A highly efficient protocol for the synthesis of new 3-(α-aroylamido)-4-hydroxycoumarin derivatives using SnCl2-SiO2 nanoparticles under solventfree conditions

Article abstract of DOI:10.3184/174751917X14944355549131

An efficient and simple protocol for the synthesis of the title compounds is described via a one-pot, three-component reaction of 4-hydroxycoumarin, aryl glyoxals and amides, using SnCl₂-SiO₂ nanoparticles as a heterogeneous catalyst

Full text of DOI:10.3184/174751917X14944355549131

JOURNAL OF CHEMICAL RESEARCH 2017
VOL. 41 JUNE, 321–324
RESEARCH PAPER 321
A highly efficient protocol for the synthesis of new 3-(α-aroylamido)-4-
hydroxycoumarin derivatives using SnCl2–SiO2 nanoparticles under solvent-
free conditions
Mona Arfavi-Safaria,c, Hossein Anaraki-Ardakanib*, Rashid Badric and Elham Tahanpesarc
aDepartment of Chemistry, Khuzestan Science and Research Branch, Islamic Azad University, Ahvaz, Iran
bDepartment of Chemistry, Mahshahr Branch, Islamic Azad University, Mahshahr, Iran
cDepartment of Chemistry, Ahvaz Branch, Islamic Azad University, Ahvaz, Iran
An efficient and simple protocol for the synthesis of the title compounds is described via a one-pot, three-component reaction of
4-hydroxycoumarin, aryl glyoxals and amides, using SnCl –SiO nanoparticles as a heterogeneous catalyst under solvent-free conditions.
The advantages of this synthesis include excellent yields2, mild2reaction conditions, atom economy, a reusable catalyst and no need for
chromatographic separations.
Keywords: solvent-free, SnCl2–SiO2 nanoparticles, aryl glyoxal, 4-hydroxycoumarin, multi-component reactions
Coumarin and its derivatives are an important class of heterocyclic
compounds and are the key core of various natural products.1,2
The application of coumarin derivatives as bioactive molecules
against different kinds of diseases is of great interest for medicinal
chemists. Coumarin derivatives have a wide spectrum of biological
activities, such as anticancer, anticoagulant, anti-HIV, antimalarial
and anti-inflammatory activities, and are usually associated with
low toxicity.3–7 The most significant are 3-substituted-4-hydroxy
coumarin derivatives, which have important clinical applications8,9
(Fig. 1).
A literature survey reveals that tin salts show high Lewis acidity
compared with other transition metal salts, in the order Sn2+ >> Zn2+
> Pb2+ ≈ Hg2+.10 As Sn2+ salts have higher Lewis acidity compared
with other metal salts, we selected SnCl2 as a homogeneous catalyst.
Furthermore, to improve the efficiency, loading, applicability
and recyclability of the catalyst, we chose silica nanoparticles as
a partner due to their high surface area, large pore volume and
recyclability. Hence, silica nanoparticles may be useful as supports
for the immobilisation of Sn2+ salts. We immobilised SnCl2 by
reaction of the hydroxyl groups on silica (Scheme 1), thus converting
a homogeneous SnCl2 catalyst into a heterogeneous catalyst
with improved features for the synthesis of 3-(α-aroylamido)-4-
hydroxycoumarin derivatives.
Multi-component reactions (MCRs) are important for generating
high levels of diversity, as they allow more than two building blocks
to be combined in a practical, time-saving, one-pot operation,
giving rise to complex structures by simultaneous formation of two
or more bonds.
MCRs have received considerable attention because of their
wide range of applications in pharmaceutical chemistry for the
creation of structural diversity and combinatorial libraries for drug
discovery.11,12
Recently, we reported the reaction of 4-hydroxycoumarin,
aromatic aldehydes and amides in the presence of p-toluene
sulfonic acid to produce 3-(α-amidobenzyl)-4-hydroxycoumarin
derivatives.13 Khodabakhshi et al. have reported a three-component
process for the synthesis of aroylamido coumarin derivatives from
reaction of aryl glyoxal, benzamide and 4-hydroxycoumarin in
the presence of molybdate sulfuric acid, tungstate sulfuric acid,
zirconium oxychloride and Fe3O4 nanoparticles.14–17 However,
these methods have drawbacks, such as requiring long reaction
times,13,17 acidic conditions,13-15 column chromatography to purify
the products14–16 and expensive catalysts, as well as catalysts that are
not recyclable.13,14,16 In all of these reports, reactions with aromatic
amides were reported. Therefore, there is scope to develop more
efficient and convenient methods for the synthesis of new coumarin
O
O
OH
OH
O
OH
O
OH
O
O
O
O
O
O
NO2
Warfarin
Phenprocoumon
Coumatetralyl
Acenocoumarol
Fig. 1 3-Substituted-4-hydroxy coumarin derivatives.
