Visible-Light-Initiated One-Pot, Three-Component Synthesis of 2-Amino-4 H-pyran-3,5-dicarbonitrile Derivatives

Article abstract of DOI:10.1021/acscombsci.9b00124

A novel approach for the visible-light-initiated synthesis of 2-amino-4H-pyran-3,5-dicarbonitrile derivatives via a one-pot, three-component reaction of aldehydes or isatins, malononitrile, and α-cyano ketones has been developed. The reaction was carried

Full text of DOI:10.1021/acscombsci.9b00124

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Article
Visible-Light Initiated One-pot, Three-Component Synthesis
of 2-Amino-4H-pyran-3,5-dicarbonitrile Derivatives
Mo Zhang, Meng-Nan Chen, Jiao-Mian Li, Nan Liu, and Zhan-Hui Zhang
ACS Comb. Sci., Just Accepted Manuscript • DOI: 10.1021/acscombsci.9b00124 • Publication Date (Web): 21 Aug 2019
Downloaded from pubs.acs.org on August 27, 2019
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Visible-Light Initiated One-pot, Three-Component Synthesis of
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2-Amino-4H-pyran-3,5-dicarbonitrile Derivatives
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Mo Zhang, Meng-Nan Chen, Jiao-Mian Li, Nan Liu and Zhan-Hui Zhang*
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National Demonstration Center for Experimental Chemistry Education, Hebei Key Laboratory of Organic Functional
Molecules, College of Chemistry and Material Science, Hebei Normal University, No. 20, South 2nd Ring East Road,
Shijiazhuang 050024, P. R. China
ABSTRACT: A novel approach for visible-light initiated synthesis of 2-amino-4H-pyran-3,5-dicarbonitrile
derivatives via one-pot, three-component reaction of aldehydes or isatins, malononitrile and α-cyano
ketones has been developed. The reaction was carried out at room temperature in ethanol/water to give the
corresponding products with a wide range of functional groups in high yield. This process did not require
any additives and chromatographic separation, and could be applied for the gram-scale synthesis.
Keywords:
Visible-light,
Catalyst-free,
2-Amino-4H-pyran-3,5-dicarbonitrile
Spirooxindoles,
Multi-component reaction, Green synthesis
O
H2N
O
NH2
CN
O
O
R
R1
CN
CN
R
RCHO
R1
N
NC
O
H
CN
+
White LED
EtOH/H2O (1:1), r. t.
R1
O
White LED
EtOH/H2O (1:1), r. t.
R
CN
NC
N
H
27 examples, 78-95% yield
29 examples, 75-94% yield
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INTRODUCTION
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With the increasing awareness of protecting our fragile environment and great progress
in green and sustainable chemistry, the use of a renewable energy source for
developing efficient and selective chemical transformations gained widespread
attention.1 In the past few years, visible light as clean, safe, non-polluting, inexpensive,
abundant, and sustainable energy has been utilized for the design of a variety of
organic reactions under mild reaction conditions and low-energy irradiation and
remarkable achievements have already been demonstrated.2-9 In a photo-promoted
organic synthetic chemical reaction, light acts as a reagent for inducing conversion of a
compound as it is usually carried out by a chemical reagent.10 Moreover,
multicomponent reactions (MCRs) have become a fascinating and powerful synthetic
tool in organic synthesis, medicinal and combinatorial chemistry by the reaction of
three or more different starting materials in a one-pot manner for the construction of
complex molecular structures with shortened reaction time, increased yield, less side
products and simple workup procedures compared to conventional reaction
strategies.11-22 At the same time, catalyst-free protocols have become an important
