L-proline N-sulfonic acid-functionalized magnetic nanoparticles: A novel and magnetically reusable catalyst for one-pot synthesis of 3,4-dihydropyrimidine-2-(1 H)-thiones under solvent-free conditions

Article abstract of DOI:10.1039/c6ra10558k

In accordance with the principles of green chemistry, magnetite nanoparticles (MNPs) have been studied in organic research and industry because of their reusability and facile recoverability. In this study, l-proline N-sulfonic acid-functionalized magneti

Full text of DOI:10.1039/c6ra10558k

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L-Proline N-sulfonic acid-functionalized magnetic nanoparticles: A novel and
magnetically reusable catalyst for one-pot synthesis of 3, 4-dihydropyrimidine-
2-(1H)-thiones under solvent-free conditions
M. Afradi,a N. Foroughifar,a,* H. Pasdara and H. Moghanianb
a Department of Chemistry, Tehran North Branch, Islamic Azad University, Tehran, Iran
b Department of Chemistry, Dezful Branch, Islamic Azad University, Dezful, Iran
Eꢀmail:n_foroughifar@yahoo.com
Abstract
With regard to green chemistry’s purposes, magnetite nanoparticles (MNPs) have
been dramatically considered in organic research and industry, because of the
reusability and facile recoverability. Accordingly in this research,
Lꢀproline Nꢀ
sulfonic acidꢀfunctionalized magnetic nanoparticles have been prepared as a novel
magnetically reusable heterogeneous acid catalyst using a facile process. The
catalytic performance of this novel magnetic solid acid catalyst has been studied in
the synthesis of 3,4ꢀdihydrpyrimidineꢀ2ꢀ[1H]thione derivatives in oneꢀpot threeꢀ
component condensation reaction of thiourea, aromatic aldehydes, and tꢀbutyl
acetoacetate under solventꢀfree classical heating conditions, with high yield and
short reaction times. The structure of obtained nanoparticles was assessed by
scanning electron microscopy (SEM), vibrating sample magnetometery (VSM),
thermaogravimeter analysis (TGA), Xꢀray diffraction (XRD), energy dispersive Xꢀ
ray analysis (EDXA). The results, exhibit the synthesized magnetic nanoparticles
are superparamagnetic with a size range of 10–20 nm. More importantly, the
heterogeneous catalyst could be recovered easily with the assistance of an external
magnetic field and reused many times without significant loss of catalytic activity.
Keywords:
Lꢀproline,
magnetite
nanoparticles,
multiꢀcomponent
reaction,
dihydropyrimidineꢀ2ꢀthiones
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1. Introduction
Multiꢀcomponent reactions (MCRs) as a strong methodology for the speedy synthesis of
biological substantial, varied and complex organic molecules via undemanding creation of
multiple new covalent bonds in a oneꢀpot transformation have founded [1ꢀ5]. One of the
classical multicomponent techniques for the synthesis of 3,4ꢀdihydropyrimidineꢀ2ꢀ(1H)ꢀ
ones (DHPMs) or thiones is the threeꢀcomponent Biginelli condensation of aldehyde, βꢀ
ketoester and urea or thiourea [6]. Generally, DHPMs and their derivatives have in turn
attracted excellent regard in medicine and organic chemistry because of their fascinating
pharmacological and therapeutic utilizations [7ꢀ13]. They exhibit a wide range of
medicinal applications such as antitumor, antiꢀinflammatory, antihypertensive, potassium
channel antagonist, antiꢀHIV, antiꢀmicrobial, antiviral, antiꢀmalarial, antibacterial and
antifungal [14ꢀ26]. Thus, numerous methods have been exploited for the synthesis of
dihydropyrimine derivatives in the literature using extensive kind of catalysts such as
Bronsted and Lewis acids, ionic liquids, zeolites, quantum dots (QDs), graphite and
heterogeneous acid catalysts [27ꢀ44], because of pharmacological and medicinal
significance of DHPMs. It is remarkable that many of the disseminated manners suffer
from one or more drawbacks such as monotonous workup, unfavorable yield, long reaction
times, applying organic solvents, toxicity, prohibitive and reusability of catalysts [45].