Cl
Sn
H
O
OH OH OH
Si
Si Si
O
O
OH
Si
SnCl2, DCM
Si
Si
O
O
O
O
O
O
O
r.t. 24 h
Scheme 1
* Correspondent. E-mail: hosseinanaraki@yahoo.com

322 JOURNAL OF CHEMICAL RESEARCH 2017
derivatives. To the best of our knowledge, there are no reports
on the use of SnCl2–SiO2 nanoparticles (NPs) in the synthesis of
3-(α-aroylamido)-4-hydroxycoumarin derivatives.
Considering the above reports and in continuation of our studies
on one-pot MCRs,18–20 we here report for the first time a one-pot,
three-component reaction of 4-hydroxycoumarin or 4-hydroxy-
6-methylpyran-1-one 1, aryl glyoxals 2 and aliphatic amides 3, in
the presence of SnCl2–SiO2 NPs as a heterogeneous catalyst for the
synthesis of 3-(α-aroylamido)-4-hydroxycoumarin derivatives 4 in
solvent-free conditions (Scheme 2).
Aryl glyoxals 2 were prepared by the reaction between their
corresponding acetophenone and SeO2 according to reported
procedures.21 First, to optimise the reaction conditions, the
reaction of 4-hydroxycoumarin with p-methyl phenyl glyoxal and
acetamide was selected as a model. As the formation of bis-aroyl
coumarins22 is possible, we first treated acetamide with p-methyl
phenyl glyoxal to form the corresponding imine and then added
4-hydroxycoumarin to the mixture. In all cases, the reaction was
performed under solvent-free conditions. To find the best and most
effective catalyst, we screened the model reaction in the presence of
different nanocatalysts, such as CaO, FeCl3, Fe3O4, SiO2, SnCl2 and
SnCl2–SiO2 (Table 1). The results showed that SnCl2–SiO2 NPs was
the most efficient catalyst for the reaction in solvent-free conditions
(Table 1, entry 7). Only a trace amount of the product was formed in
the absence of catalyst (Table 1, entry 1).
SiO2 NPs. In the absence of the SnCl2–SiO2 NPs, only a trace amount
of the product was formed. In the presence of SnCl2–SiO2 NPs, it
was found that 20 mol% of SnCl2–SiO2 NPs is optimal to carry out
the reaction over a short duration. However, further increase of the
molar amount of the catalyst from 20 mol% to 40 mol% did not
significantly increase the yield of the product.
To study the scope of the reaction, a series of aryl glyoxals
were employed. The results are shown in Table 2. In all cases, the
aromatic ring of the aryl glyoxal substituted with either electron-
donating or electron-withdrawing groups underwent the reaction
smoothly and gave the products in good yields (Table 2).
Compounds 4a–i were new and their structures were deduced
1
by elemental and spectral analysis. The H NMR spectrum of
compound 4a exhibited a two-singlet signal at δ = 2.21 and 2.35
ppm for the protons of the methyl groups. The methine and NH
protons are coupled and two doublets were observed for them at
6.03 and 8.09 ppm, respectively. When the 1H NMR spectrum was
recorded after addition of some D2O to the CDCl3 solution of 4a,
the doublet related to the NH proton disappeared and the doublet
corresponding to the methine proton was converted to a singlet.
The proton of the hydroxyl group resonated at 12.78 ppm as a broad
singlet. The 13C NMR spectrum of compound 4a showed 18 distinct
signals consistent with the proposed structure.
