Sodium ethylene diamine tetraacetate catalyzed synthesis of chromene derivatives via multi-component reactions at low catalyst loading

Article abstract of DOI:10.1007/s11164-017-3015-3

An efficient and practical protocol for the synthesis of chromenes derivatives catalyzed by a low-loading sodium ethylene diamine tetraacetate (2?mol%) as a catalyst via multicomponent reaction is reported. A wide range of aromatic aldehydes easily underg

Full text of DOI:10.1007/s11164-017-3015-3

Res Chem Intermed
DOI 10.1007/s11164-017-3015-3
Sodium ethylene diamine tetraacetate catalyzed
synthesis of chromene derivatives via multi-component
reactions at low catalyst loading
1
1
1
2
Lu Chen
•
Jiaqi Lin
•
Bin Chen
•
Liqin Zhao
Received: 5 March 2017 / Accepted: 19 June 2017
Ó Springer Science+Business Media B.V. 2017
Abstract An efficient and practical protocol for the synthesis of chromenes
derivatives catalyzed by a low-loading sodium ethylene diamine tetraacetate
(
2 mol%) as a catalyst via multicomponent reaction is reported. A wide range of
aromatic aldehydes easily undergo condensations with malononitrile and 4-hy-
droxycoumarin (4-hydroxy-6-methyl-2-pyrone or dimedone) under mild conditions
to afford the desired products of good purity in excellent yields. This protocol has
several advantages, such as mild conditions, high yields, and an inexpensive cat-
alyzed system.
Keywords EDTA-4Na Á Chromenes Á Multicomponent reaction Á Atom
economy
Introduction
Chromenes are the specific selection owing to their important pharmaceutical and
biological properties, whose derivatives exist widely in natural products and exhibit
many features such as anticancer, anti-anaphylactin, anticoagulant, diuretic, and
spasmolytic activitites [1–4]. Especially, 2-amino-4H-chromenes have been applied
to cure cancer, psoriasis and rheumatoids, and are also widely used in laser dyes,
optical brighteners, pigments, cosmetics and agrochemicals (Fig. 1) [1, 4–7]. Hence,
&
Lu Chen
wyuchemcl@126.com
Liqin Zhao
zhaoliqin@tyut.edu.cn
1
2
School of Chemical and Environmental Engineering, Wuyi University, Jiangmen, China
Taiyuan University of Technology, Taiyuan, China
123

L. Chen et al.
Fig. 1 4H-Benzo[b]pyran and representative derivatives exhibiting biological activity
the preparation of 4H-pyrans has been receiving renewed interest of researchers
because of their wide range of biological, industrial and synthesis applications.
Furthermore, the development of a practical methodology is available to synthesize
biologically active heterocyclic compounds and often plays an important role in
pharmaceutical discovery. The multicomponent reactions (MCRs) strategy, which
has considerable merits over conventional two-component reactions in some
aspects, such as variable and high bond forming efficiency and atom economy, have
been broadly applied in combinatorial and medicinal chemistry [8].
Many protocols for synthesis have been reported, including the use of
microwaves, [9] ultrasonic irradiation [10] and a variety of reagents such as
cerium(III) chloride [11], acidic ionic liquids [12, 13], deep eutectic solvents
[
[
14, 15], Sc(OTf) [16], NbCl [17], L-proline [18], ZnO zeolite [19], meglumine
3 5
20], silica-bonded S-sulfonic acid [21], glycerol [22], Cu(II) oxymetasilicate [23],
potassium phosphate [24], sodium selenate [25], S-proline [26], MgO [27],
tetrabutylammonium bromide [28], CuO nanoparticles [29], Fe O nanoparticles
2
3
[
(
30], starch solution [31], Fe O @SiO magnetic nanocatalyst [32], and RuBr
3 4 2 2
PPh ) [33]. Although these methods show many advantages, some of them meet
3
4
limitations in special aspects such as sekeletoncomplicated preparation of catalyst,
long reaction times, relatively expensive catalyzed systems, harsh reaction
conditions, and even tedious work-ups. As our goal is to design an inexpensive
catalyzed system to promote the synthesis of various biologically active chromenes,
we have to note that the price of EDTA-4Na is US$33 per 100 g. Hence, we hope to
report here sodium ethylene diamine tetraacetate (EDTA-4Na) as a cheap and
efficient catalyst for the synthesis of chromenes under mild conditions via MCRs
strategy.
Experimental
Apparatus and analysis
Unless otherwise noted, all commercial materials and solvents were used without
further purification. Melting points were measured on an Electrothemal X6
microscopy digital melting point apparatus and are corrected. IR spectra were
1
23

