60
40
20
0
1
2
3
4
5
Reaction cycle number
Figure 3. Reusability of ionic liquid [bmim]BF4.
the poor solubility of products in ionic liquids and water, they were
easily separated by simple filtration from the mixture of water and
ionic liquid, the filtrate was then extracted with ether and dried at
90 °C in vacuum for several hours to be recycled. As shown in Fig-
ure 3, the reaction medium can be recycled at least four times
without significant decrease of the yields, ranging from 90% to 84%.
In conclusion, an efficient, environmentally benign, atom-eco-
nomical, and simple methodology for the preparation of 2-ami-
no-4-aryl-4H,8H-6-methyl-8-oxo-pyrano[3,2-b]pyran derivatives
Figure 2. X-Ray crystal structure of compound 4y.
CN
CN
R
Et3N
-H2O
Ar-CH
C
+
Ar-CHO
R
5
1
2
in
a
three-component reaction in ionic liquid is reported.26
Prominent among the advantages of this method are operational
simplicity, mild reaction conditions, higher yields, and environ-
mental friendliness. Meanwhile, ionic liquid [bmim]BF4 could be
reused for several rounds without apparent loss of activity.
Et3N
H
Ar
O
O
O
O
5
Et3N
-H
O
R
C
N
OH
O
O
O
6
Acknowledgments
3
We are grateful to the National Natural Science Foundation of
China (No. 21104064, 21172188), the Natural Science Foundation
of XuZhou Normal University (10XLR03, 11XLR13), and the Priority
Academic Program Development of Jiangsu Higher Education Insti-
tutions for financial support.
Ar
O
Ar
O
O
O
R
R
O
O
H Et3N
NH2
NH
4
Supplementary data
7
Scheme 2. Plausible mechanism for formation of 4(a–z).
Supplementary data associated with this article can be found,
in the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.
11.006.
described above. At the same time, we have also observed delicate
electronic effects: aldehydes with electron-withdrawing groups re-
acted rapidly, while electron donating groups decreased the reac-
tivity, requiring longer reaction times. The results were
summarized in Table 2. All the products were characterized by
melting points, 1H NMR, IR, and HRMS. The structures of products
4d and 4y were further confirmed by X-ray crystallography (Fig. 1
and Fig. 2).23
With the above-mentioned results in hand, a plausible mecha-
nism of this reaction was proposed in Scheme 2.24,25 The first step
was Knoevenagel condensation between aromatic aldehyde 1 and
malononitrile or cyanoacetate 2 to form intermediate 5. Then, the
Michael addition of allomaltol 3 to intermediate 5 would furnish
intermediate 6. Finally, the product 4 was obtained by an intramo-
lecular cyclization and tautomerism.
References and notes
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Ferreira, V. F. Org. Biomol. Chem. 2011, 9, 4315.
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A.; Bastow, K. F.; Lang, J.-Y.; Hung, M.-C.; Lee, K.-H. Org. Biomol. Chem. 2010, 18,
803.
6. Ferreira, S. B.; da Silva, F. d. C.; Bezerra, F. A. F. M.; Lourenco, M. C. S.; Kaiser, C.
R.; Pinto, A. C.; Ferreira, V. F. Arch. Pharm. 2010, 343, 81.
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9. Schiller, R.; Tichotova, L.; Pavlik, J.; Buchta, V.; Melichar, B.; Votruba, I.; Kunes,
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10. Hussain, H.; Aziz, S.; Schulz, B.; Krohn, K. Nat. Prod. Commun. 2011, 6, 841.
Finally, the recovery and reuse of the ionic liquid [bmim]BF4
were studied by using the preparation of 4a as a model. Due to

230
Y. Li et al. / Tetrahedron Letters 54 (2013) 227–230
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2011, 17, 895.
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1191.
13. Wang, S. M.; Milne, G. W. A.; Yan, X. J.; Posey, I. J.; Nicklaus, M. C.; Graham, L.;
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18. Li, Y. L.; Du, B. X.; Wang, X. S.; Shi, D. Q.; Tu, S. J. J. Heterocycl. Chem. 2006, 43,
685.
19. Li, Y. L.; Gu, D. G.; Xu, X. P.; Ji, S. J. Chin. J. Chem. 2009, 27, 1558.
20. Li, Y. L.; Chen, H.; Shi, C. L.; Shi, D. Q.; Ji, S. J. J. Comb. Chem. 2010, 12, 231.
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Constantieux, T. Chem. Soc. Rev. 2011, 40, 1347.