A possible mechanism for the formation of the products 4a–i is
proposed in Scheme 3. The reaction of aryl glyoxal 2 with amides 3
in the presence of the SnCl2–SiO2 NPs catalyst is proposed to give
the corresponding iminium ion 5. Next attack of 4-hydroxycoumarin
or 4-hydroxy-6-methylpyran-1-one 1 by the iminium ion 5 followed
by a 1,3-H shift leads to the final product 4 (Scheme 3).
The reusability of the catalyst was tested in the synthesis of
3-(α-aroylamido)-4-hydroxycoumarin derivatives. The catalyst
was recovered after each run, washed with ethanol, dried in an oven
at 100 °C for 20 min before use and tested for its activity in the
subsequent run. The catalyst was tested for three runs. The catalyst
showed very good reusability. It was determined that the catalyst
can be recycled for at least two cycles without any change in activity.
To find the optimum amount of catalyst, we screened the model
reaction in the absence and presence of several amounts of SnCl2–
Table 1 Preparation of N-[1-(4-hydroxy-2-oxo-2H-chromen-3-yl)-2-oxo-
2-p-tolyl-ethyl]-acetamide (4a) using different catalystsa
Catalyst
(mol %)
Time
(h)
Yieldb
(%)
Entry
Catalyst
1
2
3
4
5
6
7
8
9
–
–
20
20
20
20
20
20
20
20
3
2
2
2
2
2
2
2
2
trace
30
35
40
35
45
50
MgO
Al2O3
CaO
FeCl3
SiO2
SnCl2
Fe3O4
SnCl2-SiO2
Conclusion
In summary, the reaction between 4-hydroxycoumarin or
4-hydroxy-6-methylpyran-1-one, aryl glyoxals and aliphatic amides
in the presence of a catalytic amount of SnCl2–SiO2 NPs provides
a simple one-pot entry for the synthesis of 3-( -aroylamido)-
4-hydroxycoumarin derivatives of potential synthetic and
pharmaceutical interest. This method has advantages, such as the
use of a safe, inexpensive and recyclable catalyst, avoidance of
75
82
aReaction conditions: 4-hydroxy coumarin (1.0 mmol), acetamide (1.1 mmol), p-methyl
phenyl glyoxal (1.0 mmol), neat 100°C.
bIsolated yield.
O
O
O
Ar
Y
R
4
z
N
H
O
3
O
Y
OH
O
z
O
SnCl2-SiO2 NPs
H
+
+
R
NH2
Ar
solvent-free,100 0C
HO
O
O
O
O
Ar
OH
1
2
O
4
z
Y
z
Y
Y-Z
OH
O
O
H3C
Scheme 2 Reaction between 4-hydroxycoumarin or 4-hydroxy-6-methylpyran-1-one, aryl glyoxals and aliphatic amides, catalysed by SnCl2–SiO2 NPs.

JOURNAL OF CHEMICAL RESEARCH 2017 323
Experimental
Melting points were determined with an Electrothermal 9100 apparatus.
Elemental analyses were performed using a Heraeus CHN-O-Rapid
analyser. Mass spectra were recorded on a FINNIGAN-MAT 8430 mass
spectrometer operating at an ionisation potential of 70 eV. IR spectra were
recorded on a Shimadzu IR-470 spectrometer. 1H and 13C NMR spectra
were recorded on a Bruker DRX-400 Avance spectrometer in solution in
CDCl3 using TMS as an internal standard. The chemicals used in this work
were purchased from Fluka (Buchs, Switzerland) and were used without
further purification.
organic solvents, high yields of products and short reaction times.
Furthermore, all products were obtained through simple filtration
with no need for column chromatography, which reduces the waste
as well as environmental pollution.
Table 2 Three-component reaction of 4-hydroxycoumarin or 4-hydroxy-
6-methylpyran-1-one, aryl glyoxals and amides, catalysed by SnCl2–
SiO2 NPs
Time Yield
(min) (%)
Entry Substrate
Ar
R
M.p. (°C)
O
O
O
O
O
O
Preparation of nano silica-supported stannous chloride
4a
4-CH3-C6H4 CH3
120 82 202–205
120 78 196–198
Nano silica gel-supported tin (II) chloride was prepared according to
the procedure reported in the literature with some modifications.23,24
In a typical procedure, tin (II) chloride dihydrate (0.28 g) was added to a
suspension of silica gel nanoparticles (3.075 g) in dichloromethane (DCM)
(25.0 mL). The mixture was stirred at r.t. overnight. Then the solvent was
removed under reduced pressure and the residue was heated at 100 °C under
vacuum for 5 h to furnish SnCl2–SiO2 NPs. The prepared SnCl2–SiO2 NPs
were structurally characterised by SEM analysis and the IR spectrum.