Sodium ethylene diamine tetraacetate catalyzed synthesis…
obtained as potassium bromide pellets or as liquid films between two potassium
1
bromide pellets with a Brucker Vector 22 spectrometer. H NMR spectra were
1
3
recorded in DMSO at 300 or 400 MHz, and C NMR spectra were recorded in
DMSO at 75 or 100 MHz, respectively. C, H and N analysis were performed by a
Perkin-Elmer 2400 CHN elemental analyzer. HRMS was carried out on a MAT
9
5XP (Thermo).
General procedures for synthesis of chromenes
An equimolar (2 mmol) mixture of an aromatic aldehyde (1), malononitrile (2),
4
2
5
-hydroxycoumarin (3) or 4-hydroxy-6-methyl-2-pyrone (5) or dimedone (7) and
mol% sodium ethylene diamine tetraacetate was vigorously stirred at 50°C in
mL EtOH:H O (40:60) for the specific times indicated in Tables 2 and 3. The end
2
of the reaction was monitored by TLC. Then, the crude product obtained was poured
into cold water. The resulting precipitated solid was purified by recrystallization
from hot methanol to afford the pure products 4 or 6 or 8. The structures of all the
1
13
products were identified by IR, H NMR, C NMR, elemental analysis and HRMS
spectra. The spectral data of selected products are given below:
2
-Amino-5-oxo-4-phenyl-4H,5H-pyrano[3,2-c]chromene-3-carbonitrile (4a)
-1 1
IR (KBr): 3379, 3288, 3181, 2199, 1710, 1675, 1607 cm ; H NMR (300 MHz,
DMSO-d6) d 7.90(d, J = 7.8 Hz, 1H, ArH), 7.65–7.68(m, 1H, ArH), 7.40–7.48(m,
1
H, ArH), 7.20–7.32(m, 5H, ArH), 4.41(s, H, CH). C NMR: (75 MHz, DMSO-d6)
3
2
d 160.6, 158.9, 154.5, 153.2, 144.3, 133.9, 129.7, 128.7, 128.2, 125.8, 123.6, 120.4,
1
3
17.6, 114.3, 105.4, 59.1. HRMS Calculated for C H N O : 316.0848, found:
19 12 2 3
16.0842.
2
-Amino-4-(4-chlorophenyl)-5-oxo-4H,5H-pyrano[3,2-c]chromene-3-carbonitrile
4c)
(
-1 1
IR (KBr): 3386, 3313, 3191, 2194, 1714, 1677, 1608 cm ; H NMR (300 MHz,
DMSO-d6) d 7.88(d, J = 7.9 Hz, 1H, ArH), 7.65–7.68(t, H, ArH), 7.39–7.47(m,
2
H, ArH), 7.34(d, J = 8.5 Hz, 2H, ArH), 7.26(d, J = 8.5 Hz, 2H, ArH), 4.44(s, H,
1
3
CH). C NMR: (75 MHz, DMSO-d ) d 160.6, 159.2, 154.6, 153.3, 143.3, 133.9,
6
132.8, 130.6, 129.4, 125.7, 123.6, 120.1, 117.3, 113.9, 104.6, 58.8. HRMS
Calculated for C H ClN O : 350.0458, found: 350.0455.
1
9
11
2 3
2
-Amino-4-(4-nitrophenyl)-5-oxo-4H,5H-pyrano[3,2-c]chromene-3-carbonitrile
4f)
(
-
1
1
IR (KBr): 3480, 3430, 3370, 3337, 2196, 1718, 1674, 1606 cm
300 MHz, DMSO-d6) d 8.15(d, J = 8.6 Hz, 1H, ArH), 7.91(d, J = 7.7 Hz, 1H,
ArH), 7.67–7.72(m, 1H, ArH), 7.55(d, J = 8.6 Hz, 2H, ArH), 7.44–7.49(m, 2H,
; H NMR
(
1
3
ArH), 4.63(s, H, CH). C NMR: (75 MHz, DMSO-d ) d 160.7, 159.3, 154.9, 153.5,
6
123