Organocatalysis as a powerful strategy in organic synthesis has embraced characteristic
regard on the presentation of novel organocatalyst system and their enforceability in
organic transformation [46, 47]. Sulfuric acid is applied as an efficacious, indispensable
and irretrievable homogeneous acid catalyst to generate disparate chemicals [48].
Sulfonation with chlorosulfonic acid as an appropriate, quick, and effective procedure has
embraced much consideration for the heterogenization of homogeneous catalysts [49ꢀ51].
According to green chemistry objective, magnetic nanoparticles (MNPs) due to some
features such as easy preparation and functionalization, considerable durability and
reusability, high surface area, nontoxic and facile removing with aid of external magnet
from the ultimate mixture have approved as heterogeneous support in catalytic
transformation [52ꢀ55]. Moreover, surface functionalization of magnetic nanoparticles is a
delicate and acceptable way to remove the giant gap between heterogeneous and
homogeneous catalysis [56]. Hence, sulfuric acid coated magnetite nanoparticles as a new
retrievable heterogeneous acid catalyst unscrews new way to demonstrate a wonderful and
efficacious system for simplify catalyst retrieve in various organic reactions [57, 58].
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In this paper, we investigated the synthesis of 3,4ꢀdihydropyrimidineꢀ2ꢀ[1H]ꢀthiones by
applying aromatic aldehydes, thiourea and tꢀbutyl acetoacetate in the presence of novel,
reusable and efficacious sulfonic acidꢀfunctionalized Lꢀproline Nꢀsulfonic acidꢀ
functionalized magnetic nanoparticle (MNPꢀLꢀProlineꢀSO3H) catalyst under solventꢀfree
system with high yields and short reaction times. It is substantial that, there is no inkling in
the literatures on the synthesis of MNPꢀLꢀProlineꢀSO3H, and we aspire this new catalyst
can be handled to many other reactions such as Robinson annulation [59], Mannich
reaction [60] and others.
2. Experimental
All solvents and chemical reagents were bought from the Merck chemical company and
used in our examinations without additional purification. FTꢀIR spectra of all samples in
our study were gained in the subꢀregion 400ꢀ4000 cmꢀ1 with potassium bromide pellets
with PerkinꢀElmer 550 spectrometer. Melting points were specified by applying of
1
Electrothermal 9200 apparatus and are not corrected. H NMR and 13C NMR of products
were registered with Bruker Advance spectrometer instrument in DMSOꢀd6 as a solvent
and TMS as an internal standard. Thin layer chromatography (TLC) was performed on
silica gel poly gram SILG/UV 254 nm plates. Xꢀray diffraction (XRD) of the catalyst was
accomplished using X'PertPro (Cu kα radiation, λ=1.54 Å) in the region of 2ϴ = 20°ꢀ 80°.
The morphology of MNPꢀLꢀProlineꢀSO3H was figured out with SEM, (Hituch S4160
scanning electron microscopy). To study magnetite feature of nanocatalyst, a varying
magnetic field from ꢀ10000 to 10000 on a BHVꢀS5 vibrating sample magnetometer (VSM)
was utilized. Thermal gravimetric analysis patterns of nanoꢀmagnetic solid acid catalyst
was carried out on a thermal analyzer with heating rate of 10°C minꢀ1 over a temperature
limited area of 30ꢀ800 under N2 atmosphere.
2.1 Synthesis of Fe3O4@L-proline magnetic nanoparticles (MNP- L-proline)
A mixture of FeCl3.6H2O (4 mmol, 1.081 g) and FeCl2.4H2O (2 mmol, 0.398 g) were
dissolved in 150 ml of distilled water to obtain an orange solution under N2 atmosphere.
Afterward, 1 ml of Tween 80 was surcharged to the resultant solution and the mixture was
mixed under intensive stirring and stable temperature of 100°C for approximately 4 h.
Thereupon, 0.8 g of Lꢀproline and NH4OH ( 25wt %, 15 ml) was added into the above
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solution until the pH was enhanced to 11, to form a black suspension. The black solution
was refluxed at 100°C for 6h with intensive mixing. Fe3O4@Lꢀproline nanoparticles were
isolated from the aqueous mixture by applying an external magnet, washed with distilled
water until neutrality and eventually dried at 60°C in vacuum for 24h.
