Magnetic Graphitic Carbon Nitride-Catalyzed Highly Efficient Construction of Functionalized 4 H -Pyrans

Article abstract of DOI:10.1055/s-0036-1589145

A high-yielding, practical, efficient, and environmentally benign one-pot multicomponent synthesis of functionalized 2-amino-4 H -pyrans from β-dicarbonyl compounds, malononitrile, and aldehydes is presented. Good to excellent yields were obtained under m

Full text of DOI:10.1055/s-0036-1589145

SYNLETT
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©
Georg Thieme Verlag Stuttgart · New York
2018, 29, A–E
letter
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Synlett
N. Azizi et al.
Letter
Magnetic Graphitic Carbon Nitride-Catalyzed Highly Efficient
Construction of Functionalized 4H-Pyrans
Najmedin Azizi*a,b
Tahereh Soleymani Ahooieb
0
0
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0
0-
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1-
6
8
5
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X
N
N
N
Mohammad Mahmodi Hashemib
Issa Yavarib
N
N
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N
N
N
N
Easy operation procedure
Good to excellent yields
Truly recyclable catalyst
a
N
N
Chemistry and Chemical Engineering Research Center of Iran,
P.O. Box 14335-186, Tehran, Iran
Department of Chemistry, Science and Research Branch,
Islamic Azad University, Tehran, Iran
azizi@ccerci.ac.ir
N
N
b
N
N
N
O
Ph
CN
CN
Fe3O4@g-C3N4
CHO
CN
O
O
NH2
EtOH (1 mL), 60 °C
0–190 min
O
3
2
1 examples
72–97%
Aryl, alkyl and heteroaryl aldehydes
Dimedone, ethylacetoacetate, acetylacetone
Received: 02.10.2017
Accepted after revision: 08.11.2017
Published online: 03.01.2018
thesis of benzopyrans and their derivatives has attracted
much attention. Polyfunctional 4H-pyrans demonstrate a
4
DOI: 10.1055/s-0036-1589145; Art ID: st-2017-d0727-l
broad spectrum of biological and pharmaceutical proper-
ties, such as antiagenesis, antiallergy, and antitumor activi-
Abstract A high-yielding, practical, efficient, and environmentally be-
nign one-pot multicomponent synthesis of functionalized 2-amino-4H-
pyrans from β-dicarbonyl compounds, malononitrile, and aldehydes is
presented. Good to excellent yields were obtained under mild reaction
condition and with short reaction times by using magnetite-supported
graphitic carbon nitride as a truly recyclable catalyst. This efficient and
simple technique avoids the use of solvent extraction and column chro-
matography. In addition, the catalyst can be easily and effectively re-
covered and reused several times without significant loss of its catalytic
activity.
ties.5 In addition, amino- and cyano-functionalized 4H-
pyrans have been used as synthetic intermediates in organ-
6
ic synthesis. Because of the broad spectrum of biological
activities of benzopyrans, many methods for the synthesis
of benzopyran derivatives, including two-step and one-pot
7
three-component reactions have been reported. However,
most of these give moderate yields, even after prolonged re-
action times, and they require subsequent workup and
product purification. Consequently, there is still scope to
develop a method involving exclusively green solvents and
a recoverable catalyst.
Key words pyrans, multicomponent reactions, graphitic carbon ni-
tride, ferrite, catalyst support, green chemistry
F
Multicomponent reactions (MCRs), used for the con-
struction of complex molecules by performing multiple
steps in a single operation, have emerged as a group of use-
ful strategies in organic synthesis, and are receiving consid-
Me
O
F
F
F
CO2H
NH2
Me
F
Me
N
CN
O
N
1
erable attention. Ongoing development of novel synthetic
Amlexanox antiallergic
N
O
NH2
methods and catalysts in MCR chemistry have opened up
Ph
O
Ph
2
ways of rendering such transformations green. Increasing-
CN
Antibacterial
ly, severe economic and environmental constraints are forc-
ing the synthetic community to develop novel procedures
and synthetic concepts to optimize the efficiency of known
MCRs. Indeed, the green performance of multicomponent
chemistry involving a combination of MCRs and recover-
able catalysts in green solvents justifies its central position
in the toolbox of sustainable synthetic methodologies.3
Since the discovery of cromakalim (Figure 1) as a typical
ATP-sensitive potassium-channel opener, used to treat
hypertension by relaxing vascular smooth muscle, the syn-
N
O
NH2
OMe
EAAT1 inhibitor
O
MeO
Br
CN
HO
N
O
O
NH2
HN
Cromakalim
Apoptosis Inducer
Figure 1 Selected bioactive compounds containing a 4H-pyran core
©
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N. Azizi et al.