strategy due to their simple workup, low cost, reduced contamination and avoiding the
effects of catalysts on sensitive substrates.23 These characteristics meet the
requirements of green chemistry. Although some achievements have been made in this
field, the study of visible light- initiated catalyst-free MCRs remains is still in its
infancy and new MCRs remain to be further explored.24-27
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As one of the major classes of valuable oxygen-containing heterocyclic compounds,
pyrans are a prevalent structural motif found in a number of natural products, synthetic
pharmaceuticals and functional materials. Moreover, these compounds have been efficiently
used
as
pigments
and
biodegradable
agrochemicals.28
Among
them,
2-amino-4H-pyran-3,5-dicarbonitriles have received considerable attention due to their
well-documented biological properties in the fields of natural products, pharmaceuticals and
agrochemicals. They can be used as antibacterial,29-30 antioxidant,30 antifungal,31
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anticancer,32-33 and antiulcer34 agents, as exemplified in Figure 1. Owing to their intriguing
biological activities, a plethora of methods have been developed for the preparation of these
important compounds. In 2010, Lakshmi et al developed InCl3-catalyzed tandem
Knoevenagel–Michael reaction of 3-cyanoacetyl indole, aromatic aldehydes and malononitrile
for synthesis of 3-pyranyl indole derivatives in ethanol under reflux conditions.30 Also in
2010, they disclosed the reaction of isatin, malononitrile and 3-cyanoacetyl indole could be
carried out in the presence of in Et3N to prepare spirooxindoles including
2-amino-4H-pyran-3,5-dicarbonitrile skeleton.31 In 2016, Wu’ group have reported the first
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organocatalytic
Michael/cyclization
cascade
reaction
sequence
between
3-oxo-3-phenylpropanenitrile and isatylidene malononitriles in CH2Cl2 for the construction of
spiro[4H-pyran-oxindoles] derivatives.35 Despite these advances, the established protocols are
insufficient to meet green chemistry standards suffering from several limitations, such as the
requirement of multistep synthesis of the precursors and expensive catalysts, high energy
consumption under harsh reaction conditions. Therefore, the development of an
environmentally friendly and practical method with high generality for synthesis of
2-amino-4H-pyran-3,5-dicarbonitriles under mild reaction conditions remains appealing and
challenging.
OMe
Cl
O
CN
NC
CN
NC
NC
CN
NC
CN
H2N
O
O
H2N
H2N
O
H2N
O
N
CH3
N
H
N
H
antifungal activity
antibacterial activity
CH3
antibacterial activity
antioxidant activity
H
N
N
O
NH2
CN
Cl
N
NH2
H2N
S
CN
HN
O
NH2
CN
O
NC
O
O
S
NC
CN
O
N
H
O
CN
O
Cl
antiulcer activity
anticancer activity
anticancer activity
Figure 1. Selected bioactive molecules with 2-amino-4H-pyran-3,5-dicarbonitrile substructure
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Our laboratory has focused on the development of environmentally friendly
approaches for organic transformations.36-38 Herein, we report a novel, visible-initiated,
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catalyst
free
transformation
to
construct
functionalized
9
2-amino-4H-pyran-3,5-dicarbonitrile derivatives via one-pot, three-component reaction
of aldehydes or isatins, malononitrile and α-cyano ketones at room temperature
(Scheme 1).
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O
H2N
NH2
O
O
R
R1
RCHO
O
CN
R
CN
CN
N
NC
O
H
CN
+
CN
R1
White LED
EtOH/H2O (1:1), r. t.
R1
O
White LED
R
N
EtOH/H2O (1:1), r. t.