Figure 2 indicates that the original morphology of the nanoparticles was
approximately spherical with the diameter varying between 25 and 60 nm.
OH
O
4b
4c
4d
4e
4f
C6H5
C6H5
CH3
OH
O
C2H5
130 82
200
OH
O
Synthesis of 3-(α-aroylamido)-4-hydroxycoumarin derivatives (4a–i);
general procedure
4-CH3-C6H4 C2H5
100 75 198–200
A mixture of aryl glyoxal (1 mmol), amides (1.1 mmol) and SnCl2–
SiO2 NPs (20 mol%) was stirred and heated at 70 °C for 30 min. Then
OH
O
4-Cl-C6H4
C2H5
100 80
110 76
190
189
OH
O
O
O
O
O
4-CH3-C6H4 CH3
OH
O
4g
4h
4i
C6H5
CH3
120 82 190–192
120 85 200–202
OH
O
4-CH3-C6H4 C2H5
OH
O
4-Cl-C6H4
CH3
120 80
201
OH
Fig. 2 SEM image of synthesised SnCl2–SiO2 NPs.
Scheme 3 Suggested pathway for the formation of compounds 4a–i.

324 JOURNAL OF CHEMICAL RESEARCH 2017
4-hydroxycoumarin or 4-hydroxy-6-methylpyran-1-one (1 mmol) was
added to the mixture and the reaction was stirred for the appropriate
amount of time (100–130 min) at 100 °C. The reaction progress was
monitored by TLC (EtOAc:hexane, 1:2). After reaction completion,
the mixture was added to hot EtOH and centrifuged to separate the
catalyst. The solvent was evaporated and the products were purified by
recrystallisation from EtOH.
MHz, CDCl3): δ 2.05 (3H, s, CH3), 2.21 (3H, s, CH3), 5.91 (1H, d, 3JHH
=
7 Hz, CH–NH), 6.06 (1H, s, CH=C), 7.26–7.82 (6H, arom), 8.10 (1H, d,
3JHH = 7 Hz, NH); 13C NMR (75 MHz, CDCl3): δ 19.63 (CH3), 22.52 (CH3),
51.24 (CH–NH), 101.97, 103.07, 128.08, 128.58, 129.50, 132.96, 135.75,
162.04 (C arom and olefin), 170.94, 173.63, 194.19 (3C=O). Anal. calcd for
C16H15NO5: C, 63.78; H, 5.02; N, 4.65; found: C, 63.69; H, 5.11; N, 4.57%.
N-[1-(4-Hydroxy-6-methyl-2-oxo-2H-pyran-3-yl)-2-oxo-2-p-tolyl-
N-[1-(4-Hydroxy-2-oxo-2H-chromen-3-yl)-2-oxo-2-p-tolyl-ethyl]-
ethyl] propionamide (4h): White powder; m.p. 200–202 °C; IR (KBr) (νmax
,
acetamide (4a): White powder, m.p. 202–205 °C; IR (KBr) (νmax, cm−1):
cm−1): 3290 (N–H), 1692 (C=O); MS (m/z, %): 329 (7); H NMR (300
MHz, CDCl3): δ 1.18 (3H, t, 3JHH = 7.5 Hz, CH3), 2.09 (3H, s, CH3), 2.19
(3H, s, CH3), 2.34 (2H, m, CH2), 5.92 (1H, d, 3JHH = 6 Hz, CH–NH), 6.05
(1H, s, CH=C), 7.15–7.72 (5H, arom), 7.95 (1H, broad, NH); 13C NMR (75
MHz, CDCl3): δ 9.59 (CH3), 19.79 (CH3), 28.98 (CH2), 50.99 (CH), 102.13,
103.05, 128.18, 129.09, 129.28, 131.61, 133.10, 144.57, 163.12 (C arom and
olefin), 169.41, 176.59, 194.61 (3C=O); Anal. calcd for C18H19NO5: C, 65.64;
H, 5.81; N, 4.25; found: C, 65.52; H, 5.73; N, 4.11%.