Letter
Fe3O4
N
N
N
N
N
N
N
N
N
N
N
N
N
Fe+2 & Fe+3 in H O
2
N
N
N
H2N
N
NH2
N
N
N
Heating at 500 °C
Heating at 550 °C
N
80 °C, 30 min
N
N
N
N
N
N
N
N
N
N
NH3, pH = 10
80 °C, 30 min
N
N
NH2
Melamine
N
N
N
N
N
N
g-C3N4 nanosheet
g-C3N4 nanosheet
Scheme 1 Preparation of Fe O @g-C N
4
3
4
3
In a continuation of our interest in green chemistry-ori-
ented organic synthesis in novel solvents, we describe a
The catalytic activity of Fe O @g-C N was evaluated in
3 4 3 4
8
a one-pot synthesis of the 4H-chromene 4a through the
condensation of benzaldehyde (1; 1 mmol), malononitrile
(2; 1 mmol) and dimedone (3; 1 mmol) as model substrates
in a series of experiments designed to optimize the reaction
conditions (Table 1). To our satisfaction, the reaction pro-
ceeded smoothly in ethanol at ambient temperature within
two hours in the presence of Fe O @g-C N (20 mg). Simple
simple method for the construction of structurally diverse
fused pyran derivatives under extremely mild conditions.
Carbon-based nanomaterials possess unique physical,
chemical, and mechanical properties, and extensive re-
search efforts are being made to utilize these materials for a
wide variety of applications as catalysts, optoelectronic ma-
terials, and electrodes in fuel cells, as well as in the biomed-
3
4
3
4
separation of the catalyst with an external magnet, fol-
lowed by crystallization of the product from ethanol gave
the desired 4H-chromene 4a in 72% isolated yield. (Table 1,
entry 1). To determine the optimum temperature, the reac-
tion was carried out at 40, 60, and 80 °C, which afforded 80,
97, and 97% yields of 4a, respectively (entries 2–4). Raising
9
ical field. Among such carbon materials, graphitic carbon
nitride (g-C N ) exhibits distinctly different properties,
3
4
such as excellent thermal conductivity, high electrical
mobility, and great mechanical strength.10 Furthermore,
g-C N can be easily synthesized by a hydrothermal
3
4
method, without any organic solvents, from melamine or
urea derivatives, and it is insoluble in most solvents.11 Be-
cause of these characteristics, g-C N has attracted atten-
Table 1 Optimization of the Reaction Conditions for the Synthesis of
benzopyran 4a
3
4
tion, as it provides potential means for clean energy pro-
12
duction and environmental remediation. However, g-C N4
3
CHO
CN
CN
O
Ph
O
has been relatively less explored as a catalyst in organic
synthesis.
Here, we report a simple and efficient three-component
reaction of a 1,3-dicarbonyl compound, an aldehyde, and
malononitrile to give a highly functionalized benzopyran or
pyran derivative with magnetic nanoparticle-supported
CN
1
+
2
Fe3O4@g-C3N4
Solvent, 1 h
O
O
NH2
4a
3
g-C N (Fe O @g-C N ) as a catalyst under mild condi-
a
3
4
3
4
3
4
Entry
Solvent
Temp (°C)
Yield (%)
tions. In addition to being an excellent nanocomposite in
permitting the magnetic separation of the catalyst,
Fe O @g-C N also provides the basic environment required
to accomplish the reaction without the need for an external
base.