L. Chen et al.
151.8, 147.6, 134.2, 130.3, 125.8, 124.7, 123.5, 119.9, 117.6, 113.9, 103.8, 57.9.
HRMS Calculated for C H N O : 361.0699, found: 361.0695.
1
9 11 3 5
2
-Amino-4-(4-methoxyphenyl)-5-oxo-4H,5H-pyrano[3,2-c]chromene-3-carbonitrile
4j)
(
-
1 1
IR (KBr): 3391, 3314, 3194, 2196, 1715, 1676, 1609 cm ; H NMR (300 MHz,
DMSO-d6) d 7.87(d, J = 7.6 Hz, 1H, ArH), 7.54–7.57(m, 1H, ArH), 7.39–7.43(m,
2
H, ArH), 7.13(d, J = 8.5 Hz, 2H, ArH), 6.83(d, J = 7.7 Hz, 2H, ArH), 4.41(s, H,
1
3
CH), 3.73(s, 3H, CH3). C NMR: (75 MHz, DMSO-d ) d 160.8, 159.6, 158.9,
6
1
54.2, 152.9, 136.5, 133.8, 129.6, 125.3, 123.5, 120.5, 117.6, 114.9, 113.9, 105.3,
9.3, 56.4. HRMS Calculated for C H N O : 346.0954, found: 346.0948.
5
2
0 14 2 4
2
-Amino-7-methyl-5-oxo-4-phenyl-4H,5H-[4,3-b]pyran-3-carbonitrile (6a)
-
1
1
; H NMR
IR (KBr): 3397, 3316, 3201, 2927, 2198, 1712, 1677, 1634 cm
(
300 MHz, DMSO-d6) d 7.19–7.37(m, 5H, ArH), 6.29(s, 1H, CH), 4.28(1H, CH),
.22(3H, CH3). C NMR: (75 MHz, DMSO-d ) d 162.7, 161.0, 158.7, 157.8,
43.2, 133.5, 128.1, 127.2, 126.6, 119.0, 112.5, 100.4, 97.6, 57.5, 36.0, 19.1; HRMS
13
2
1
6
Calculated for C H N O : 280.0848, found: 280.0842.
6 12 2 3
1
2-Amino-4-(4-methoxyphenyl)-7-methyl-5-oxo-4H,5H-pyrano[4,3-b]pyran-3-
carbonitrile (6d)
-
1
1
; H NMR
IR (KBr): 3398, 3321, 3202, 2925, 2197, 1713, 1675, 1642 cm
(
300 MHz, DMSO-d6): d 7.13–6.83(m, 4H, ArH), 6.31(s, 1H, CH), 4.56(s, 1H,
CH), 3.63(s, 3H, CH ), 2.20(s, 3H, CH ); C NMR (75 MHz, DMSO-d6): d 163.8,
13
3
3
1
5
3
61.5, 159.9, 156.6, 132.7, 130.5, 129.4, 126.6, 122.3, 120.5, 113.8, 101.5, 99.6,
8.3, 55.6, 38.3, 20.8; HRMS Calculated for C H N O : 310.0954, found:
10.0947.
1
7 14 2 4
2-Amino-3-cyano-4-(4-benzyl)-7,7-dimethyl-5-oxo-4H-5,6,7,8-
tetrahydrobenzo[b]pyran (8a)
-1 1
IR (KBr): 3396, 3325, 3252, 3212, 2964, 2200, 1681, 1605, 1215, 1038 cm ; H
NMR (400 M, DMSO-d6): d (J, Hz): 0.90 (s, 3H, CH ), 0.99 (s, 3H, CH ), 2.05 (d,
3
3
J = 16.2 Hz, 1H), 2.21 (d, J = 16.2 Hz, 1H), 3.57 (s, 2H, CH ), 4.12 (s, 1H, CH),
2
1
3
7
1
3
7
.11–7.20 (m, 3H, ArH), 7.25–7.29 (m, 2H, ArH). C NMR (100 M, DMSO-d6):
96.7, 163.6, 159.6, 145.8, 129.4, 128.2, 127.7, 120.8, 113.8, 59.4, 51.1, 40.3, 36.7,
2.9, 29.5, 27.9. Found, %: C 73.39; H 6.33; N 9.59. C H N O . Calculated, %: C
1
8 18 2 2
3.45; H 6.16; N 9.52.
1
23