CN
H
Scheme 1. Visible-light-initiated one-pot synthesis of 2-amino-4H-pyran-3,5-dicarbonitrile derivatives
RESULTS AND DISCUSSION
At first, the reaction conditions were optimized using model reaction of benzaldehyde 1{1},
3-oxo-3-phenylpropanenitrile 2{1} and malononitrile under various reaction conditions
(Table 1). Various solvents such as CH2Cl2, CHCl3, CH3CN, EtOAc, THF, ethyl lactate (EL),
EtOH, DMF, glycerol, PEG 400 and choline chloride (ChCl)/glycerol (1:1) were screened in
the absence of any catalyst under visible light illumination with an 18 W white light-emitting
diode (LED) under an air atmosphere at room temperature. It was found the reaction indeed
occurred to give desired product 4{1,1} in 18-56% yields. The yield of 4{1,1} was improved
when the reaction was performed in a mixed solvent of PEG 400/H2O, EL/H2O, and
EtOH/H2O. Different ratios of EtOH and H2O were tested and found that its ratio of 1:1 was
suitable for this transformation, giving the expected product in 92% (entry 15). The effect of
different sources of visible light was also examined. The investigation indicated that the light
source has no significantly effect on product yield. With a green LED, the yield was only
slightly improved (entry 20). From a practical standpoint, white light was chosen as light
source. When the reaction was performed under darkness, only 13% yield of product was
formed (entry 22). This observation indicated that visible light is a critical factor for this
reported reaction procedure in the absence of catalyst conditions.
Table 1. Investigation of the reaction conditions for the synthesis of product 4{1,1}a
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NH2
CHO
O
CN
CN
O
visible light
CN
+
+
solvent, r. t.
CN
CN
{1,1}
1
{1}
3
2
{1}
4
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Entry Light source
Solvent
Time (h)
Yield (%)b
1
White light
White light
White light
White light
White light
White light
White light
White light
White light
White light
White light
White light
White light
White light
White light
White light
White light
White light
Blue lightc
Green lightd
Ultraviolet lighte
Dark
H2O
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
12
36
20
21
22
24
26
28
30
42
18
56
20
61
70
92
57
60
38
90
94
87
13
2
CH2Cl2
3
CHCl3
4
CH3CN
5
EtOAc
6
THF
7
EL
8
EtOH
9
DMF
10
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22
Glycerol
PEG 400
ChCl/Glycerol (1:1)
PEG 400/H2O (1:1)
EL/H2O (1:1)
EtOH/H2O (1:1)
EtOH/H2O (2:1)
EtOH/H2O (3:2)
EtOH/H2O (9:1)
EtOH/H2O (1:1)
EtOH/H2O (1:1)
EtOH/H2O (1:1)
EtOH/H2O (1:1)
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aReaction conditions: benzaldehyde (1 mmol), 3-oxo-3-phenylpropanenitrile (1.0 mmol),
malononitrile (1 mmol), solvent (2 ml), light irradiation (18 W, wavelength in the range 390–750 nm),
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b
c
room temperature unless otherwise specified in the Table. Isolated yields. Blue light (460–470 nm).
dGreen light (520–530 nm). eUltraviolet light (390–400 nm).
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Based on the establishment of the optimal reaction conditions, the scope and generality of
this visible-light promoted three-component reaction were further evaluated. The structural
diversity of the starting materials is shown in Figure 2. First, a variety of aldehydes were
examined and the representative results are compiled in Scheme 2. Benzaldehydes bearing
both electron-donating or -withdrawing substitutions at the phenyl ring reacted smoothly
under
the
optimal
reaction
conditions,
furnishing
the
corresponding
2-amino-4H-pyran-3,5-dicarbonitriles (4) with high to excellent yields. Furthermore, it was
observed that the position of the substituent on the benzene ring did not significantly affect
the reaction. An array of versatile functional groups, including base- and acid-sensitive
moieties, such as alkyl, methoxy, phenoxy, hydroxyl, trifluoromethyl, nitro, cyano, boric acid,
halogen groups were compatible under the standard reaction conditions. Besides the arene
aldehydes, the heterocycle aldehyde such as thiazole-2-carbaldehyde 1{15} has been proved
to be compatible, and generated the expected products 4{15,1} in high yields. We were
pleased to find that alkyl aldehyde such as cyclohexanecarbaldehyde 1{16} was still a
suitable reactant under the standard conditions, leading to the desired product 4{16,1} with
85% yield. Lilialdehyde was then subjected to the established reaction conditions, effectively
exhibiting good performance to deliver the respective product 4{17,1} in 78% yield.
