Synthesis of new 4-aroyl-pyrano[c]chromenes via a one-pot, three-component reaction based on aryl glyoxals

Article abstract of DOI:10.1016/j.tetlet.2014.05.072

A new library of pyrano[c]chromenes containing an aroyl group has been synthesized by a novel multicomponent process involving the reaction of various aryl glyoxals with 4-hydroxycoumarin and malononitrile. The reactions were catalyzed efficiently by ammonium dihydrogen phosphate to yield the desired products in good to excellent yields.

Full text of DOI:10.1016/j.tetlet.2014.05.072

Tetrahedron Letters 55 (2014) 3753–3755
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Tetrahedron Letters
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Synthesis of new 4-aroyl-pyrano[c]chromenes via a
one-pot, three-component reaction based on aryl glyoxals
a
a
Saeed Khodabakhshi a,b, Bahador Karami a, , Khalil Eskandari , Mahnaz Farahi
⇑
a Department of Chemistry, Yasouj University, Yasouj 75918-74831, Iran
b Grupo de Lactamas y Heterociclos Bioactivos, Departamento de Química Orgánica I, Unidad Asociada al CSIC, Facultad de Química, Universidad Complutense de Madrid,
28040 Madrid, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 17 February 2014
Revised 4 May 2014
Accepted 15 May 2014
Available online 23 May 2014
A new library of pyrano[c]chromenes containing an aroyl group has been synthesized by a novel
multicomponent process involving the reaction of various aryl glyoxals with 4-hydroxycoumarin and
malononitrile. The reactions were catalyzed efficiently by ammonium dihydrogen phosphate to yield
the desired products in good to excellent yields.
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
Aryl glyoxal
Malononitrile
4-Hydroxycoumarin
Demand for the rapid generation of small molecules, particu-
larly heterocyclic compounds, has increased with the advent of
high-throughput pharmaceutical screening.1 Multicomponent
reactions (MCRs) represent a very useful tool at the interface of
the fields of organic synthesis and chemical biology due to their
superior atom economy, convergent nature, and straightforward
experimental procedures. In addition, they are valuable in the
pharmaceutical industry for the construction of low molecular
weight compounds.
Among a number of both biologically active and natural com-
pounds, 2-amino-4H-chromenes are important structural motifs.2
In particular, 4-aryl/alkyl-2-amino-4H-chromenes bearing a nitrile
or ester group at the 3-position have attracted significant attention
because of their pro-apoptotic activity against various tumors,3–5
as a single agent or in combination with chemo-or radiotherapy.
Pyranochromenes have received particular interest because they
possess both a coumarin and pyran moiety. A commonly used
method for the synthesis of pyranochromenes bearing a nitrile
and an amine group is via the three-component reaction of hydrox-
ycoumarins, malononitrile, and carbonyl compounds.6–8 It should
be noted that much attention has also been paid to modify this
type of MCR.9 The use of aryl glyoxals in the synthesis of heterocy-
clic compounds has been reviewed by Eftekhari-Sis.10 Despite the
fact that, in some cases, aryl glyoxals act similar to aromatic
aldehydes, we found that there were no reports on the synthesis
of pyrano[c]chromenes through a three-component reaction based
on aryl glyoxals.
In continuationof ourstudiesonthedevelopmentofnewpyrano-
fusedcoumarins,11–17 herein, thesynthesisof pyrano[c]chromenes4
via the one-pot, multicomponent reaction of 4-hydroxycoumarin
(1), aryl glyoxals 2, and malononitrile (3) is presented (Scheme 1).
It is noteworthy that the expected products 4 were obtained in
excellent yield, and no biscoumarin 5 was observed.18
However, a number of our preliminary attempts to carry out
this reaction did not furnish the desired product 4. Initially, we
used 4-hydroxycoumarin (1), phenyl glyoxal, and malononitrile
(3) as the model reaction system to investigate systematically
the reaction conditions.19 Using Na2CO3 as the base and EtOH as
the solvent under reflux, the desired product was not formed and
TLC of the reaction mixture showed several spots.
The reaction was also conducted at room temperature in the
presence of Na2CO3 in both EtOH and an equal mixture of EtOH/
H2O, but the reaction led to undesired and non-isolable products.
By changing the catalyst to NH4H2PO4 and heating at reflux in
EtOH/H2O (1:1), no observable difference was apparent. After
further investigations, it was found that the reaction proceeded
efficiently by controlling the temperature. The best conditions
were established as room temperature for 30–40 min and then
heating under reflux conditions to give the desired products 4 in
good to excellent yields.
Using the optimized conditions, a variety of aryl glyoxals 2 were
used for the synthesis of new 4-aroyl-pyrano[c]chromenes 4
(Table 1).
⇑
Corresponding author. Tel.: +98 7412223048; fax: +98 7412242167.
E-mail address: karami@mail.yu.ac.ir (B. Karami).
http://dx.doi.org/10.1016/j.tetlet.2014.05.072
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.