Sodium ethylene diamine tetraacetate catalyzed synthesis…
0
2-Amino-3-cyano-4-(4 -chlorobenzyl)-7,7-dimethyl-5-oxo-4H-5,6,7,8-
tetrahydrobenzo[b]pyran (8b)
-1 1
IR (KBr):: 3382, 3184, 2189, 1675, 1605, 1217, 1034 cm ; H NMR (400 M,
DMSO-d6): (J, Hz): 0.91 (s, 3H, CH ), 0.99 (s, 3H, CH ), 2.09–2.24 (m, 2H, CH ),
2
3
3
2
.48 (s, 2H, CH ), 4.16 (s, H, CH), 7.13 (d, J = 8.5 Hz, 2H, ArH), 7.31 (d,
2
1
3
J = 8.6 Hz, 2H, ArH). C NMR (100 M, DMSO-d6): 196.8, 163.9, 159.7, 144.7,
32.2, 129.8, 129.1, 120.2, 113.8, 58.9, 51.2, 40.6, 36.8, 33.4, 29.7, 28.2. Found, %:
C 65.70; H 5.31; N 8.58. C H ClN O . Calculated, %: C 65.75; H 5.21; N 8.52.
1
1
8
17
2 2
0
-Amino-3-cyano-4-(4 -nitrobenzyl)-7,7-dimethyl-5-oxo-4H-5,6,7,8-
tetrahydrobenzo[b]pyran (8d)
2
-
1
1
; H NMR
IR (KBr): 3383, 3330, 2191, 1677, 1606, 1216, 1039, 1210 cm
400 M, DMSO-d6): 0.91 (s, 3H, CH ), 1.00 (s, 3H, CH ), 2.10–2.25 (s, 3H,
3 3
(
CH ), 2.38–2.36 (m, 2H, CH ), 2.44 (s, 2H, CH ), 4.32 (s, 1H, CH), 7.41 (d,
3
2
2
1
3
J = 8.7 Hz, 2H, ArH), 8.14 (d, J = 8.6 Hz, 2H, ArH). C NMR (100 M,
DMSO-d6): 197.3, 165.5, 159.7, 153.4, 147.5, 129.6, 124.8, 120.5, 112.7, 57.9,
5
0.6, 40.6, 36.8, 32.9, 29.5, 27.9. Found, %: C 63.68; H 4.98; N 12.45.
C H N O . Calculated, %: C 63.71; H 5.05; N 12.38.
1
8 17 3 4
0
2-Amino-3-cyano-4-(4 -methylbenzyl)-7,7-dimethyl-5-oxo-4H-5,6,7,8-
tetrahydrobenzo[b]pyran (8l)
-1 1
IR (KBr): 3427, 3331, 3222, 2958, 2192, 1677, 1603, 1207, 1034 cm ; H NMR
(
400 M, DMSO-d6): 0.90 (s, 3H, CH ), 0.99 (s, 3H, CH ), 2.20(s, 3H, CH ),
3 3 3
2
2
1
2
7
.04–2.21 (m, 2H, CH ), 2.48 (s, 2H, CH ), 4.08 (s, 1H, CH), 6.98(d, J = 8.1 Hz,
2 2
1
3
H, ArH), 7.05 (d, J = 8.1 Hz, 2H, ArH). C NMR(100 M, DMSO-d6): 196.7,
63.4, 159.5, 142.9, 136.6, 129.9, 128.2, 120.8, 113.9, 59.4, 50.8, 40.3, 36.3, 32.8,
9.5, 27.8, 21.6. Found, %: C 73.96; H 6.52; N 9.16.C H N O . Calculated, %: C
1
9 20 2 2
4.00; H 6.54; N 9.08.
0
2-Amino-3-cyano-4-(4 -methoxybenzyl)-7,7-dimethyl-5-oxo-4H-5,6,7,8-
tetrahydrobenzo[b]pyran (8m)
-
1
1
; H NMR
IR (KBr): 3374, 3323, 3183, 2194, 1684, 1607, 1214, 1035 cm
(
CH ), 2.26 (s, 2H, CH ), 2.47 (s, 2H, CH ), 3.67 (s, 3H, OCH ), 4.08 (s, 1H,
400 M, DMSO-d6): 0.90 (s, 3H, CH ), 0.99 (s, 3H, CH ), 2.04–2.21 (m, 2H,
3 3
2
2
2
3
1
3
CH), 6.80 (d, J = 8.7 Hz, 2H, ArH), 7.01 (d, J = 8.7 Hz, 2H, ArH).
NMR(100 M, DMSO-d6): 196.7, 163.5, 128.3, 127.3, 120.8, 113.8, 59.4, 51.3,
C
40.3, 36.6, 32.6, 29.2, 27.6. Found, %: C 70.38; H 6.28; N 8.59.C H N O .
19 20 2 3
Calculated, %: C 70.35; H 6.21; N 8.64.
123