2.2 Synthesis of L-proline N-sulfonic acid-functionalized magnetic nanoparticles (MNP-
L-Proline-SO3H)
A 250 ml suction flask was provided with a stable pressure dropping funnel. The gas vent
was attached to a vacuum system via an adsorbing solution of alkali trap. Firstly, 1 g of
Fe3O4@Lꢀproline was surcharged into the flask and distribute in 10 ml of nꢀhexane by
ultrasonic batch for 1h. Thereafter, 0.5 g of chlorosulfonic acid was added dropꢀwise to a
cooled (iceꢀbatch) suspension of Fe3O4@Lꢀproline during an interval of time,
approximately 30 min at room temperature. The resulting suspension was stirred for 90
min, to eliminate of remaining HCl by suction. Finally, the Lꢀproline Nꢀsulfonic acidꢀ
functionalized magnetic nanoparticles was isolated using an external magnet and washed
with toluene (2×15 ml) and distilled water (2×10 ml) respectively, and dried in an vacuum
oven at 60°C.
2.3 General procedure for the synthesis of 3,4-Dihydropyrimidine-2(1H)-thiones
In a round bottomed flask, a mixture of thiourea (1.5 mmol), aromatic aldehyde (1 mmol)
and tꢀbutyl acetoacetate (1 mmol) were placed and stirred at 100°C in the presence of
MNPꢀLꢀProlineꢀSO3H (0.075 g) for 3h. Upon completion of the reaction, the resultant was
dissolved in hot ethanol to separate the catalyst by an external magnet. The solvent was
then evaporated; the crude solid products were recrystallized from the ethanol and dried at
60°C under vacuum for 4h.
All of desirable products were characterized by 1H NMR, 13CNMR and FTꢀIR
spectroscopy. Spectra data for all compounds are provided below:
2.3.1 tꢀButylꢀ6ꢀmethylꢀ4ꢀphenylꢀ2ꢀthioxoꢀ1,2,3,4ꢀtetrahydropyrimidineꢀ5ꢀcarboxylate (4a)
IR (KBr): νmax
=
3380, 3190, 2850, 1704, 1594, 1181, 762, 700 cmꢀ1; 1H NMR (300 MHz,
DMSOꢀd6): δ= 1.37 (t, 9H, tꢀBu), 2.11 (s, 3H, CH3), 5.11 (s, 1H, Hꢀ4), 7.23ꢀ7.50 (m, 5H,
ArꢀH), 8.52 (s, 1H, NH), 8.76 (s, 1H, NH); 13C NMR(75 MHz, DMSOꢀd6): δ=174.6, 163.1,
159.4, 140.3, 127.7, 125.8, 125.4, 101.3, 79.1, 56.4, 27.9, 17.4.
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2.3.2
tꢀButylꢀ6ꢀmethylꢀ4ꢀ(4ꢀchlorophenyl)ꢀ2ꢀthioxoꢀ1,2,3,4ꢀtetrahydropyrimidineꢀ5ꢀ
carboxylate (4b)
IR (KBr): νmax
=
3423, 3203, 2877, 1731, 1560, 1514, 1180, 1087, 830 cmꢀ1; 1H NMR (300
MHz, DMSOꢀd6): δ= 1.11 (t, 9H, tꢀBu), 2.10 (s, 3H, CH3), 5.13 (s, 1H, Hꢀ4), 6.94ꢀ7.18 (m,
4H, ArꢀH), 8.56 (s, 1H, NH), 8.91 (s, 1H, NH); 13C NMR(75 MHz, DMSOꢀd6): δ=172.6,
162.4, 157.7, 140.5, 128.7, 125.8, 122.3, 104.9, 78.7, 59.5, 24.2, 17.3.