1
2
EtOH
EtOH
EtOH
EtOH
25
40
60
80
60
60
60
60
60
60
60
72
80
97
97
80
78
72
60
65
50
76
3
4
3
4
3
4
Fe O @g-C N composites were synthesized by a calci-
3
4
3
4
5
2
H O
nation method. The g-C N was synthesized by calcination
3
4
6
PEG
of melamine at 500 °C for five hours, as reported in the lit-
10a
7
DMF
erature, and then dispersed in aqueous ethanol (50%) un-
der sonication. An aqueous solution of iron salts was added
to the dispersion of g-C N in the presence of ammonia, and
8
MeCN
EtOAc
toluene
no solvent
3
4
9
the mixture was stirred for 30 minutes at 80 °C under N2.
The product was then separated magnetically, washed with
water and ethanol, and dried under vacuum at 60 °C to af-
ford Fe O @g-C N , as a dark-brown solid (Scheme 1).
10
1
1
a
Yield of isolated product.
3
4
3
4
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N. Azizi et al.
Letter
the temperature not only affected the yield of the product,
but also reduced the reaction time to one hour. Little
change in the yield or reaction time was observed when the
loading of Fe O @g-C N , was lowered to 10 mg or increased
drawing or electron-donating groups on the aromatic ring,
a wide range of substituted benzopyrans were obtained in
high yields within a short reaction time. Functionalities on
the aromatic ring such as Cl, Br, F, NO , OH, and OMe were
3
4
3
4
2
to 40 mg. Various solvents such as DMF, PEG, EtOAc, MeCN,
compatible with the reaction conditions. The aliphatic
aldehyde octanal was also a good substrate for the reaction,
and gave the corresponding product 4k in 71% yield. More
importantly, a series of 4H-pyran derivatives were readily
obtained when the conditions were extended to three-
component domino reactions of aromatic aldehydes, malo-
nonitrile, and 1,3-dicarbonyl compounds such as acetyl-
acetone, ethyl acetoacetate, or methyl acetoacetate. The re-
sults summarized in Table 2 show that all reactions pro-
ceeded well to afford the corresponding pyran derivatives in
good to excellent yields.
toluene, and H O or neat conditions were tested in the pres-
2
ence of Fe O @g-C N , but all resulted in lower yields than
3
4
3
4
that obtained in ethanol (entries 5–11).
With the optimal conditions established, we proceeded
to examine the scope of this transformation with various
aromatic aldehydes, 1,3-dicarbonyl compounds, and malono-
nitrile for the construction of a range of pyran derivatives
(Table 2). In general, the reaction proceeded smoothly un-
der mild conditions to afford the desired products in good
to excellent yields. For the reaction of malononitrile and di-
medone with aromatic aldehydes bearing electron-with-
Table 2 Fe O @g-C N -Catalyzed Synthesis of 4H-Pyran Derivatives
3
4
3
4
Fe3O4@g-C3N4
20 mg)
O
R
O
O
O
CN
CN
(
CN
RCHO
EtOH (1mL)
0 oC, 30–190 min
1
2
NH2
6
3
4
7
2–97%
a
Entry
R
1,3-Dione
Product
Yield (%)
Physical state
Ref.