L. Chen et al.
Results and discussion
We initially began our investigation with the reaction of an equimolar (2 mmol)
mixture of 4-bromo-benzaldehyde 1, malononitrile 2, and 4-hydroxycoumarin 3 and
10 mol% EDTA-4Na at 80 °C in a Schlenk tube with 5 mL 95% ethanol. The target
product 4a was obtained with 75% yield smoothly. Under the inspiration of this
good result, we optimized this model reaction with the different conditions such as
ratio (EtOH:H O), reaction temperature and catalyst loading. After screening of this
2
reaction, the yield of the desired compounds 4a was improved to 91% (Table 1,
Entry 14).
When the mixture of aldehyde 1, malononitrile 2, and 4-hydroxycoumarin 3 were
employed in the solution of 5 ml EtOH:H O (40:60) in the presence of 2 mol%
2
sodium ethylene diamine tetraacetate at 50 °C, high yields of 2-amino-4-aryl-3-
cyano-5-oxo-4H,5H-pyrano-[3,2-c]chromenes 4 were obtained within 40 min, and
representative compounds are shown in Table 2, respectively (Scheme 1).
The effects of electrons and the nature of substituents on the aromatic ring
indicated obvious influences in terms of yields and reaction times. From Table 2, we
found that the aromatic aldehydes with electron-withdrawing functional groups are
employed rapidly to obtain the desired target compounds (4b, 4c), and the aromatic
aldehyde with electron-donating groups (such as 4j, 4k) was employed for
Table 1 Optimizing of synthesis of 3,4-dihydropyrano[c]chromene derivatives
a,b
Entry
Catalyst
mol%)
EtOH:H
(5 mL)
2
O
Temperature
(°C)
Time
(min)
Yield
(%)
(
1
2
3
4
5
6
7
8
9
10
10
10
10
10
10
10
10
10
10
10
0
95:5
80
80
80
80
80
80
70
60
50
40
r.t.
50
50
50
50
50
50
60
60
60
60
60
60
60
60
60
60
60
60
60
60
60
60
60
75
80
81
88
83
52
87
88
90
70
45
Trace
89
91
85
83
86
80:20
60:40
40:60
20:80
0:100
40:60
40:60
40:60
40:60
40:60
40:60
40:60
40:60
40:60
40:60
40:60
1
1
1
1
1
1
1
1
a
0
1
2
3
4
5
6
7
b
1
2
5
15
20
Reaction conditions: 4-hydroxycoumarin (2 mmol), 4-bromo-benzaldehyde (2 mmol), and malononi-
2
trile (2 mmol) in the catalyst in 5 mL EtOH–H O
b
Isolated yield
1
23

