An efficient and one-pot green synthesis of novel 6-oxo-7-aryl-6,7-dihydrochromeno pyrano[2,3-b]pyridine derivatives

Article abstract of DOI:10.1016/j.tetlet.2018.08.038

A simple and efficient protocol has been developed for the construction of novel 6-oxo-7-aryl-6,7-dihydrochromenopyrano[2,3-b]pyridine derivatives using one-pot, three-component cyclocondensation of 4-hydroxycoumarin, various aromatic aldehydes and 2-amin

Full text of DOI:10.1016/j.tetlet.2018.08.038

Accepted Manuscript
An efficient and one-pot green synthesis of novel 6-oxo-7-aryl-6,7-dihydro-
chromeno pyrano[2,3-b]pyridine derivatives
Abolfazl Olyaei, Zahra Shafie, Mahdieh Sadeghpour
PII:
S0040-4039(18)31030-X
https://doi.org/10.1016/j.tetlet.2018.08.038
TETL 50213
DOI:
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
26 June 2018
16 August 2018
20 August 2018
Please cite this article as: Olyaei, A., Shafie, Z., Sadeghpour, M., An efficient and one-pot green synthesis of novel
6
-oxo-7-aryl-6,7-dihydrochromeno pyrano[2,3-b]pyridine derivatives, Tetrahedron Letters (2018), doi: https://
doi.org/10.1016/j.tetlet.2018.08.038
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7
-aryl-6,7-dihydrochromenopyrano[2,3-b]pyridine
derivatives
Abolfazl Olyaei *, Zahra Shafie , Mahdieh Sadeghpour
a,
a
b
ArCHO
2
NH2Cl
H N NH2
O
N
NH2
OH
CN
CN
2
O
+
CN
H N CN solvent-free
O
O
2
O
Ar NH2
4a-l
2 examples up to 87%
1
3
o
9
0 C
1

