A new three-component coupling reaction of aryl glyoxal, malononitrile, and 4-hydroxy coumarin catalysed by recyclable TiO2 nanoparticles

Article abstract of DOI:10.3184/174751914X14050999895192

Aryl glyoxals reacted with malononitrile and 4-hydroxycoumarin in the presence of a catalytic amount of TiO₂ nanoparticles to give a hitherto unknown family of pyranochromenes in up to 80% yield. This new three-component reaction yielded some novel pyrano[3,2-c]chromene-5-ones containing an aroyl substituent. Using a recyclable and safe catalyst along with a green solvent system made the process eco-friendly and economic.

Full text of DOI:10.3184/174751914X14050999895192

JOURNAL OF CHEMICAL RESEARCH 2014
VOL. 38 AUGUST, 473–476
RESEARCH PAPER 473
A new three-component coupling reaction of aryl glyoxal, malononitrile,
and 4-hydroxy coumarin catalysed by recyclable TiO2 nanoparticles
Saeed Khodabakhshia* Mozhgan Shahamirianb and Mojtaba Baghernejada
aYoung Researchers and Elite Club, Gachsaran Branch, Islamic Azad University, Gachsaran, Iran
bDepartment of Chemistry, Faculty of Science, Sarvestan Branch, Islamic Azad University, Sarvestan, Iran
Aryl glyoxals reacted with malononitrile and 4‑hydroxycoumarin in the presence of a catalytic amount of TiO2 nanoparticles to
give a hitherto unknown family of pyranochromenes in up to 80% yield. This new three‑component reaction yielded some novel
pyrano[3,2‑c]chromene‑5‑ones containing an aroyl substituent. Using a recyclable and safe catalyst along with a green solvent
system made the process eco‑friendly and economic.
Keywords: aryl glyoxal, pyrano[3,2-c]chromene-5-one, TiO2 nanoparticle catalyst
Multicomponent reactions (MCRs) have attracted the attention
of many organic chemists because they allow the creation
of several bonds in a single operation and offer considerable
advantages such as operational simplicity, convergence, facile
automation, reduction in the number of workup, extraction and
purification processes, and hence minimise waste generation,
rendering the transformations green.1–3 Coumarins fused with
other heterocycles are important compounds due to their special
biological and photodynamic properties.4–7 Among coumarin
fused heterocycles, pyrano[3,2-c]chromene-5-ones represent a
promising class of synthetic targets because of their interesting
biological properties.8,9 To date, many synthetic methodologies
for the synthesis of this class of compounds have been studied
by many research groups. Generally, pyrano[3,2-c]chromene-
5-ones are accessible via a three-component reaction of
4-hydroxycoumarin, aromatic aldehydes and active methylenes
compounds.10–14 In recent years, nanocatalysts have attracted
special attention due to their greater efficiency in comparison
with their bulk case counterparts. Among nanocatalysts,
TiO2 nanoparticles as safe metal oxide materials were used
for several organic reactions and showed high efficiency.15–17
To our knowledge, there is no report on the synthesis of
pyrano[3,2-c]chromene-5-ones starting from aryl glyoxals
instead of aromatic aldehydes. Here, by deployment of TiO2
NPs, a green three-component strategy to produce a novel class
of pyrano[3,2-c]chromene-5-ones containing an aryloyl group
is described.
Results and discussion
Among nano-sized transition metal oxides, titanium oxide
nanoparticles (TiO2 NPs) have gained importance as they
exhibit interesting catalytic properties which cannot be
achieved by their bulk counterparts. TiO2 is not classified as
hazardous according to the United Nations’ (UN) Globally
Harmonized System of Classification and Labeling of
Chemicals and is a water-insoluble material which can be
recovered and reused, thereby reducing waste. Figure 1 (A)
shows the X-ray diffraction pattern for titanium dioxide
nanoparticles. Six diffraction peaks at 25.18º, 37.71º, 47.81º,
54.81º, 61.39º, and 69.99º and intensity of the characteristic
peaks of the samples are in good agreement with the standard
data for the TiO2 nanoparticle structure. The scanning electron
microscope (SEM) image of TiO2 nanoparticles is shown in
Fig. 1 (B). The nanoparticles have spherical shape with average
diameter of 50 nm.