2.3.3
carboxylate (4c)
IR (KBr): νmax
3393, 3190, 2830, 1706, 1606, 1510, 1248, 1172, 1028, 830 cmꢀ1; 1H NMR
tꢀButylꢀ6ꢀmethylꢀ4ꢀ(4ꢀmethoxylphenyl)ꢀ2ꢀthioxoꢀ1,2,3,4ꢀtetrahydropyrimidineꢀ5ꢀ
=
(300 MHz, DMSOꢀd6): δ= 0.99 (t, 9H, tꢀBu), 1.94 (s, 3H, CH3), 3.86 (s, 3H, OCH3), 5.21 (s,
1H, Hꢀ4), 7.15ꢀ7.37 (m, 4H, ArꢀH), 8.51 (s, 1H, NH), 8.79 (s, 1H, NH); 13C NMR(75 MHz,
DMSOꢀd6): δ= 170.6, 163.5, 158.7, 155.4, 131.6, 123.8, 109.7, 101.3, 80.7, 59.7, 56.2, 27.4,
15.6.
2.3.4
carboxylate (4d)
IR (KBr): νmax
tꢀButylꢀ6ꢀmethylꢀ4ꢀ(3ꢀnitrophenyl)ꢀ2ꢀthioxoꢀ1,2,3,4ꢀtetrahydropyrimidineꢀ5ꢀ
=
3332, 3184, 2878, 1718, 1562, 1536, 1521, 1352, 1151, 1118, 839 , 735
cmꢀ1; 1H NMR (300 MHz, DMSOꢀd6): δ= 1.18 (t, 9H, tꢀBu), 1.91 (s, 3H, CH3), 4.90 (s, 1H,
Hꢀ4), 7.63ꢀ8.19 (m, 4H, ArꢀH), 8.53 (s, 1H, NH), 8.79 (s, 1H, NH); 13C NMR(75 MHz,
DMSOꢀd6): δ= 172.6, 162.4, 157.7, 146.4, 143.4, 134.6, 128.7, 120.8, 119.4, 103.4, 70.7,
59.5, 22.2, 17.3.
2.3.5
carboxylate (4e)
IR (KBr): νmax
3421, 3185, 2836, 1701, 1554, 1471, 1183, 1103, 1037, 754 cmꢀ1; 1H NMR
tꢀButylꢀ6ꢀmethylꢀ4ꢀ(2ꢀchlorophenyl)ꢀ2ꢀthioxoꢀ1,2,3,4ꢀtetrahydropyrimidineꢀ5ꢀ
=
(300 MHz, DMSOꢀd6): δ= 1.03 (t, 9H, tꢀBu), 2.02 (s, 3H, CH3), 4.91 (s, 1H, Hꢀ4), 7.23ꢀ7.63
(m, 4H, ArꢀH), 8.62 (s, 1H, NH), 8.94 (s, 1H, NH); 13C NMR(75 MHz, DMSOꢀd6): δ= 173.8,
166.1, 161.9, 140.3, 131.7, 128.8, 128.7, 128.5, 125.1, 103.4, 78.6, 54.9, 28.1, 18.6.
2.3.6
carboxylate (4f)
IR (KBr): νmax
3434, 3207, 2906, 1728, 1543, 1494, 1455, 1227, 1184, 1098, 755 cmꢀ1; 1H
tꢀButylꢀ6ꢀmethylꢀ4ꢀ(2ꢀhydroxyphenyl)ꢀ2ꢀthioxoꢀ1,2,3,4ꢀtetrahydropyrimidineꢀ5ꢀ
=
NMR (300 MHz, DMSOꢀd6): δ= 1.27 (t, 9H, tꢀBu), 2.05 (s, 3H, CH3), 4.38 (s, 1H, OH),
5.09(s, 1H, Hꢀ4), 6.78ꢀ7.21 (m, 4H, ArꢀH), 8.96 (s, 1H, NH), 9.08 (s, 1H, NH); 13C
NMR(75 MHz, DMSOꢀd6): δ= 171.4, 164.8, 159.3, 149.4, 129.9, 128.7, 120.8, 119.4, 113.4,
100.8, 79.6, 56.4, 26.2, 17.7.