1
Tetrahedron Letters
journal homepage: www.elsevier.com
An efficient and one-pot green synthesis of novel 6-oxo-7-aryl-6,7-dihydrochromeno
pyrano[2,3-b]pyridine derivatives
a,
a
b
Abolfazl Olyaei , Zahra Shafie , Mahdieh Sadeghpour
a
Department of Chemistry, Payame Noor University (PNU), PO BOX 19395-4697, Tehran, Iran
Department of Chemistry, College of Science, Takestan Branch, Islamic Azad University, Takestan, Iran
b
—
——
A CR o Tr r eI sCp oL n Ed inIgNa uF t hO or. Tel.: +0098-28-33376366; Af a Bx : S+ T0 0R9 8A- 2C8 -T3 3
26400; e-mail: Olyaei_a@pnu.ac.ir
2
Article history:
Received
Received in revised form
Accepted
A simple and efficient protocol has been developed for the construction of novel 6-oxo-7-aryl-
6,7-dihydrochromenopyrano[2,3-b]pyridine derivatives using one-pot, three-component
cyclocondensation of 4-hydroxycoumarin, various aromatic aldehydes and 2-aminoprop-1-ene-
1,1,3-tricarbonitrile using 10 mol % guanidine hydrochloride as the organocatalyst under
o
Available online
solvent-free conditions at 90 C for the first time. The significant features of this protocol are
operational simplicity, provide good to high yields, avoidance of toxic solvents, straightforward
work-up, no column chromatographic purification and atom-economy which is considered to be
relatively environmentally benign.
Keywords:
chromene
2
4
-aminoprop-1-ene-1,1,3-tricarbonitrile
-hydroxycoumarin
2
009 Elsevier Ltd. All rights reserved.
guanidine hydrochloride
The chromene skeleton is considered as one of the most
important heterocyclic ring systems in organic synthetically
chemistry and is implanted in many edible fruits and vegetables.1
These compounds have occupied an important place in drug
research because of their various biological and pharmacological
activities such as antioxidant, antileishmanial, antibacterial,
antifungal, hypotensive, anticoagulant, antiviral, diuretic,
at synthesis of polyfunctionalized heterocyclic moieties,28 we
considered it necessary to develop a general rapid, high yielding,
environmentally benign and easy synthetic protocol for a variety
of chromene derivatives.
We report in this paper, an efficient and one-pot synthesis of
a variety of chromene derivatives namely 6-oxo-7-aryl-6,7-
dihydrochromeno pyrano[2,3-b]pyridines 4, catalyzed by
guanidine hydrochloride as organocatalyst. In order to find the
most appropriate reaction conditions and to evaluate the catalytic
2
antiallergenic, and antitumor activities. Other properties such as
3
4
5
laser dyes, optical brighteners, fluorescence markers,
6
7
pigments, cosmetics, and potent biodegradable agrochemicals
efficiency of
guanidinium chloride, a model study was
are well known for decades. Recently, there have been many
methods reported for the preparation of chromenes and their
derivatives such as dihydropyrano[3,2-c]chromenes by three-
component condensations of 4-hydroxycoumarin, aldehydes and
malononitrile in the presence of different catalysts such as basic
conducted to determine the best conditions for the synthesis of
8,10-diamino-6-oxo-7-phenyl-6,7-dihydrochromeno[3',4':5,6]
pyrano[2,3-b]pyridine-9-carbonitrile (4a) (Table 1). The solvents
2 3
H O, CH CN, EtOH, 1,4-dioxane, THF, and solvent-free
conditions in the presence of 10 mol % guanidinium chloride
catalyst were tested (Table 1, entries 1-8). As can be seen in
Table 1, the reaction was found to proceed slowly in the protic
solvents under reflux and a low yield of the product observed
after 150 min (Table 1, entries 1-2). Also, it was revealed that the
reaction did not proceed in the presence of the catalyst when the
reaction was carried out in refluxing aprotic solvents such as
8
9
10
ionic liquid, thiourea dioxide, ammonium acetate, potassium
1
1
12
13
14
phthalimide, Fe
3
O
4
nanoparticles, Mg(ClO
4 2 2 4
) , Na SO , iron
1
5
16
ore pellet,
tetragonal ZrO
potassium phthalimide-N-oxyl (POPINO),
nanoparticle (t-ZrO NP), potassium sodium
2
O , Ni@Imine-Li -MMT and nano-SiO .
2 3 2
1
7
2
1
8
19
+
20
21
tartrate, nano-Al
-Aminoprop-1-ene-1,1,3-tricarbonitrile has attracted a great
deal of interest due to its wide applications in the field of
pharmaceuticals. The title reagent had great applicability in
heterocyclic synthesis since it was used for the synthesis of
pyridines, pyrimidines, pyridazines, thiophenes, thiazoles and
2
3
CH CN, THF and 1,4-dioxane for 150 min (Table 1, entries 3-5).
2
2
In the next step, the model reaction was also examined under
solvent-free conditions in the presence of the 10 mol% catalyst.
The reaction was conducted at a range of temperatures, including
2
3,24
o
their analogs.
It should be noted that this compound in the
70, 90 and 120 C. It was found that, by increasing temperature
o
o
synthesis of chromene derivatives has been less widely used, and
few articles have been reported so far in literature.25,26 Recently,
we have reported an efficient tandem reaction approach to the
synthesis of 12H-benzo[5,6]chromeno[2,3-b]pyridines from 2,3-
dihydroxynaphthalene, 2-aminoprop-1-ene-1,1,3-tricarbonitrile
and aldehydes using 10 mol % guanidine hydrochloride as the
from 70 C to 90 C the yield of the product was improved (Table
1, entries 6-7). It should be noted that by increasing reaction time
o
at 90 C showed no significant change in the yield of the reaction.
o
The yield also decreased by increasing temperature from 90 C to
o
120 C (Table 1, entry 8). We also evaluated the quantity of
o
catalyst required for the synthesis of compound 4a at 90 C.
Catalyst loadings in the range of 5–20 mol% were tested (Table
1, entries 7, 9-11). A low yield of the product was observed in the
presence of the 5 mol% catalyst. Loading of the catalyst from 10
to 20 mol% did not improve yields to a greater extent. Thus,
catalyst under solvent-free conditions.27 Thus, in view of the
importance of chromenes for diverse therapeutic activity and in
continuation to our endeavor of developing methodologies aimed