As a part of our programs for developing green organic
methodologies,18 especially the synthesis of heterocyclic
compounds,19 we have investigated the synthesis of
pyrano[3,2-c]chromene-5-ones 4 as a novel class of pyrano
fused heterocycles containing an aryloyl substituent via a one-
pot, three-component reaction of 4-hydroxycoumarin (1), an
aryl glyoxal 2 and malononitrile (3) in the presence of TiO2
NPs (Scheme 1). We found that the reactions proceeded with
selectivity and the expected product 4 was formed in high yield.
Fig. 1 (A) X‑ray diffraction pattern of TiO2 nanoparticles. (B) SEM image of TiO2 nanoparticles.
* Correspondent. E-mail: saeidkhm@yahoo.com

474 JOURNAL OF CHEMICAL RESEARCH 2014
O
O
OH
Ar
O
CN
H2C
NC
CN
3
O
O
O
O
4
1
H2N
+
OH
H
Ar
O
O
OH
O
Ar
OH
2
OH
Conditions: EtOH/H2O (1:1), TiO2 NPs (3 mol%),
r.t. to reflux
O
5
O
Scheme 1 Synthesis of aroylated pyrano[3,2‑c]chromene‑5‑ones 4 using TiO2 NPs.
In order to determine the optimum amount of the catalyst,
A mechanistic pathway (Scheme 2) describes a catalytic
cycle for the synthesis of compounds 4a–j. In the first step, a
Knoevenagel condensation takes place between aryl glyoxal
and malononitrile in which TiO2 promotes the condensation as
a versatile catalyst. In the next step, a Michael-type addition
of 4-hydroxycoumarin to the corresponding aroylidene
malononitriles occurs, and this is followed by an intramolecular
heterocyclisation reaction leading to the formation of 4. As can
be seen, the TiO2NP catalyses each of the two final steps. To
investigate the reusability of TiO2 Nps in synthesis of 4a, the
catalyst was recovered and reused three times and showed no
appreciable loss in activity.
various amounts of TiO2 were employed for various times in
the synthesis of test compound 4a and the results are shown in
Fig. 2. As can be seen, the effect of TiO2 NPs in comparison with
catalyst-free and bulk cases is appreciable. Clearly, enhancing
the contact between the reactants and the nanocatalyst with its
high surface area had a dramatic effect.
The highest yield was obtained (80%) when the reaction
was loaded with 3 mol% of the nanoparticles. As a result, the
reaction mixture was stirred with catalytic amount (3 mol%) of
TiO2 NPs at room temperature and then heated under reflux in
EtOH/H2O (1:1).
Havingoptimisedtheconditions, thegeneralityofthismethod
was investigated by the reaction of a series of aryl glyoxals with
1 and 3 in the presence of 3 mol% TiO2 NPs and the results of
this study are shown in Table 1. It was found that, various aryl
glyoxals containing electron-donating or electron-withdrawing
functional groups at different positions showed little difference
in reaction time and yields of products 4b–h (entries 2–8). Two
naphthoyl analogues also gave good yields of the corresponding
products 4i and j (entries 9 and 10). The structures of
compounds 4a–j were characterised on the basis of their IR
and NMR spectroscopic data and their elemental analysis.
We also investigated the use of alkyl cyanoacetates instead
of malononitriles 3 to synthesise the corresponding products,
but there was no product formation even after 8 h under the
optimised reaction conditions.
Experimental
All chemicals were purchased from Merck or Aldrich. Aryl glyoxals
were synthesised according to our previously reported method.20
TiO2 NPs, with a particle size of average diameter of 50 nm, were
prepared according to the Alinezhad method.15 Reaction progress
was monitored by TLC (silica-gel 60 F254, hexane/EtOAc). Mass
spectra were recorded on an Agilent 5975c with a triple axis detector.