Subsequently, the reactions of different α-cyano ketones were also investigated under the
optimized reaction conditions. The results demonstrated that electronic properties of the
substituents on the benzene rings of α-cyano ketones had no obvious influence on the
efficiency, and the corresponding products were obtained in high yields. In addition, this
reaction could be applied to 4,4-dimethyl-3-oxopentanenitrile 2{5} and achieved the desired
products in 88-92% yield.
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CHO
CHO
CHO
CHO
CHO
CHO
CHO
CHO
NO2
OMe
F
6
7
8
OMe
Br
NO2
CF3
1
{1}
1
{7}
1
1
{8}
{3}
1
1
{6}
{2}
1
{5}
1
{4}
9
CHO
CHO
CHO
CHO
CHO
CN
CHO
CHO
O
O
CHO
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S
O
N
CMe3
NO2
OMe
Cl
1
{17}
1
1
{16}
{15}
1
{14}
1
{11}
1
{12}
1
{13}
1
{9}
1
{10}
1
1
Chemset Diversity reagents {1-17}
O
O
O
O
O
CN
CN
CN
Me
CN
F
CN
Cl
2
{4}
2
{2}
2
2
{5}
2
{3}
{1}
2
2
Chemset Diversity reagents {1-5}
O
Br
O
O
O
O
O
Me
F
MeO
Cl
O
O
O
O
O
O
N
N
N
H
N
N
N
H
H
H
H
H
5
{1}
5
5
{4}
{2}
5
{6}
5
5
{3}
{5}
O
O
O
O
O
O
Br
O2N
O
O
O
O
O
N
O
N
N
N
N
H
H
N
H
H
H
Br
Cl
5
H
CF3
F
5
{7}
5
{10}
{8}
5
5
{11}
{9}
5
{12}
5
5
Chemset Diversity reagents {1-12}
Figure 2. Chemsets selected for the library of 2-amino-4H-pyran-3,5-dicarbonitriles: aldehydes
(chemset 1), α-cyano ketones(chemset 2), and isatins (chemset 5).
Scheme 2. Synthesis of 2-amino-4H-pyran-3,5-dicarbonitriles using aldehydes
NH2
CN
R
O
CN
White LED
O
+
+
RCHO
CN
R1
EtOH/H2O (1:1), r. t.
R1
CN
1
2
3
CN
4
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NH2
NH2
CN
NH2
NH2
NH2
CN
CN
CN
CN
O
CN
O
CN
O
O
O
O
O
N
R'
Ph
Ph
Ph
Ph
Ph
CN
S
CN
CN
R'
R'
4
{14,1}: 78%
4
{15,1}: 87%
'
4
4
4
4
4
{9,1}: R = OMe, 93%
'
NH2
'
4
4
4
4
{5,1}: R = OMe, 92%
4
4
4
{2,1}: R = OMe, 93%
NH2
'
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{10,1}: R = CMe3, 81%
'
CN
'
{6,1} R = Br, 92%
{3,1}: R = F, 94%
CN
'
O
{11,1}: R = Cl, 88%
'
O
'
{7,1}: R = NO2, 94%
{4,1}: R = NO2, 93%
'
{12,1}: R = NO2, 95%
'
Ph
{8,1}: R = CF3, 85%
Ph
'
{13,1}: R = CN, 91%
CN
CN
4
{17,1}: 78%
NH2
4
{16,1}: 85%
NH2
NH2
NH2
CN
CN
O
CN
CN
Ph
O
O
O
Me
Ph
CN
CN
R'
CN
CN
'
Cl
F
4
4
{1,3}: R = F, 92%
F
CN
4
{1,2}: 93%
'
4
{3,2}: 90%
4
{1,4}: R = Cl, 94%
{13,3}: 88%
NH2
NH2
NH2
CN
NH2
CN
NH2
CN
O
CN
O
CN
O
O
O
NO2
NO2
CN
MeO
CN
CN
CN
CN
CN
Cl
4
{13,5}: 92%
4
{7,5}: 90%
4
{2,5}: 88%
4
{7,4}: 91%
4
{1,5}: 88%
a Isolated yields.