Sodium ethylene diamine tetraacetate catalyzed synthesis…
Table 2 Synthesis of 2-amino-4-aryl-3-cyano-5-oxo-4H,5H-pyrano-[3,2-c]chromenes
Scheme 1
a,b
Entry
Ar-
Product
Time/min
Yield %
Mp/°C
Lit. Mp/°C
1
2
3
4
5
6
7
8
9
C
6
H
5
4a
4b
4c
4d
4e
4f
20
15
15
15
15
15
15
20
20
40
40
40
40
35
35
40
91
96
95
95
92
95
90
89
83
81
74
68
78
67
62
68
257–259
250–252
264–266
270–272
246–248
266–268
254–255
250–252
251–253
224–226
256–258
208–210
250–252
256–258
252–254
225–227
256–258 [26]
254 [36]
6 4
4-Br-C H
4-Cl-C
6
6
H
H
4
4
263–265 [26]
271–273 [36]
257–259 [26]
260–262 [34]
254–255 [35]
247–248 [38]
255 [36]
2-Cl-C
2,4-Cl
2
-C
-C
-C
6 3
H
4-NO
2
6 4
H
3-NO
2
6
H
4
4g
4h
4i
3-Br-C
4-CH -C
4-OCH -C
4-HO-C
6
H
4
3
6
H
4
10
11
12
13
14
15
16
a
3
6
H
4
4j
226–228 [35]
258–260 [37]
210–211 [38]
246–248 [39]
256–257 [37]
253–255 [37]
227–229 [40]
6
H
4
4k
4l
2-CH -C
3
6
6
H
H
4
3-CH -C
3
4
4m
4n
4o
4p
3-MeO-4-OH-C
6 3
H
2-Furyl
2-Thionyl
Reaction conditions: 4-hydroxycoumarin (2 mmol), aldehyde (2 mmol), and malononitrile (2 mmol) in
the presence of EDTA-4Na (2 mol%) in 5 mL EtOH–H
b
2
O (40:60 v/v) under 50 °C
Isolated yield
formation of desired product with low yields. On the other hand, the yields of 4l, 4m
and 4n are relatively lower mostly because of their stronger steric hindrance.
Then, we employed 4-hydroxy-6-methyl-2-pyrones as the starting material in
order to broaden the scope of synthesis of 3,4-dihydropyrano[c]chromene, and high
yields of 2-amino-4-aryl-7-methyl-5-oxo-4H,5H- pyrano[4,3-b]pyran-3-carbonitrile
6
were obtained within 45 min, respectively (see Table 3) (Scheme 2).
From Table 3, the results indicated that the reaction speed of the aromatic
aldehyde with electron-withdrawing functional groups is faster than with electron-
donating functional groups (6b, 6c vs. 6d, 6f). On the other hand, the ortho-
substituted aldehydes were employed to obtain relatively low yields compare with
para-substituted aldehydes.
123