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2.3.7
carboxylate (4g)
IR (KBr): νmax
3403, 3196, 2918, 1701, 1558, 1452, 1175, 1098, 813 cmꢀ1; 1H NMR (300
tꢀButylꢀ6ꢀmethylꢀ4ꢀ(4ꢀmethylphenyl)ꢀ2ꢀthioxoꢀ1,2,3,4ꢀtetrahydropyrimidineꢀ5ꢀ
=
MHz, DMSOꢀd6): δ= 1.20 (t, 9H, tꢀBu), 1.93 (s, 3H, CH3), 2.27 (s, 3H, CH3), 5.12 (s, 1H,
Hꢀ4), 7.10ꢀ7.12 (m, 4H, ArꢀH), 8.51 (s, 1H, NH), 8.98 (s, 1H, NH); 13C NMR(75 MHz,
DMSOꢀd6): δ= 169.4, 164.4, 157.7, 139.5, 132.4, 127.8, 124.1, 100.4, 78.4, 55.7, 26.5,
17.8,14.2.
2.3.8
carboxylate (4h)
IR (KBr): νmax
3382, 3250, 2902, 1698 ,1548, 1465, 1171, 1111, 812 cmꢀ1; 1H NMR (300
tꢀButylꢀ6ꢀmethylꢀ4ꢀ(2ꢀmethylphenyl)ꢀ2ꢀthioxoꢀ1,2,3,4ꢀtetrahydropyrimidineꢀ5ꢀ
=
MHz, DMSOꢀd6): δ= 1.31 (t, 9H, tꢀBu), 1.90 (s, 3H, CH3), 3.29 (s, 3H, CH3), 5.07 (s, 1H, Hꢀ
4), 6.79ꢀ7.21 (m, 4H, ArꢀH), 8.69 (s, 1H, NH), 9.15 (s, 1H, NH); 13C NMR(75 MHz, DMSOꢀ
d6): δ= 173.2, 166.7, 158.4, 141.1, 139.5, 132.7, 130.0, 125.7, 124.8, 123.6, 83.4, 56.5,
27.8, 19.6 , 17.8.
2.3.9
carboxylate (4i)
IR (KBr): νmax
3333, 3185, 2881, 1717, 1559, 1534, 1352, 1151, 1118, 792 cmꢀ1; 1H NMR
tꢀButylꢀ6ꢀmethylꢀ4ꢀ(2ꢀnitrophenyl)ꢀ2ꢀthioxoꢀ1,2,3,4ꢀtetrahydropyrimidineꢀ5ꢀ
=
(300 MHz, DMSOꢀd6): δ= 1.06 (t, 9H, tꢀBu), 1.81 (s, 3H, CH3), 4.83 (s, 1H, Hꢀ4), 7.55ꢀ8.11
(m, 4H, ArꢀH), 9.10 (s, 1H, NH), 9.32 (s, 1H, NH); ); 13C NMR(75 MHz, DMSOꢀd6):
δ=172.1, 163.5, 156.3, 145.2, 141.6, 130.1, 127.7, 126.9, 122.9, 103.1, 79.7, 52.5, 25.5,
17.2.
2.3.10
carboxylate (4j)
IR (KBr): νmax
tꢀButylꢀ6ꢀmethylꢀ4ꢀ(4ꢀhydroxyphenyl)ꢀ2ꢀthioxoꢀ1,2,3,4ꢀtetrahydropyrimidineꢀ5ꢀ
=
3385, 3242, 2847, 1718, 1548, 1513, 1253, 1173, 835 cmꢀ1; 1H NMR (300
MHz, DMSOꢀd6): δ= 1.07 (t, 9H, tꢀBu), 1.83 (s, 3H, CH3), 3.96 (s, 1H, OH), 5.00 (s, 1H, Hꢀ
4), 7.64ꢀ7.83 (m, 4H, ArꢀH), 8.94 (s, 1H, NH), 9.19 (s, 1H, NH); 13C NMR(75 MHz, DMSOꢀ
d6): δ=172.1, 164.6, 158.1, 155.4, 133.9, 124.4, 114.8, 100.1, 78.6, 56.1, 27.9, 16.4.