1
1
3309 (N–H), 1690 (C=O); MS (m/z, %): 351 (7); H NMR (300 MHz,
CDCl3): δ = 2.21 (3 H, s, CH3), 2.35 (3 H, s, CH3), 6.03 (1H, d, 3JHH = 6 Hz,
CH–NH), 7.16–8.01 (8H, m, arom), 8.08 (1H, d, 3JHH = 6 Hz, NH), 12.78
(1H, broad, OH); 13C NMR (75 MHz, CDCl3): δ 21.70 (CH3), 22.54 (CH3),
51.73 (CH–NH), 104.81, 116.54, 116.60, 124.13, 124.64, 128.20, 129.43,
131.49, 132.85, 144.75, 153.27, 161.64 (C arom and olefin), 165.41, 173.44,
192.18 (3C=O). Anal. calcd for C20H17NO5: C, 68.37; H, 4.88; N, 3.99;
found: C, 68.59; H, 4.75; N, 3.90%.
N-[2-(4-Chloro-phenyl)-1-(4-hydroxy-6-methyl-2-oxo-2H-pyran-3-yl)-
N-[1-(4-Hydroxy-2-oxo-2H-chromen-3-yl)-2-oxo-2-phenyl-ethyl]-
2-oxo-ethyl]-acetamide (4i): White powder; m.p. 201 °C; IR (KBr) (νmax
,
acetamide (4b): White powder; m.p. 196–198 °C; IR (KBr) (νmax, cm−1):
1
cm−1): 3295 (N–H), 1693 (C=O); MS (m/z, %): 335 (11); H NMR (300
1
3376 (N–H), 1695 (C=O); MS (m/z, %): 337 (9); H NMR (300 MHz,
MHz, CDCl3): δ 2.01 (3H, s, CH3), 2.20 (3H, s, CH3), 5.90 (1H, d, 3JHH
=
CDCl3): δ 2.21(3H, s, CH3), 6.08 (1H, d, 3JHH = 6.5 Hz, CH–NH), 7.09–7.82
(9H, m, arom), 8.06 (1H, d, 3JHH = 6.5 Hz, NH), 12.82 (1H, broad, OH);
13C NMR (75 MHz, CDCl3): δ 23.42 (CH3), 50.12 (CH), 101.12, 121.54,
125.52, 126.82, 128.41, 128.78, 129.85, 130.81, 133.24, 143.17, 152.11,
161.19 (C arom and olefin), 163.93, 171.15, 187.46 (3C=O). Anal. calcd for
C19H15NO5: C, 67.65; H, 4.48; N, 4.15; found: C, 67.55; H, 4.32; N, 4.23%.
N-[1-(4-Hydroxy-2-oxo-2H-chromen-3-yl)-2-oxo-2-phenyl-ethyl]-
propinamide (4c): White powder; m.p. 200 °C; IR (KBr) (νmax, cm−1): 3340
(N–H), 1694 (C=O); MS (m/z, %): 351 (6); 1H NMR (300 MHz, CDCl3): δ
1.23 (3H, t, CH3,3JHH = 7.5 Hz), 2.46 (2H, q,3JHH = 7.5 Hz, CH2), 6.05 (1H,
d, 3JHH = 6 Hz, CH–NH), 7.12–8.03 (9H arom and OH), 8.16 (1H, d,3JHH = 6
Hz, NH); 13C NMR (75 MHz, CDCl3): δ 10.04 (CH3), 29.82 (CH2), 50.45
(CH–NH), 92.62, 117.54, 122.56, 125.57, 126.83, 128.46, 128.66, 128.89,
133.27, 136.81, 152.45, 161.93 (C arom), 162.15, 173.74, 187.45 (3C=O).
Anal. calcd for C20H17NO5: C, 68.37; H, 4.88; N, 3.99; found: C, 68.45; H,
4.77; N, 3.86%.