the subsequent runs without further purification. The crude product was
purified by recrystallization from ethanol to give 4 as a white powder. The
spectral data can be found in Supplementary data. Compound 4a: mp 219–
221 °C; IR (KBr):
m ;
3552, 3480, 3414, 2204, 1733, 1638, 1426, 1209, 1015 cmÀ1
1H NMR (400 MHz, DMSO-d6): d 7.47 (d, J = 8.0 Hz, 2H, ArH), 7.34 (d, J = 8.0 Hz,
2H, ArH), 7.28 (s, 2H, NH2), 6.28 (s, 1H, @CH), 4.86 (s, 1H, CH), 2.14 (s, 3H, CH3);
13C NMR (100 MHz, DMSO-d6): d 169.5, 165.4, 159.2, 148.5, 139.9, 136.1, 132.5,
129.7, 128.9, 119.1, 113.7, 55.3, 18.9; HRMS Calcd for C16H10ClN2O3 (MÀH)À:
requires 313.0380. Found: 313.0352. Compound 4b: mp 229–231 °C; IR (KBr):
m ;
3551, 3479, 3413, 2203, 1731, 1638, 1426, 1209, 1012 cmÀ1 1H NMR
(400 MHz, DMSO-d6): d 7.60 (d, J = 7.6 Hz, 2H, ArH), 7.28 (m, 4H, ArH+NH2),
6.28 (s, 1H, @CH), 4.84 (s, 1H, CH), 2.14 (s, 3H, CH3); 13C NMR (100 MHz,
DMSO-d6): d 169.5, 165.4, 159.2, 148.5, 140.3, 136.1, 131.9, 130.1, 121.1, 119.1,
113.7, 55.2, 19.0; HRMS Calcd for C16H10BrN2O3 (MÀH)À: requires 356.9875.
Found: 356.9892. Compound 4d: mp 220–222 °C; IR (KBr):
m
3552, 3479, 3413,
2203, 1653, 1638, 1330, 1209, 1113 cmÀ1 1H NMR (400 MHz, DMSO-d6): d
;
7.64–7.71 (m, 4H, ArH), 7.32 (s, 2H, NH2), 6.29 (s, 1H, @CH), 5.04 (s, 1H, CH),
2.14 (s, 3H, CH3); 13C NMR (100 MHz, DMSO-d6): d 169.5, 165.4, 159.3, 147.8,
141.9, 136.3, 131.5, 131.2, 130.7, 130.0, 128.3, 119.0, 113.8, 54.9, 19.0; HRMS
Calcd for C17H10F3N2O3 (MÀH)À: 347.0638. Found: 347.0654. Compound 4s:
22. Gu, Y. L. Green Chem. 2012, 14, 2091.
23. Crystallographic data for the structures of 4d and 4y reported in this Letter
have been deposited at the Cambridge Crystallographic Data Centre with No.
CCDC-884496 and 882918, respectively.
24. Sun, J.; Xia, E. Y.; Zhang, L. L.; Yan, C. G. Eur. J. Org. Chem. 2009, 30, 5247.
25. Shaabani, A.; Ghadari, R.; Ghasemi, S.; Pedarpour, M.; Rezayan, A. H.; Sarvary,
A.; Ng, S. W. J. Comb. Chem. 2009, 11, 956.
mp 207–209 °C; IR (KBr):
m 3551, 3478, 3414, 2187, 1671, 1636, 1616, 1444,
1212 cmÀ1
;
1H NMR (400 MHz, DMSO-d6):
d 7.86 (s, 2H, NH2), 7.35 (d,
J = 7.6 Hz, 2H, ArH), 7.25 (d, J = 7.6 Hz, 2H, ArH), 6.24 (s, 1H, @CH), 4.80 (s, 1H,
CH), 3.47 (s, 3H, OCH3), 2.16 (s, 3H, CH3); 13C NMR (100 MHz, DMSO-d6): d
169.6, 165.4, 159.2, 157.8, 149.3, 142.4, 136.0, 130.0, 119.3, 118.3, 115.0, 114.3,
113.6, 55.9, 19.0; HRMS Calcd for C17H13ClNO5 (MÀH)À: requires 346.0482.
26. General procedure for preparation of 4: a mixture of aromatic aldehyde 1
Found: 346.0469. Compound 4y: mp 216–218 °C; IR (KBr): m 3457, 3311, 1692,
(1 mmol), malononitrile or cyanoacetate
2
(1 mmol), and allomaltol
3
(1
1644, 1504, 1106 cmÀ1 1H NMR (400 MHz, DMSO-d6): d 7.91 (s, 2H, NH2), 7.57
;
mmol) was stirred at room temperature in ionic liquid [bmim]BF4 (2 mL)
containing Et3N (1 mmol). After completion of the reaction as indicated by TLC,
water (5 mL) was added and the product was filtered off and washed with
water. The remaining aqueous layer containing the ionic liquid was extracted
with ether (8 mL) for three times to remove organic impurity, and then dried
under vacuum at 90 °C for about 15 h to afford ionic liquid, which was used in
(d, J = 8.4 Hz, 1H, ArH), 7.48 (d, J = 2.0 Hz, 1H, ArH), 7.23 (dd, J1 = 8.4 Hz,
J2 = 2.0 Hz, 1H, ArH), 6.26 (s, 1H, @CH), 4.86 (s, 1H, CH), 3.90–3.96 (m, 2H, CH2),
2.17 (s, 3H, CH3), 1.00 (s, 3H, CH3); 13C NMR (100 MHz, DMSO-d6): d 169.6,
167.3, 165.4, 159.5, 150.3, 144.3, 135.8, 130.9, 129.8, 129.7, 128.0, 113.7, 74.3,
59.0, 19.0, 14.0; HRMS Calcd for C18H14Cl2NO5 (MÀH)À: requires 394.0249.
Found: 394.0249.