Isatins and their derivatives have been shown to have a broad spectrum of biological
activity. These interesting features prompted us to further explore the application of this
reaction for synthesis of spirooxindole 2-amino-4H-pyran-3,5-dicarbonitriles using isatins. As
shown in Scheme 3, isatins substituted with either electron-rich groups or electron-poor
groups were all converted into their corresponding products 6 with high yields regardless of
the electronic properties of the substituents on aromatic ring. The position of the substituents
on the phenyl ring of isatins had little influence on the efficiency of the reaction. Halogen
atoms such as fluoro, chloro, and bromo on the aromatic ring were not affected under the
present reaction conditions, providing ample opportunity for further functionalization
possible. The results from this section demonstrated that this approach was broadly applicable
for the synthesis of 2-amino-4H-pyran-3,5-dicarbonitrile derivatives.
Scheme 3. Synthesis of spirooxindole 2-amino-4H-pyran-3,5-dicarbonitriles using isatins
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H2N
NC
O
O
R1
O
CN
White LED
O
R
+
+
CN
CN
Ph
R1
EtOH/H2O (1:1), r. t.
N
O
CN
R
H
N
6
5
2
3
H
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H2N
H2N
O
H2N
H2N
NC
H2N
NC
O
Ph
O
F
O
O
Ph
NC
Ph
NC
NC
CN
O
Br
R
CN
O
CN
O
CN
CN
N
O
O
N
H
N
N
N
H
R
H
6
6
6
H
{1,9}: R = F, 91%
{1,10}: R = Cl, 90%
{1,12}: R = CF3, 89%
H
6
6
6
6
6
{1,4}: R = Me, 90%; {1,5}: R = F, 91%
{1,6}: R = Cl, 93%; {1,7}: R = Br, 92%
{1,8}: R = NO2, 94%
6
6
{3,1}: 92%
{1,1}: 93%
6
{1,2}: 89%
H2N
NC
H2N
F
F
O
H2N
O
O
H2N
F
Cl
O
NC
NC
R
Br
CN
NC
CN
O
CN
O
CN
O
O
N
N
N
H
H
H
N
R
H
6
6
6
6
{3,3}: R = OMe, 75%; {3,5}: R = F, 92%
{3,6}: R = Cl, 94%; {3,7}: R = Br, 90%
{3,8}: R = NO2, 93%
6
6
6
6
{3,9}: R = F, 91%
6
{3,2}: 90%
6
{3,10}: R = Cl, 92%
{3,11}: R = Br, 91%
{3,12}: R = CF3, 92%
6
{4,1}: 91%
H2N
Cl
H2N
O
H2N
NC
O
Cl
Cl
O
NC
NC
R
Br
CN
CN
CN
O
O
O
N
N
H
N
H
H
6
6
{4,9}: R = F, 93%
{4,10}: R = Cl, 92%
6
6
6
6
{4,4}: R = Me, 91%; {4,5}: R = F, 92%
{4,6}: R = Cl, 91%; {4,7}: R = Br, 90%
R
6
{4,2}: 89%
a Isolated yields.
Furthermore, to demonstrate the scalability of our method of this visible light-initiated
MCR process, we carried out the model reaction on a 10 mmol scale to provide the expected
product 4{1,1}in 94% yield (Scheme 4). This shows that our methodology be potentially
scaled up to gram-scale synthesis.
Scheme 4. Gram-scale synthesis of 4{1,1}
NH2
CHO
CN
O
O
CN
CN
White LED
CN
+
+
EtOH/H2O (1:1), r. t.