1
IR spectra were recorded on a FT-IR JASCO-680 and the H NMR
spectra were obtained on a Bruker-Instrument DPX-400 or 300 MHz
Avance 2 model. The vario El CHNS was used for elemental analysis.
SEM studies of the nanostructures were carried out with a JEOL JEM
3010 instrument operating at an accelerating voltage of 300 kV. X-Ray
diffraction (XRD, D8, Advance, Bruker, AXS) patterns were obtained
for characterisation of the heterogeneous catalyst. Melting points were
measured on an electrothermal KSB1N apparatus.
Fig. 2 Optimisation of catalyst (TiO2 nanoparticles) using the synthesis of 4a as test compound.

JOURNAL OF CHEMICAL RESEARCH 2014 475
O
OH
OH
Ar
H
H
TiO2
O
HO
TiO2
CN
H
H
O
CN
4
H
Ar
H
N
T
i
H2O
O
2
C
NC
H
H
H
O
O
NC
O
O
Ar
Ar
O
N
O2Ti
H
O
O
Scheme 2 Suggested mechanism for TiO2‑catalysed synthesis of 4.
O
(hexane/AcOEt, 1:1). After completion of the reaction, the precipitate
was filtered, dried, and dissolved in hot EtOH/THF (3:1) to separate
the catalyst. The pure 4 was obtained after recrystallisation from
EtOH/THF (3:1).
Table 1 Synthesis from compounds 1, 2a–j and
3 of aroylated
pyrano[3,2‑c]chromene‑5‑ones 4a–j using TiO2 NPs in EtOH/H2O
(Scheme 1)
Isolated
yield/%
Entry
Product
Ar
Time/min
M.p./ºC
2-Amino-4-benzoyl-3-cyano-4H,5H-pyrano[3,2-c]chromene-5-
1
1
2
3
4
5
6
7
8
9
4a
4b
4c
4d
4e
4f
4g
4h
4i
Ph
4‑F–Ph
4‑Cl–Ph
4‑Br–Ph
3‑NO2–Ph
4‑NO2–Ph
3‑MeO–Ph
4‑MeO–Ph
1‑Naphthyl
2‑Naphthyl
80
80
83
85
80
90
80
85
93
95
120
130
120
110
120
115
135
130
105
100
272–274
253–255
263–265
263–265
248–250
273–275
268–270
266–268
271–273
278–280
one (4a): H NMR δ 8.16 (s, 2H, J=7.2 Hz), 7.90 (dd, 1H, J1 =8.2,
J2ꢀ=ꢀ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) ppm; 13C NMR δ 198.1, 160.0, 159.5,
154.7, 152.1, 135.3, 134.1, 133.3, 129.1, 128.8, 125.0, 122.1, 118.5, 116.8,
112.5, 101.9, 51.9, 37.1 ppm. Anal. calcd for C20H12N2O4: C, 69.76; H,
3.51; N, 8.14; found: C, 69.55; H, 3.41; N, 8.09%.
2-Amino-3-cyano-4-(4ʹ-flouro-benzoyl)-4H,5H-pyrano[3,2-c]
1
chromene-5-one (4b): H NMR δ 8.27 (m, 2H), 7.90 (dd, 1H, J=8.2,
1.8 Hz), 7.82–7.76 (m, 1H), 7.70 (s, 2H), 7.58–7.53 (m, 2H), 7.46 (t, 2H,
J=8.8 Hz), 5.44 (s, 1H) ppm; 13C NMR δ 196.7, 160.0, 159.5, 154.7,
152.1, 133.3, 132.3, 132.1, 125.0, 122.1, 118.5, 116.8, 116.1, 115.8, 112.5,
101.7, 51.8, 37.1 ppm; MS (m/z): 362.3, 239.2, 123.1, 95.1, 75.1. Anal.
calcd for C20H11FN2O4: C, 66.30; H, 3.06; N, 7.73; found: C, 66.37; H,
3.00; N, 7.61%.