2
loading of 10 mol% guanidine hydrochloride under solvent-free
3
boiling CH CN and the resulting precipitate was filtered and the
conditions was sufficient to push the reaction forward (Table 1,
entry 7).
pure product was obtained.
Encouraged by the successful cyclocondensation of 4-
hydroxycoumarin, various aromatic aldehydes and 2-aminoprop-
1-ene-1,1,3-tricarbonitrile under solvent-free conditions to give
Table 1. Optimization of reaction conditions for the synthesis of
a
4
a
Amount
of
catalyst
6-oxo-7-aryl-6,7-dihydrochromeno
pyrano[2,3-b]pyridine
Temperature
Time
(min)
Yield
(%)
Entry
Solvent
o
b
derivatives, we next attempted on the formation of the product 4a
by executing the reaction of 4-hydroxycoumarin (1.0 mmol) and
benzaldehyde (1.0 mmol) with double molar ratios of
malononitrile under similar reaction conditions. The result
(
C)
1
2
3
4
5
6
7
8
9
10 mol%
10 mol%
10 mol%
10 mol%
10 mol%
10 mol%
10 mol%
10 mol%
5 mol%
15 mol%
20 mol%
H
2
O
reflux
reflux
reflux
reflux
reflux
70
90
120
90
90
150
150
150
150
150
90
60
60
60
60
30
25
-
-
-
70
82
73
65
83
83
EtOH
CH
3
CN
1,4-dioxane
showed that the product
2-amino-4-phenyl-5-oxo-4H,5H-
THF
pyrano-[3,2-c]chromene-3-carbonitrile (5) was obtained as only
product instead of expected target product 4a (Scheme 2).
-
-
-
-
-
-
1
1
0
1
OH
CHO
90
60
a
Reaction conditions: 4-hydroxycoumarin (1.0 mmol), benzaldehyde (1.0
mmol), and 2-aminoprop-1-ene-1,1,3-tricarbonitrile (1.0 mmol), solvent 5
mL.
Isolated yields.
+
+
2
CN
NC
b
O
O
Using the optimized conditions (solvent-free, 10 mol%
o
NH2Cl
catalyst, 90 C), a series of products 4a–l were synthesized with
solvent-free
this simple reaction procedure (Scheme 1).29 The reaction time
and percentage yield for each of the products are presented in
Figure 1.
o
90 C
H N
NH2
2
OH
CN
O
NH2
CN
O
N
NH2
CN
CN
+
ArCHO
+
O
O
+
O
OH
H N
CN
3
O
O
NH2
1
2
3
NH Cl
2
solvent-free
5
4a
o
90 C
H N
NH2
2
not formed
Scheme 2. Synthesis of pyrano-[3,2-c]chromene 5
O
N
NH2
1
Identification of 4a–l was carried out on the basis of H-NMR,
1
3
C-NMR, FT-IR, mass spectra and elemental analysis. It is very
O
important to mention here that in the Mass spectra of these
compounds showed the base peak at m/z = 305 which is related
to the general fragmentation pattern in these compounds include
loss of the phenyl derivatives. This fragmentation also confirms
the structure of the synthesized compounds.
CN
O
Ar
NH2
4
a-l
Scheme 1. Synthesis of 6-oxo-7-aryl-6,7-dihydrochromenopyrano
2,3-b]pyridine derivatives 4
The proposed mechanism for the preparation of 6-oxo-7-aryl-
[
6
,7-dihydrochromeno pyrano[2,3-b]pyridines is depicted in
Scheme 3. As is shown, nucleophilic attack of 4-
hydroxycoumarin to the activated aldehyde (by guanidine
The results indicated that this guanidine hydrochloride
catalyzed three-component reaction worked well for a wide range
of aryl aldehydes possessing various functional groups including
electron-donating and electron-withdrawing substituents. In all
cases, the reaction proceeded smoothly to produce the
corresponding product in good to high yield. However, when
some aliphatic aldehydes such as acetaldehyde and
propionaldehyde were used in this protocol under the above
optimized conditions, unfortunately, the expected products could
not be obtained. It should be noted that the purification of the
title compounds is very easy. After cooling the reaction mixture
hydrochloride), followed by
H
2
O
elimination provides
intermediate 6. Next, the Michael addition of 2-aminoprop-1-
ene-1,1,3-tricarbonitrile (activated by guanidine hydrochloride)
to intermediate 6 provides the intermediate 7 which then
undergoes tautomerization and subsequent intramolecular
cyclization twice, to afford final the corresponding 6-oxo-7-aryl-
6
,7-dihydrochromeno pyrano[2,3-b]pyridines 4.
3
to room temperature, CH CN was added to the mixture and the
solid products were formed, which can be easily separated by
simple filtering. The crude product was stirred for 5 min in
O
N
NH2
CN
O
N
O
O
O
NH2
O
NH