CN
{1,1} (2.80 g, 94%)
10 mmol
10 mmol
10 mmol
4
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To obtain insights into the reaction mechanism of this visible light-initiated
three-component reaction, a series of control experiments were performed. As shown in
Scheme 5, the Knoevenagel condensation of malononitrile with benzaldehyde took place in
standard condition with the elimination of water to give the corresponding
2-benzylidenemalononitrile (I) in 92% yield. However, when the reaction of
3-oxo-3-phenylpropanenitrile with malononitrile was conducted under same condition, no
2-phenyl-1-propene-1,1,3-tricarbonitrile (II) were detected. Carrying out the reaction of
2-benzylidenemalononitrile (I) and 3-oxo-3-phenylpropanenitrile under the standard
conditions generated the desired product 4{1,1} in 93% yield. Additionally, the fact that a
slight decrease in yield of product (86%) was observed under a nitrogen atmosphere ruled out
the role of oxygen in this reaction. When the reaction was carried out in the dark at 50 °C, the
corresponding product 4{1,1} was obtained in 13% yield.
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In addition, 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO), a radical scavenger, was
added to the model reaction, only 11% yield of the desired product 4{1,1} was obtained.
Moreover, when the above reaction was treated with 2,6-di-tert-butyl-4-methyl-phenol
(BHT), another free radical trapping reagent, the reaction was severely inhibited and only
15% of the 4{1,1} was obtained. Meanwhile, radical adducts III, IV and V were detected in
the reaction solution by HPLC-MS analysis, indicating that radicals were produced and
trapped by BHT. These results indicated that radical intermediates were involved in this
transformation.
Scheme 5. Control experiments
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CHO
CN
CN
CN
CN
Standard condition
1 h
5
6
7
8
+
I
, 92%
NC
1
{1}
9
CN
CN
O
CN
CN
Standard condition
4 h
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CN
+
Ph
Ph
2
II,
{1}
0%
NH2
CN
CN
Ph
O
O
Standard condition
4 h
CN
CN
+
Ph
Ph
CN
4
{1,1} (93%)
CHO
CHO
CHO
CHO
O
nitrogen atmosphere
r. t., 4 h
CN
CN
4
{1,1} (86 %)
+
+
+
+
+
Ph
CN
O
O
O
50 oC, dark
CN
CN
CN
CN
CN
4
{1,1} (13 %)
+
+
+
Ph
Ph
Ph
r. t., 4 h
Standard condition
CN
CN
4
{1,1} (11 %)
TEMPO (3.0 equiv), 5 h
Standard condition
BHT (3.0 equiv), 5 h
CN
CN
4
{1,1} (15%)
OH
OH
OH
HN
CN
CN
CN
CN
O
+
-
IV
(M+Na)
+
III
(M-Na)
V
(M+Na)
Although the exact mechanism for this reaction pathway remains unclear at this stage, on
the basis of the aforementioned control experiments and recent literatures,24 a plausible
mechanism is proposed in Scheme 6. Firstly, the intermediate A was formed via
tautomerization of malononitrile under light irradiation. Subsequently, intermediate A and
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benzaldehyde underwent Knoevenagel condensation to generate intermediate I with the
elimination of a water molecule. UV/Vis absorption spectra showed that benzaldehyde 1{1},
3-oxo-3-phenylpropanenitrile 2{1} and malononitrile (3) have no absorption at the
wavelength of visible light (Figure 3). The intermediate I has a weak absorption in the visible
region and it may absorb light under the irradiation conditions. Consequently, visible light
irradiation of intermediate I results in its conversion into the excited state of I (intermediate
B).
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Figure 3. UV/Vis absorption spectra
The excited state of I is a good hydrogen abstractor and a much better electron acceptor.
An electron transfer from the enol D (Which is in equilibrium with its own ketone) to the
electronically excited state of I would give a radical ion pair that can neutralize by proton
transfer from the enol radical cation to the malodinitrile alkene radical anion. By that, the
C/E-radical pair is formed, which can combine to give the intermediate F. Finally,
intermediate F underwent a tautomerisation followed by cyclization, leading to the formation
of the desired product 4{1,1}.