3754
S. Khodabakhshi et al. / Tetrahedron Letters 55 (2014) 3753–3755
OH
O
Ar
Table 1 (continued)
N
O
Yielda (%) Time (min) Mp (°C)
H
H
Entry Ar
Product
OH
+
+
C
H
HO
O
N
1
2
3
O
O
O
NH2
O
CN
6
4-O2N-C6H4
90
75
273–275
NH2
Ar
O
HO
CN
NO2
HO
O
O
4f
Ar
O
HO
O
O
O
O
5
4
O
O
O
NH2
Conditions:EtOH/H2O (1:1), NH4H2PO4 (10 mol%), r.t. to reflux
O
CN
7
3-MeO-C6H4
85
80
268–270
Scheme 1. Synthesis of pyrano[c]chromenes.
MeO
Aryl glyoxals possessing either electron-withdrawing or elec-
tron-donating groups were successfully employed in this reaction
(Table 1).
4g
O
O
O
NH2
Table 1
O
CN
8
4-MeO-C6H4
90
75
266–268
Synthesis of 4-aroyl-pyrano[c]chromenes using NH4H2PO4 (10 mol %) in EtOH/H2O
(1:1)
Yielda (%) Time (min) Mp (°C)
OMe
Entry Ar
Product
4h
O
O
O
O
O
O
NH2
NH2
1
C6H5
85
75
272–274
O
CN
9
1-Naphthyl
85
80
271–273
O
CN
4a
4b
4i
O
O
O
NH2
O
O
O
NH2
O
CN
2
4-F-C6H4
80
85
253–255
O
CN
10
2-Naphthyl
93
70
278–280
F
4j
O
O
O
a
The isolated yield.
NH2
O
CN
3
4-Cl-C6H4
90
80
263–265
All the products were characterized from their elemental and
spectral data including NMR and FT-IR spectroscopy. As a represen-
tative example, the 1H NMR spectrum of compound 4g showed sig-
nals for the aromatic protons at 7.91–7.31 ppm. The singlet at
7.69 ppm corresponded to the amine protons. Two sharp singlets
at 5.40 ppm and 3.87 ppm were due to the methine and methyl pro-
tons, respectively. The 13C NMR spectrum of compound 4g also con-
firmed the suggested structure showing the expected 21 signals. The
IR spectrum of compound 4g contained a characteristic absorption
Cl
4c
O
O
O
NH
4
4-Br-C6H4
88
90
263–265
O
CN
band due to the conjugated cyano-group in the region of 2196 cmÀ1
.
Br
Mechanistically, a reasonable pathway for the synthesis of pyr-
ano[c]chromenes 4 is described in Scheme 2. The process involves
a typical cascade reaction in which the aryl glyoxal 2 first
condenses with malononitrile (3) to produce the corresponding
aryloylidene malononitrile 5 catalyzed by NH4H2PO4. Next, inter-
mediate 5 is attacked via a Michael-type addition of 1 to give the
intermediate 6, followed by intramolecular heterocyclization to
form the product 4.
4d
O
O
O
NH2
CN
O
5
3-O2N-C6H4
85
90
248–250
O2N
4e
In conclusion, this Letter describes the first report on the one-pot,
three-component, NH4H2PO4-catalyzed synthesis of new pyr-
ano[c]chromenes by employing 4-hydroxycoumarin, malononitrile,