7
7
7
7
7
7
7
7
7
7
7
7
7
7
7
7
7
7
7
7
7
i
1
2
3
4
5
6
7
8
9
Ph
4-ClC
3-O NC
dimedone
dimedone
dimedone
dimedone
dimedone
dimedone
dimedone
dimedone
dimedone
dimedone
dimedone
dimedone
dimedone
dimedone
4a
4b
4c
4d
4e
4f
97
95
92
95
97
78
90
82
84
86
72
80
81
85
82
80
78
84
80
82
78
colorless crystals
colorless crystals
yellow powder
colorless crystals
colorless crystals
colorless crystals
colorless crystals
colorless crystals
white powder
c
a
m
d
a
a
d
h
i
6
H
4
2
6 4
H
6 4
3-BrC H
Tol
4-HOC
4-BrC
4-MeOC
4-FC
6 4
H
6
H
4
4g
4h
4i
6
H
4
6
H
4
10
11
12
13
14
15
16
17
18
19
20
1
4-MeO
2
CC
6
H
4
4j
white powder
i
Me(CH
2
)
7
4k
4l
white powder
n
n
n
b
b
c
j
2-thienyl
2-furyl
4-pyridyl
Tol
yellow powder
yellow powder
yellow powder
white powder
4m
4n
4o
4p
4q
4r
ethyl acetoacetate
ethyl acetoacetate
ethyl acetoacetate
methyl acetoacetate
methyl acetoacetate
acetylacetone
Ph
colorless crystals
white powder
4-MeOC
Ph
6 4
H
colorless crystals
colorless crystals
white powder
b
o
o
4-BrC
Ph
6
H
4
4s
4t
2
Tol
acetylacetone
4u
white powder
a
Isolated yield.
©
Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–E

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N. Azizi et al.
Letter
The recovery and reuse of the magnetic catalyst were
studied for the preparation of 4a as a model (Figure 2). Be-
cause of the low solubility of Fe O @g-C N in organic sol-
(3) (a) Slobbe, P.; Ruijter, E.; Orru, R. Med. Chem. Commun. 2012, 3,
1189. (b) Gu, Y.; Jérôme, F. Green Chem. 2010, 12, 1127. (c) Gu,
Y.; Jérôme, F. Chem. Soc. Rev. 2013, 42, 9550.
3
4
3
4
(
4) Saleh, T. S.; Abd El-Rahman, N. M.; Elkateb, A. A.; Shaker, N. O.;
Mahmoud, N. A.; Gabal, S. A. Ultrason. Sonochem. 2012, 19, 491.
5) Pratap, U. R.; Jawale, D. V.; Netankar, P. D.; Mane, R. A. Tetrahe-
dron Lett. 2011, 52, 5817.
vents, its stable nanostructure, and good magnetization, it
is easily separated by an external magnet. After the initial
reaction was complete, ethanol was added and the catalyst
was separated and reused directly in a subsequent reaction
without any pretreatment such as drying or washing. As
shown in Figure 2, the catalyst could be recycled at least ten
times without any marked decrease in the yield, which
ranged from 97% to 92%.
(
(6) Peng, Y.; Song, G. Catal. Commun. 2007, 8, 111.
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rine Chem. 2006, 127, 97. (b) Balalaie, S.; Bararjanian, M.; Sheik-
Ahmadi, M.; Hekmat, S.; Salehi, P. Synth. Commun. 2007, 37,
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Chem. 2008, 139, 129. (e) Beerappa, M.; Shivashankar, K. RSC
Adv. 2015, 5, 30364. (f) Singh, K.; Singh, J.; Singh, H. Tetrahedron
1996, 52, 14273. (g) Kaupp, G.; Naimi-Jama, M. R.; Schmeyers, J.
Tetrahedron 2003, 59, 3753. (h) Gao, S.; Tsai, C. H.; Tseng, C.; Yao,
C.-F. Tetrahedron 2008, 64, 9143. (i) Rosati, O.; Pelos, A.;
Temperini, A.; Pace, V.; Curini, M. Synthesis 2016, 48, 1533.
(
2
j) Azizi, N.; Dezfooli, S.; Mahmoudi Hashemi, M. J. Mol. Liq.
014, 194, 62. (k) Azizi, N.; Dezfooli, S.; Khajeh, M.; Hashemi, M.