Scheme 6. Plausible reaction mechanism
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9
O
N
HN
CN
CN
- H2O
C
C
H
1
{1}
A
3
Photochemical
activation
I
CN
N C
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Photochemical
activation
N
C
N
C
C
C
C
N
NC
B
NH
CN
CN
CN
CN
O
H
O
CN
E
O
D
CN
2
{1}
H
O
NH2
CN
NH
NH
Cyclization
O
O
H
C
Tautomerisation
C
NC
NC
CN
CN
NC
F
4
{1,1}
G
CONCLUSION
In summary, we have successfully developed a novel, simple, straightforward, and
efficient strategy for the synthesis of functionalized 2-amino-4H-pyran-3,5-dicarbonitrile
derivatives via visible light-initiated one-pot, three-component reaction of aldehydes or isatins,
malononitrile and α-cyano ketones. Without the use of any catalyst and thermal energy, the
reactions proceeded at ambient temperature to give the desired products in high yields. The
present protocol provides a step-economic and convenient method for the synthesis of
2-amino-4H-pyran-3,5-dicarbonitrile derivatives and represents fringe benefits in terms of
sustainability, operational feasibility, broad substrate scope and easy scalability. The
developed protocol significantly broadens the scope of visible light-initiated multi-component
reaction. We expect that this method can be readily adopted by pharmaceutical chemists to
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prepare potentially biologically active compounds that were previously difficult to access.
Further investigations of the reaction mechanism and its application are ongoing in our
laboratory.
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EXPERIMENTAL
Unless otherwise noted, all reagents were obtained commercially and were used as received
without further purification. Melting points were determined on an X-5 digital melting point
apparatus and are not corrected. The FT-IR spectra were obtained on a Bruker Tensor 27
1
13
Fourier transform infrared spectroscope. The H NMR and C NMR spectra were recorded
on a Bruker AV III-500 or Zhongke Niujin AS 400 spectrometer using TMS as internal
standard. The mass spectra were performed on a 3200 Qtrap instrument with an ESI source.
Irradiation experiments were performed using a WP-VLH-1020 photoreactor from Xi'an
WATTECS experimental equipment co. LTD.
General procedure for synthesis of 2-amino-4H-pyran-3,5-dicarbonitriles
In a tube equipped with a magnetic stirrer bar, aldehydes or isatins (1 mmol), malononitrile (1
mmol) and α-cyano ketones (1 mmol) were added in EtOH/H2O (1:1, 2 ml). Then resulting
mixture was stirred at room temperature with the irradiation of an 18 W white LEDs. For each
reaction, light source was placed app. 2.0 cm away from the reaction vessels. The reaction
progress was monitored by TLC. Upon completion, water was added and the solid precipitate
was filtered and purified by recrystallized from ethanol to obtain the desired pure products.
■ ASSOCIATED CONTENT
Supporting Information
Spectra data and copies of 1H NMR and 13C NMR spectra of all compounds. This material is available free
of charge via the Internet at http://pubs.acs.org.
■ AUTHOR INFORMATION
Corresponding Author
*Fax: +86-311-80787431. zhanhui@mail.nankai.edu.cn
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ORCID
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Zhan-Hui Zhang: 0000-0002-1082-5773
Author Contributions
9
Mo Zhang and Meng-Nan Chen contributed equally.
Notes
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The authors declare no competing financial interest.
■ ACKNOWLEDGMENTS
We gratefully acknowledge the National Natural Science Foundation of China (No. 21272053) and the
Science, Technology Research Foundation of Hebei Normal University (L2018Z06) and National
Undergraduate Training Programs for Innovation and Entrepreneurship (201910094001) for financial
support.
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2-Amino-4H-pyran-3,5-dicarbonitrile Derivatives
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Mo Zhang, Meng-Nan Chen, Jiao-Mian Li, Nan Liu and Zhan-Hui Zhang*
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