2-Amino-(4ʹ-chlorobenzoyl)-3-cyano-4H,5H-pyrano[3,2-c]
chromene-5-one (4c): 1H NMR δ 8.20 (d, 2H, J=8.4 Hz), 7.89 (dd, 1H,
J1 =8.2, J2ꢀ=ꢀ1.4 Hz), 7.81–7.69 (m, 5H), 7.57–7.52 (m, 2H), 5.43 (s, 1H)
ppm; 13C NMR δ 197.2, 160.0, 159.5, 154.7, 152.1, 139.2, 134.1, 133.3,
130.9, 129.0, 125.0, 122.1, 118.4, 116.8, 112.5, 101.6, 51.7, 37.2 ppm.
Anal. calcd for C20H11ClN2O4: C, 63.42; H, 2.93; N, 7.40; found: C,
63.61; H, 2.99; N, 7.35%.
2-Amino-4-(4ʹ-bromobenzoyl)-3-cyano-4H,5H-pyrano[3,2-c]
chromene-5-one (4d): 1H NMR δ 8.10 (d, 2H, J=8.6 Hz), 7.91–7.76 (m,
4H), 7.71 (s, 2H), 7.58–7.53 (m, 2H), 5.42 (s, 1H) ppm; 13C NMR 197.5,
159.5, 154.7, 152.1, 134.4, 133.4, 132.0, 131.0, 125.0, 122.1, 116.8, 112.5,
101.6, 51.7, 37.2 ppm. Anal. calcd for C20H11BrN2O4: C, 56.76; H, 2.62;
N, 6.62; found: C, 56.89; H, 2.51; N, 6.58%.
2-Amino-3-cyano-4-(3ʹ-nitrobenzoyl)-4H,5H-pyrano[3,2-c]
chromene-5-one (4e): 1H NMR δ 8.83 (t, 1H, J=1.8 Hz), 8.65 (d, 1 H,
J=7.8 Hz), 8.61–8.57 (m, 1H), 7.98–7.89 (m, 2H), 7.82–7.77 (m, 3H),
10
4j
Preparation of TiO2 nanoparticles
Titanium tetra-n-butoxide (5 mL) was dissolved in absolute EtOH
(5 mL) and dispersed under sonication to form a mixture, which was
then added dropwise to a mixture of HNO3 (65%) (1 mL), H2O (5 mL)
and absolute EtOH (20 mL) under ultrasonic irradiation in a sonication
cell for 15 min in order to effect the hydrolysis. After continuous
sonication for 1 h, a semitransparent sol was obtained. Subsequently,
the sonication was conducted so that the temperature was raised from
25 to 80 °C by the end of the reaction. The formed precipitate was
filtered, washed with de-ionised water and anhydrous alcohol several
times, and dried at 70 °C in the air for 12 h to produce a dry gel powder
after grinding. TiO2 NPs were finally obtained by calcination of the
dry gel precursor at 480 °C for 2 h in air.
Synthesis of 4 using TiO2 NPs
To a stirred solution of 4-hydroxycoumarin (1 mmol), aryl glyoxal
(1 mmol), and malononitrile (1.2 mmol) in EtOH/H2O (1:1, 10 mL),
TiO2 NPs (0.03 mmol) was added. The mixture was stirred under
reflux for 40 min. The reaction progress was monitored by TLC

476 JOURNAL OF CHEMICAL RESEARCH 2014
7.59–7.53 (m, 2H), 5.57 (s, 1H) ppm; 13C NMR δ 197.0, 160.1, 159.5,
154.8, 152.1, 148.1, 136.6, 135.2, 133.5, 130.9, 128.3, 125.1, 123.1,
122.2, 118.5, 116.8, 112.5, 101.3, 51.2, 37.6 ppm. Anal. calcd for
C20H11N3O6: C, 61.70; H, 2.85; N, 10.79; found: C, 61.88; H, 2.77; N,
10.83%.