M. J. Mol. Liq. 2013, 186, 76. (l) Khan, A. T.; Lal, M.; Ali, S.; Khan,
M. M. Tetrahedron Lett. 2011, 52, 5327. (m) Guo, R.-Y.; An, Z.-M.;
Mo, L.-P.; Wang, R.-Z.; Liu, H.-X.; Wang, S.-X.; Zhang, Z.-H. ACS
Comb. Sci. 2013, 15, 557. (n) Sun, W.-B.; Zhang, P.; Fan, J.; Chen,
S.-H.; Zhang, Z.-H. Synth. Commun. 2010, 40, 587. (o) Rahala;
Rai, P.; Ibad, A.; Sagir, H.; Siddiqui, I. R. ChemistrySelect 2016, 1,
Figure 2 A reusability and recycling study of the nanocatalyst
1
300.
In summary, by using Fe O @g-C N as a recyclable cat-
alyst, we have developed a mild and green one-pot synthe-
sis of 4H-pyran derivatives in good to excellent yields (72–
7%) within a short reaction time (30–190 min), and the
3
4
3
4
(
8) (a) Azizi, N.; Khajeh-Amiri, A.; Ghafuri, H.; Bolourtchian, M. Mol.
Diversity 2011, 15, 157. (b) Azizi, N.; Saidi, M. R. Phosphorus,
Sulfur Silicon Relat. Elem. 2003, 178, 1255. (c) Mirmashhori, B.;
Azizi, N.; Saidi, M. R. J. Mol. Catal. A: Chem. 2006, 247, 159.
9) (a) Tan, C.; Cao, X.; Wu, X.-J.; He, Q.; Yang, J.; Zhang, X.; Chen, J.;
Zhao, W.; Han, S.; Nam, G.-H.; Sindoro, M.; Zhang, H. Chem. Rev.
9
(
products can be purified by simple crystallization. The
magnetically recoverable and inexpensive catalyst and sim-
ple experimental procedure with no column purification or
hazardous organic solvent are advantages of this pro-
2
017, 117, 6225. (b) Cha, C.; Shin, S. R.; Annabi, N.; Dokmec, M.
R.; Khademhosseini, A. ACS Nano 2013, 7, 2891.
(
10) (a) Kumar, S.; Surendar, T.; Kumar, B.; Baruah, A.; Shanker, V. J.
Phys. Chem. C 2013, 117, 26135. (b) Schultz, D. M.; Yoon, T. P.
Science 2014, 343, 1239176.
13,14
cess.
(
11) (a) Wang, A.; Wang, C.; Fu, L.; Wong-Ng, W.; Lan, Y. Nano-Micro
Lett. 2017, 9, 47. (b) Ong, W.-J.; Tan, L.-L.; Ng, Y. H.; Yong, S.-T.;
Chai, S.-P. Chem. Rev. 2016, 116, 7159. (c) Li, X.; Yu, J.; Low, J.;
Fang, Y.; Xiao, J.; Chen, X. J. Mater. Chem. A 2015, 3, 2485. (d) Xu,
Y.-S.; Zhang, W. D. ChemCatChem 2013, 5, 2343.
Funding Information
Financial support of this work by the Chemistry and Chemical Engi-
neering Research Center of Iran is gratefully appreciated.
)(
(12) (a) Mamba, G.; Mishra, A. K. Appl. Catal., B 2016, 198, 347.
(
1
b) Qiu, Y.; Xin, L.; Jia, F.; Xie, J.; Li, W. Langmuir 2016, 32,
2569. (c) Wang, P.; Lu, N.; Su, Y.; Liu, N.; Yu, H.; Li, J.; Wu, Y.
Appl. Surf. Sci. 2017, 423, 197. (d) Wei, Y.; Zeng, X. Synlett 2016,
7, 650. (e) Lu, J.; Li, X.-T.; Ma, E.-Q.; Mo, L.-P.; Zhang, Z.-H.