6.5 Hz, CH–NH), 6.13 (1H, s, CH=C), 7.35 (2H, d, 3JHH = 8.7 Hz, arom),
7.75 (2H, d, 3JHH = 8.7 Hz, arom), 7.95 (1H, d,3JHH = 6.5 Hz, NH);13C NMR
(75 MHz, CDCl3): δ 19.66 (CH3), 22.50 (CH3), 51.25 (CH), 102.14, 103.04,
128.74, 128.96, 129.42, 132.57, 140.03, 163.48 (C arom and olefin), 169.77,
173.46, 192.11 (3C=O). Anal. calcd for C16H14ClNO5: C, 57.24; H, 4.20; N,
4.17; found: C, 57.33; H, 4.11; N, 4.23%.
Received 10 March 2017; accepted 13 April 2017
Paper 1704636
https://doi.org/10.3184/174751917X14944355549131
Published online: 17 May 2017
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1
3376 (N–H), 1695 (C=O); MS (m/z, %): 365 (11); H NMR (300 MHz,
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ethyl]-propionamide (4e): White powder; m.p. 190 °C; IR (KBr) (νmax
,
1
cm−1): 3351 (N–H), 1694 (C=O); MS (m/z, %): 385 (7); H NMR (300
MHz, CDCl3): δ 1.23 (3H, t,3JHH = 7.5 Hz, CH3), 2.48 (2H, q, 3JHH = 7.5 Hz,
CH2), 6.02 (1H, d, 3JHH = 6 Hz, CH–NH), 7.14–8.11 (9H arom and OH),
8.02 (1H, d,3JHH = 6.5 Hz, NH); 13C NMR (75 MHz, CDCl3): δ 9.51 (CH3),
28.85 (CH2), 51.77 (CH–NH) 104.24, 116.53, 124.26, 124.65, 128.70,
129.01, 129.38, 132.57, 132.85, 134.26, 140.02, 153.20 (C arom and olefin),
167.75, 177.24, 191.86 (3C=O). Anal. calcd for C20H16ClNO5: C, 62.26; H,
4.18; N, 3.63; found: C, 62.32; H, 4.06; N, 3.51%.
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N-[1-(4-Hydroxy-6-methyl-2-oxo-2H-pyran-3-yl)-2-oxo-2-p-tolyl-
ethyl]-acetamide (4f): White powder; m.p. 189 °C; IR (KBr) (νmax, cm−1):
1
3287 (N–H), 1690 (C=O); MS (m/z, %): 315 (6); H NMR (300 MHz,
CDCl3): δ 2.15 (3H, s, CH3), 2.21 (3H, s, CH3), 2.35 (3H, s, CH3), 5.90
(1H, d, 3JHH = 6.2 Hz, CH–NH), 6.06 (1H, s, CH=C), 7.13–7.73 (5H arom),
8.02 (1H, d, 3JHH = 6 Hz, NH); 13C NMR (75 MHz, CDCl3): δ 21.01(CH3),
23.43 (CH3), 24,33 (CH3), 50.63 (CH–NH), 101.05, 128.76, 128.85, 129.45,
129.65, 133.84, 142.85, 162.25 (C arom and olefin), 167.68, 171.12, 187.43
(3C=O). Anal. calcd for C17H17NO5: C, 64.75; H, 5.43; N, 4.44; found: C,
64.82; H, 5.31; N, 4.54%.
22 S. Khodabakhshi, B. Karami, K. Eskandari, S.J. Hoseini and A. Rashidi, RSC
Adv., 2014, 4, 17891.
23 H.R. Darabi, K. Aghapoor and F. Mohsenzadeh, Bull. Korean Chem. Soc.,
2011, 32, 213.
N-[1-(4-Hydroxy-6-methyl-2-oxo-2H-pyran-3-yl)-2-oxo-2-phenyl-
ethyl]-acetamide (4g): White powder; m.p. 190–192 °C; IR (KBr) (νmax
,
cm−1): 3289 (N–H), 1683 (C=O); MS (m/z, %): 301 (12); 1H NMR (300
24 B.F. Mirjalili, A. Bamoniri and A. Akbari, J. Iran Chem. Soc., 2011, 8, 135.