126.1, 126.1, 126.0, 125.8, 125.7, 124.7, 123.4, 122.4, 119.1, 116.6, 112.9,
104.6, 53.6, 37.2 ppm. Anal. calcd for C24H14N2O4: C, 73.09; H, 3.58; N,
7.10; found: C, 73.17; H, 3.60; N, 7.04%.
The authors are grateful to Young Researchers and Elite Club
(Iran) for partial support.
2-Amino-3-cyano-4-(4ʹ-nitrobenzoyl)-4H,5H-pyrano[3,2-c]
1
chromene-5-one (4f): H NMR δ 8.46–8.38 (m, 4H), 7.90 (dd, 1H,
J=8.2, 1.4 Hz), 7.82–7.77 (m, 3H), 7.59–7.54 (m, 2H), 5.51 (s, 1H) ppm;
13C NMR δ 197.7, 160.1, 159.5, 154.8, 152.1, 150.4, 140.2, 133.5, 130.4,
125.1, 124.0, 122.2, 116.8, 112.5, 101.3, 51.2, 37.9 ppm. Anal. calcd for
C20H11N3O6: C, 61.70; H, 2.85; N, 10.79; found: C, 61.79; H, 2.72; N,
10.71%.
Received 15 May 2014; accepted 21 June 2014
Paper 1402651 doi: 10.3184/174751914X14050999895192
Published online: 12 August 2014
2-Amino-3-cyano-4-(3ʹ-methoxybenzoyl)-4H,5H-pyrano[3,2-c]
chromene-5-one (4g): H NMR δ =7.90 (dd, 1H, J1 =8.2, J2 =1.8 Hz),
References
1
1
2
3
B. Karami, R. Ferdosian and K. Eskandari, J. Chem. Res., 2014, 38, 41.
Y. Gu, Green Chem., 2012, 14, 2091.
B. Karami, K. Eskandari and S. Khodabakhshi, J. Iran. Chem. Soc., 2014,
11, 631.
7.815–7.75 (m, 2H), 7.70 (s, 2H), 7.62 (t, 1H, J=2.4 Hz), 7.57–7.52 (m,
3H), 7.32 (dd, 1H, J1 =7.8, J2ꢀ=ꢀ2.1 Hz), 5.40 (s, 1H), 3.87 (s, 3H) ppm;
13C NMR δ 197.7, 160.0, 159.6, 159.4, 154.7, 152.1, 136.6, 133.3, 130.0,
125.0, 122.1, 121.6, 120.2, 118.5, 116.8, 113.5, 112.6, 101.9, 55.3, 52.0,
37.4 ppm. Anal. calcd for C21H14N2O5: C, 67.38; H, 3.77; N, 7.48; found:
C, 67.48; H, 3.70; N, 7.56%.
4
5
H.-I. Lee, J.-H. Lee, K.-H. Park, D. Sangurdekar and W.-S. Chang, Appl.
Environ. Microbiol., 2012, 78, 2896.
S.M.A. Martins, P.C.S. Branco and A.M.D.R.L. Pereira, J. Braz. Chem.
Soc., 2012, 23, 688.
2-Amino-3-cyano-4-(4ʹ-methoxybenzoyl)-4H,5H-pyrano[3,2-c]
6
7
B. Karami, K. Eskandari and S. Khodabakhshi, Arkivoc, 2012, (ix), 76.
B. Karami, S. Khodabakhshi and K. Eskandari, Tetrahedron Lett., 2012,
53, 1445.