L. Chen et al.
Table 3 Synthesis of 2-amino-4-aryl -7-methyl-5-oxo-4H,5H-pyrano[4,3-b]pyran-3-carbonitrile
Scheme 2
a,b
Entry
Ar-
Product
Time (min)
Yield (%)
Mp/°C
Lit. Mp/°C
1
2
3
4
5
6
7
8
9
C
6
H
5
6a
6b
6c
6d
6e
6f
25
20
20
30
30
20
40
35
50
25
45
89
90
92
86
84
91
82
78
75
87
65
233–235
232–234
210–212
203–206
224–226
237–239
266–268
260–262
245–247
235–237
223–225
234–235 [38]
230–231 [40]
211–213 [41]
200–202 [41]
222–223 [40]
235–237 [27]
269–272 [40]
261–263 [40]
243–245 [40]
233–234 [40]
220–222 [40]
4-Cl-C
4-NO -C
4-OCH -C
4-CH -C
3-NO -C
2-Cl-C
2-NO -C
2-OCH
2,4-Cl
2-Furyl
6 4
H
2
6
H
4
3
6
H
4
3
6
H
4
2
6
H
4
4
6
H
4
6j
2
6
H
6h
6i
3
6 4
-C H
1
1
a
0
1
2
-C
6
H
3
6j
6k
Reaction conditions: 4-hydroxy-6-methyl-2-pyrones (2 mmol), aldehyde (2 mmol), and malononitrile
2 mmol) in the presence of EDTA-4Na (2 mol%) in 5 mL EtOH–H
O (40:60 v/v) under 50 °C
(
b
2
Isolated yield
To further explore the potential of EDTA-4Na as a catalyst for heterocyclic
synthesis, we investigated the MCRs reactions involving aromatic aldehyde,
malononitriles and dimedone and acquired the high yields of 2-amino-4-aryl-7-
methyl-5-oxo-4H,5H-pyrano[4,3-b]pyran-3-carbonitrile 8 in about 40 min, respec-
tively (Table 4). Obviously, the catalyst (EDTA-4Na) plays a crucial role in the
success of the reaction in terms of the rate and the yields, and catalyst loading
(
2 mol%) was sufficient to push the reaction forward to complete and to examine
activity of the different aromatic aldehydes, and the results are summarized in
Table 4 (Scheme 3).
The results clearly demonstrated that electronic effects and the nature of
substituents on the aromatic ring show strongly obvious effects in terms of reaction
time under the reaction conditions mentioned above. When aromatic aldehydes
containing electron-donating groups (such as the dimethylamino, methoxy and
methyl groups) were employed (Table 4, Entries 11–17), a longer reaction time was
required in most cases than those of electron-withdrawing groups (such as the nitro
group, and halide) on aromatic rings (Table 4, Entries 2–10).
1
23

Sodium ethylene diamine tetraacetate catalyzed synthesis…
Table 4 Synthesis of 2-amino-4-aryl-7-methyl-5-oxo-4H,5H-pyrano[4,3-b]pyran-3-carbonitrile
Scheme 3
a,b
Entry
Ar-
Product
Time (min)
Yield (%)
Mp/°C
Lit. Mp/°C
1
2
3
4
5
6
7
8
9
C
6
H
5
8a
8b
8c
8d
8e
8f
25
15
10
10
15
15
20
25
20
20
35
30
35
30
35
40
40
30
93
95
90
95
91
90
85
82
93
80
76
91
88
83
84
79
78
86
222–224
233–234
204–206
178–179
229–231
230–232
210–212
149–151
219–221
220–222
209–212
215–216
198–200
221–223
194–196
201–203
198–200
225–228
224–226 [20]
236–238 [21]
200–202 [21]
185–186 [20]
235–236 [20]
228–230 [43]
212–214 [42]
150–152 [44]
215–217 [20]
222–223 [42]
210–213 [46]
216–218 [20]
202–204 [20]
224–225 [20]
190–191 [20]
195–196 [45]
200–201 [20]
226–227 [20]
4-Cl-C
4-Br-C
4-NO -C
3-Cl-C
3-Br-C
3-NO -C
2-Br-C
2-Cl-C
2-NO -C
4-Me N-C
4-Me-C
4-MeO-C
3-Me-C
3-MeO-C
2-Me-C
6 4
H
6 4
H
2
6
H
4
4
4
6 4
H
6 4
H
2
6
H
8g
8h
8i
6
H
4
6 4
H
1
1
1
1
1
1
1
1
1
a
0
1
2
3
4
5
6
7
8
2
6
H
8j
2
6
H
4
8k
8l
6
H
4
6
H
4
4
4
8m
8n
8o
8p
8q
8r
6
H
4
6
H
6
H
4
2-MeO-C
6
H
2-Furyl
Reaction conditions: dimedone (2 mmol), aldehyde (2 mmol), and malononitrile (2 mmol) in the
presence of EDTA-4Na (2 mol%) in 5 mL EtOH–H
b
2
O (40:60 v/v) under 50 °C
Isolated yield
Conclusions
In conclusion, we have employed the inexpensive EDTA-4Na as a catalyst and
developed an efficient and practical strategy for the synthesis of chromenes via a
MCRs strategy in good to excellent yields. This procedure offers several advantages
including mild reaction conditions, cleaner reaction, and higher yields of products,
and will be used as a useful and attractive method for the synthesis of these
compounds.
Acknowledgement We thank Science Foundation for Young Teachers of Wuyi University (2016zk03).
123

L. Chen et al.
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