References and Notes
(
1) (a) Dömling, A. Chem. Rev. 2006, 106, 17. (b) Ramón, D. J.; Yus,
M. Angew. Chem. Int. Ed. 2005, 44, 1602. (c) Toure, B. B.; Hall, D.
G. Chem. Rev. 2009, 109, 4439. (d) de Graaff, C.; Ruijter, E.; Orru,
R. Chem. Soc. Rev. 2012, 41, 3969. (e) Shivani, B. P.; Chakraborti,
A. K. J. Org. Chem. 2007, 72, 3713. (f) Pujala, B.; Rana, S.;
Chakraborti, A. K. J. Org. Chem. 2011, 76, 8768. (g) Chakraborti,
A. K.; Rudrawar, S.; Kondaskar, A. Eur. J. Org. Chem. 2004, 3597.
2
ChemCatChem 2014, 6, 2854.
(
13) 4H-Pyrans; General Procedure
A mixture of the appropriate aldehyde 1 (1.0 mmol), malononi-
trile (2; 1.0 mmol), 1,3-dicarbonyl compound 3 (1.0 mmol), and
Fe O @g-C N (20 mg) in EtOH (1 mL) was stirred at 60 °C for 60
min until the reaction was complete (TLC). EtOH (10 mL) was
added, and the Fe O @g-C N was separated with an external
magnet. The crude product was then crystallized from EtOH.
2
4
3
4
3
4
(h) Chakraborti, A.; Rudrawara, S.; Kondaskar, A. Org. Biomol.
3
4
3
4
Chem. 2004, 2, 1277.
(2) (a) Liu, P.; Hao, J.-W.; Mo, L.-P.; Zhang, Z.-H. RSC Adv. 2015, 5,
-Amino-7,7-dimethyl-5-oxo-4-phenyl-5,6,7,8-tetrahydro-
48675. (b) Gu, Y. Green Chem. 2012, 14, 2091. (c) Orru, R. V. A.;
H-chromene-3-carbonitrile (4a)
de Greef, M. Synthesis 2003, 1471. (d) Hu, H.-C.; Liu, Y.-H.; Li, B.-
L.; Cui, Z.-S.; Zhang, Z.-H. RSC Adv. 2015, 5, 7720.
1
Colorless crystals; yield: 143 mg (97%); mp 228–230 °C. H NMR
(CDCl , 500 MHz): δ = 7.38–7.00 (m, 7 H, PhH and NH ), 4.30 (s,
3
2
1
H), 5.23 (s, 2 H), 2.39 (m, 2 H), 2.13–2.15 (m, 2 H), 1.03 (s, 3 H),
©
Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–E

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Synlett
N. Azizi et al.
Letter
0
1
2
.98 (s, 3 H). 13C NMR (CDCl , 125 MHz): δ = 196.8, 162.8, 157.9,
44.3, 129.5, 128.8, 127.9, 118.8, 114.7, 61.9, 51.6, 35.9, 33.0,
9.6, 28.1.
heated at 550 °C for 2 h, with initial heating at a rate of
10 °C/min, to obtain white g-C N nanosheets. In the final step,
3
3
4
Fe O @g-C N was prepared by the reported method (Ref. 10).
3
4
3
4
(
14) Preparation of the magnetic g-C N catalyst
The g-C N (500 mg) was dispersed in 1:1 EtOH–H O by sonica-
3
4
3
4
2
A
g-C N nanosheet was prepared by directly calcining
tion at r.t. FeCl ·6H O (1.838 g, 0.0216 mol) and FeCl ·4H O
3 2 2 2
3
4
melamine in air. An alumina crucible with a loose cover con-
taining melamine (2.0 g) was placed in a muffle furnace, and
the temperature was programmed to 550 °C for 5 h at an initial
ramp rate of 5 °C/min. After heat treatment, bulk g-C N was
(0.703 g, 0.0108 mol) were dissolved in the dispersion by soni-
cation for 30 min, and then 28% aq NH3 (10 mL) was rapidly
added to the stirred solution. The mixture was stirred under N2
for 30 min at 80 °C, then cooled to r.t. The solid was separated
3
4
obtained as a pale-yellow powder (see Ref. 10a). This bulk g-
C N (1.0 g) was added to a second alumina crucible, which was
magnetically, washed with H O and EtOH, and dried overnight
at 60 °C under vacuum.
2
3
4
©
Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–E