1
chromene-5-one (4h): H NMR δ 8.15 (d, 2H, J=9.0 Hz), 7.89 (dd,
1H, J1 =8.2, J2ꢀ=ꢀ1.4 Hz), 7.80–7.74 (m, 1H), 7.65 (s, 2H), 7.57–7.52 (m,
2H), 7.14 (d, 2H, J=9.0 Hz), 5.36 (s, 1H), 3.90 (s, 3H) ppm; 13C NMR
δ 196.2, 163.9, 160.0, 159.5, 154.6, 152.0, 133.2, 131.6, 128.1, 124.9,
122.1, 118.6, 116.7, 114.1, 112.6, 102.1, 55.6, 52.2, 36.7 ppm. Anal. calcd
for C21H14N2O5: C, 67.38; H, 3.77; N, 7.48; found: C, 67.40; H, 3.73; N,
7.40%.
2-Amino-3-cyano-4-(1ʹ-naphthoyl)-4H,5H-pyrano[3,2-c]chromene-
5-one (4i): 1H NMR δ 8.37 (m, 2H), 8.24 (d, 1H, J=8.4 Hz), 8.09–8.05
(m, 1H), 7.92 (dd, 1H, J=8.2, J2 =1.8 Hz), 7.83–7.70 (m, 4H), 7.66–7.54
(m, 4H), 5.43 (s, 1H) ppm; 13C NMR δ 200.3, 160.2, 159.6, 154.6, 152.2,
134.2, 133.4, 133.3, 133.2, 129.8, 129.0, 128.5, 128.0, 126.5, 125.1,
125.0, 124.7, 122.2, 118.3, 116.8, 112.6, 101.7, 51.4, 38.6 ppm. Anal.
calcd for C24H14N2O4: C, 73.09; H, 3.58; N, 7.10; found: C, 73.13; H,
3.55; N, 7.01%.
8
9
R. Sagar, J. Park, M. Koh and S.B. Park, J. Org. Chem., 2009, 74, 2171.
J.M. Evans, C.S. Fake, T.C. Hamilton, R.H. Poyser and G.A. Showell, J.
Med. Chem., 1984, 27, 1127.
10 G.M. Ziarani and P. Hajiabbasi, Heterocycles, 2013, 87, 1415.
11 R. Ghorbani-Vaghei, Z. Toghraei-Semiromi and R. Karimi-Nami, J. Braz.
Chem. Soc., 2011, 22, 905.
12 M.V. Dmitriev, P.S. Silaichev and A.N. Maslivets, Russ. J. Org. Chem.,
2011, 47, 1263.
13 A.T. Khan, M. Lal, S. Ali and Md. M. Khan, Tetrahedron Lett., 2011, 52,
5327.
14 A.M. Pansuriya, M.M. Savant, C.V. Bhuva, J. Singh and Y.T. Naliapara,
Arkivoc, 2009, (xii), 254.
15 H. Alinezhad, M. Tajbakhsh, F. Salehian and P. Biparva, Bull. Korean
Chem. Soc., 2011, 32, 3720.
16 F. Shirini, S.V. Atghia and M. Alipour Khoshdel, Iran. J. Catal., 2011, 1,
93.
17 B.B.F. Mirjalili and A. Akbari, Z. Naturforsch., 2009, 64b, 347.
18 B. Karami, S. Khodabakhshi and N. Nikrooz, Polycyclic Aromat. Compd.,
2011, 31, 97.
2-Amino-3-cyano-4-(2ʹ-naphthoyl)-4H,5H-pyrano[3,2-c]chromene-
1
5-one (4j): H NMR δ 8.44 (s, 1H), 7.98–7.95 (m, 2H), 7.84–7.82 (d,
1H, J=8.4 Hz), 7.76–7.72 (m, 1H), 7.62–7.52 (m, 3H), 7.49–7.42 (m,
2H), 7.39 (s, 2H), 7.33 (d, 1H, J=7.2 Hz), 5.47 (s, 1H) ppm; 13C NMR
δ 199.6, 159.5, 157.8, 153.8, 152.0, 133.2, 132.9, 130.9, 128.4, 127.4,
19 S. Khodabakhshi, B. Karami and K. Eskandari, C. R. Chimie, 2014, 17, 35.