S. Khodabakhshi et al. / Tetrahedron Letters 55 (2014) 3753–3755
3755
Ar
Supplementary data
O
O
H
HO
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2014.05.
072.
H
2
O
N
H
N
H
H
-H2O
O
H
+
H
-
H
N
H2PO4
H
H
Ar
H
References and notes
C
H
C
N
3
1. Li, M.; Zuo, Z.; Wen, L.; Wang, S. J. Comb. Chem. 2008, 10, 436.
2. Yang, G.; Luo, C.; Mu, X.; Wang, T.; Liu, X.-Y. Chem. Commun. 2012, 5880.
3. Doshi, J. M.; Tian, D.; Xing, C. J. Med. Chem. 2006, 49, 7731.
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M.; Labrecque, D.; Denis, R.; Lamothe, S.; Attardo, G.; Gourdeau, H.; Tseng, B.;
Drewea, J.; Cai, S. X. Bioorg. Med. Chem. Lett. 2008, 18, 603.
5. Das, S. G.; Doshi, J. M.; Tian, D.; Addo, S. N.; Srinivasan, B.; Hermanson, D. L.;
Xing, C. J. Med. Chem. 2009, 52, 5937.
H
H
O
H
NC
NC
NC
-NH3
H
N
H
H
H
O
OH
+
H
Ar
H
H
Ar
CN
O
NH3
N
C
O
Ar
6. Dmitrieva, M. V.; Silaicheva, P. S.; Maslivetsa, A. N. Russ. J. Org. Chem. 2011, 47,
1263.
7. Karimi, A. R.; Sedaghatpour, F. Synthesis 2010, 1731.
5
-H2O
C
H
H
N
O
8. Karami, B.; Khodabakhshi, S.; Eskandari, K. Lett. Org. Chem. 2013, 10, 105.
9. Ziarani, G. M.; Hajiabbasi, P. Heterocycles 2013, 87, 1415–1439.
10. Eftekhari-Sis, B.; Zirak, M.; Akbari, A. Chem. Rev. 2013, 113, 2958.
11. Karami, B.; Eskandari, K.; Khodabakhshi, S. ARKIVOC 2012, ix, 76.
12. Karami, B.; Khodabakhshi, S.; Eskandari, K. Tetrahedron Lett. 2012, 53, 1445.
13. Karami, B.; Khodabakhshi, S.; Eskandari, K. Lett. Org. Chem. 2013, 10, 105.
14. Karami, B.; Khodabakhshi, S.; Eskandari, K. Chem. Pap. 2013, 67, 1474.
15. Karami, B.; Khodabakhshi, S.; Nikrooz, N. Polycyclic Aromat. Compd. 2011, 31,
97.
16. Karami, B.; Akrami, S.; Khodabakhshi, S.; Rahmatzadeh, S. S. ARKIVOC 2013, iv,
323.
17. Kamaei, V.; Karami, B.; Khodabakhshi, S. Polycyclic Aromat. Compd. 2014, 34,
1.
H
H
N
H
H
O
O
H
H
H
N
H
1
NH
O
NC
H
C
O
O
O
O
-NH4
H2N
H
O
Ar
H3N
O
C
Ar
N
O
4
6
18. Kolos, N. N.; Gozalishvili, L. L.; Yaremenko, F. G. Russ. Chem. Bull. 2007, 56,
2277.
Scheme 2. Suggested mechanism for the synthesis of 4-aroyl-pyrano[c]chromenes
using NH4H2PO4 as the catalyst.
19. Typical procedure for the synthesis of pyrano[c]chromene 4a.
To a 25 mL round-bottomed flask, 4-hydroxycoumarin (1) (1.0 mmol), phenyl
glyoxal (1 mmol), malononitrile (3) (1.2 mmol), EtOH/H2O (1:1, 10 mL), and
NH4H2PO4 (0.1 mmol) were added. The mixture was stirred at room
temperature for 30 min, then stirred vigorously under reflux conditions for
45 min. The progress of the reaction was monitored by TLC. Upon completion,
the mixture was cooled to room temperature and the resulting precipitate
filtered. The product 4a was obtained after recrystallization from EtOH/THF
(3:1).
and aryl glyoxals. The reactions were selective for pyrano[c]chrom-
enes instead of biscoumarins. Additionally, high product yields, sim-
ple operation, and avoidance of toxic organic solvents are important
advantages of this method. Due to the presence of functional groups
such as primary amine, cyano, and ketone in the products, more
synthetic studies and developments are possible. This method
should allow the synthesis of other pyrano[c]chromenes for studies
on their potential biological activities.
2-Amino-4-(benzoyl)-3-cyano-4H,5H-pyrano[3,2-c]chromen-5-one (4a) IR
(KBr): 3402, 3292, 2201, 1708, 1678, 1606, 1373, 1064 cmÀ1
;
1H NMR
(DMSO-d6, 300 MHz): d = 8.16 (s, 2H, J = 7.2 Hz), 7.90 (dd, 1H, J1 = 8.2,
J2 = 1.6 Hz), 7.81–7.73 (m, 2H), 7.69 (s, 2H), 7.62 (t, 2H, J = 8.2 Hz), 7.57–7.53
(m, 2H), 5.42 (s, 1H); 13C NMR (DMSO-d6, 75 MHz): d = 198.12, 160.08, 159.55,
154.72, 152.11, 135.34, 134.13, 133.35, 129.13, 128.89, 125.03, 122.15, 118.54,
116.83, 112.58, 101.91, 51.91, 37.14; Anal. Calcd for C20H12N2O4: C, 69.76; H,
3.51; N, 8.14. Found: C, 69.55; H, 3.41; N, 8.09.
Acknowledgment
The authors are very grateful for financial support of this work
by the Yasouj University, Yasouj, Iran.