3
In summary, we demonstrated a simple and direct route for
the one-pot green synthesis of novel 6-oxo-7-aryl-6,7-
dihydrochromeno pyrano[2,3-b]pyridines from easily available
substrates using guanidinium chloride as organocatalyst. The
o
reactions were carried out under solvent-free conditions at 90 C
produced the corresponding products in good to high yields. The
notable advantages of this work are simple workup, avoidance of

4
CN
H
O
CN
CN
N
OH
O
Ar
O
NH Cl
2
C
CN
CN
H N
3
H N
NH2
2
O
2
+
ArCHO
O
1
O
O
6
O
Ar
NH2
2
7
NH2
NH
O
O
N
N
O
N
NH2
CN
C
H
C
C
C
O
O
O
CN
CN
O
Ar
NH2
O
Ar
NH2
O
Ar
4
NH2
8
9
Scheme 3. Proposed mechanism for the guanidinium chloride catalyzed synthesis of 6-oxo-7-aryl-6,7-dihydrochromeno pyrano[2,3-b]
pyridines 4
toxic solvents, no column chromatographic purification which is
considered to be relatively environmentally benign.
10. Kanakaraju, S.; Prasanna, B.; Basavoju, S.; Chandramouli, G. V.
P. Arab. J. Chem. 2017, 10, S2705.
1
1
1. Kiyani, H.; Ghorbani, F. Res. Chem. Intermed. 2015, 41, 4031.
2. Khoobi, M.; Modiri Delshad, T.; Vosooghi, M.; Alipour, M.;
Hamadi, H.; Alipour, E.; Pirali Hamedani, M.; Sadatebrahimi, S.
E.; Safaei, Z.; Foroumadi, A.; Shafiee, A. J. Magn. Magn. Mater.
2015, 375, 217.
Acknowledgments
The authors thank the Research Council of Payame Noor
University for financial support.
1
1
3. Emtiazi, H.; Amrollahi, M. A. Bulg. Chem. Commun. 2017, 49,
4
78.
4. Maghsoodlou, M. T.; Masoumnia, A.; Mousavi, M. R.; Hazeri, N.;
Supplementary Material
Aboonajmi, J.; Habibi-Khorasani, S. M.; Kiaee, S. Iran. J. Catal.
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015, 5, 169.
1
1
5. Sheikhhosseini, E.; Sattaei Mokhtari, T.; Faryabi, M.; Rafiepour,
A.; Soltaninejad, S. Iran. J. Chem. Chem. Eng. 2016, 35, 43.
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Supplementary data associated with this article can be found,
in the online version.
1
074.
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8. (a) Khoeiniha, R.; Olyaei, A.; Saraei, M. Synth. Commun. 2018,
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8, 155; (b) Khoeiniha, R.; Olyaei, A.; Saraei, M. J. Heterocycl.
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2
9. General procedure for the synthesis of 6-oxo-7-aryl-6,7-
dihydrochromeno pyrano[2,3-b]pyridines 4: In a 25 mL round
5
6
.
.
Bissell, E. R.; Mitchell, A. R.; Smith, R. E. J. Org. Chem. 1980,
bottom flask,
a mixture of 4-hydroxycomarin (1.0 mmol),
4
5, 2283.
aldehyde (1.0 mmol), 2-aminoprop-1-ene-1,1,3-tricarbonitrile (1.0
mmol) and guanidine hydrochloride (10 mol %) were taken, and
Ellis, G. P. In The Chemistry of Heterocyclic of Compounds.
Chromenes, Harmones and Chromones; Weissberger, A., Taylor,
E. C., Eds.; John Wiley: New York, NY,1977; Chapter II, pp 11-
o
the mixture was stirred at 90 C in an oil bath for appropriate
amount of time as indicated in Figure 1. The progress of the
reaction was monitored by thin-layer chromatography (TLC).
After completion, the reaction mixture was cooled to room
1
3.
7
8
9
.
.
.
Hafez, E. A. A.; Elnagdi, M. H.; Elagamey, A. G. A.; El-Taweel,
F. M. A. A. Heterocycles 1987, 26, 903.
Patel, D. S.; Avalani, J. R.; Raval, D. K. J. Saudi Chem. Soc.
temperature and CH
was allowed to form. The precipitate was filtered, washed with
CH CN and dried. The crude product was stirred for 5 min in
boiling CH CN and the resulting precipitate was filtered. The
product 4 thus obtained was found to be pure upon H and C-
3
CN (5 mL) was added and then a precipitate
2
016, 20, S401.
3
Mansoor, S. S.; Logaiya, K.; Aswin, K.; Sudhan, P. N. J. T. U.
Sci. 2015, 9, 213.
3
1
13

5
NMR, mass spectra, elemental analyses, and TLC examination.
,10-Diamino-6-oxo-7-phenyl-6,7-dihydrochromeno
14 4 3
92, 91, 77; Anal. calcd. for C22H N O : C, 69.11; H, 3.66; N,
14.66. Found: C, 69.17; H, 3.59; N, 14.71.
8
Highlightes
●
●
One-pot synthesis of 6-oxo-7-aryl-6,7-
dihydrochromenopyrano[2,3-b]pyridines
was
described.
Guanidine hydrochloride as the organocatalyst
was used.
●
Aromatic aldehydes containing various functional
groups are well tolerated in the reaction.
●
Double heterocyclization was carried out in the
reaction.
[
3',4':5,6]pyrano[2,3-b]pyridine-9-carbonitrile (4a): Light
o
-1
brown powder; m.p. = 340 C (dec.); IR (KBr, cm ): 3440, 3340,
3
1
1
239, 3043, 2846, 2210, 1716, 1654, 1612, 1562, 1481, 1369,
1
268, 1187, 1049; H NMR (300 MHz, DMSO-d
6
): δ = 4.92 (s,
), 6.87-7.00
H, methine-H), 6.38 (s, 2H, NH ), 6.47 (s, 2H, NH
2
2
(
m, 3H, Ar-H), 7.12-7.22 (m, 4H, Ar-H), 7.39-7.45 (m, 1H, Ar-
1
3
H),7.63 (d, 1H, J = 7.8 Hz, Ar-H); C NMR (75 MHz, DMSO-
d
1
1
6
): 72.45, 90.78, 105.99, 114.04, 116.38, 116.97, 117.00, 122.84,
25.25, 127.37, 128.64, 133.14, 143.23, 152.52, 154.99, 157.33,
+
57.49, 160.13, 160.39, 160.87; MS m/z (%): 382 (M) , 306, 305
(100), 277, 252, 239, 223, 211, 185, 169, 157, 140, 121, 105, 93,