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3. Result and discussion
3.1. Synthesis and characterization of the catalyst
In this investigation, we report a facile preparation of MNPꢀLꢀProlineꢀSO3H as a new,
reusable and recoverable catalyst (Scheme 1). First, the Lꢀprolineꢀcoated magnetic
nanoparticles were prepared by a chemical coꢀprecipitation of FeCl3 and FeCl2 solution in
presence of Lꢀproline [61]. Afterward, Fe3O4@Lꢀproline magnetic nanoparticle surface
was functionalized with SO3H groups by the condensation reaction of MNPꢀLꢀproline and
chlorosulfonic acid in nꢀhexane.
HO3S
HO3S
N
N
HN
O
HN
O
O
O
O
O
O
O
O
SO3H
N
NH4OH,
LꢀProline
O
Fe3O4
MNPs
ClSO3H
Fe3O4
MNPs
H
N
O
O
O
FeCl3.6H2O
+
FeCl2.4H2O
N
N
O
O
O
SO3H
dry nꢀhexane
H
100°C/ N2
O
O
O
O
O
O
O
O
N
N
SO3H
NH
SO3H
NH
Scheme 1. Preparation of MNPꢀLꢀProlineꢀSO3H
The structure of magnetite nanocatalyst (MNPꢀLꢀProlineꢀSO3H) was characterized by
applying XRD, VSM, TGA, SEM and EDAX analyses. The crystalline structure of MNPꢀ
LꢀProlineꢀSO3H was investigated by means of XRD technique (Fig. 1). All diffraction
peaks apperceived at 2Ɵ= 30.4º, 35.7º, 43.2º, 53.7º, 57.3º, 63.1º, 74.3º which can be
assigned to the (220), (311), (400), (422), (511), (440) and (533) planes of Fe3O4,
respectively. The peaks in XRD pattern of magnetite nanoparticles are in accordance with
the standard Fe3O4 (JCPDS file No. 19ꢀ0629), The appearance of these diffraction peaks
demonstrates that survival of the crystalline spinel ferrite core structure during the Lꢀ
proline coating process. The average crystalline size of MNPꢀLꢀProlineꢀSO3H particles was
calculated by using DebyeꢀScherrer's formula (D=kλ/βcosƟ); where D, k, λ, β, Ɵ are mean
grain size, Scherrer’s constant, Xꢀray wavelength, corrected diffraction line fullꢀwidth at
halfꢀmaximum (FWHM) and Bragg diffraction angle respectively. The average size of
MNPꢀLꢀProlineꢀSO3H was specified to be about 11 nm from the XRD result by applying
the above equation for the width of the peak at 2Ɵ= 35.7º (311), which is smaller than the
size determined by SEM analysis.
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Fig. 1. XRD diffraction pattern of MNPꢀLꢀProlineꢀSO3H
Scanning electron microscopy image of MNPꢀLꢀProlineꢀSO3H nanoparticles has
demonstrated in Figure 2, provides beneficial data on the morphology feature and particle
size of nanoparticles. On the basis of Figure 2, magnetic nanoparticles have approximately
spherical shape with a middle diameter from 8 to 20 nm and monotonic surface. Energy
dispersive Xꢀray spectrometer (EDAX) of MNPꢀLꢀProlineꢀSO3H nanoparticles was
depicted in Figure 3 exhibits the component of the sample. The obvious attendance of S
signal in EDAX spectrum demonstrates that Fe3O4@Lꢀproline nanoparticles have been
successfully functionalized by SO3H groups.
Fig. 2. SEM images of MNPꢀLꢀProlineꢀSO3H nanoparticles.
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Fig. 3. EDAX spectra of MNPꢀLꢀProlineꢀSO3H nanoparticles
The magnetic feature of the MNPꢀLꢀprolineꢀSO3H was evaluated by using a vibration
sample magnetometer (VSM) at room temperature (Fig. 4). The hysteresis curve allows
determination of the saturation magnetization (Ms), remanent magnetization (Mr) and
coercivity (Hc). On the basis of Figure 4, the saturation magnetization quantity for our
catalyst was measured 25 emu gꢀ1. The result represents that the functionalized magnetic
nanoparticles have a lower magnetic quantity in compared with bar magnetic nanoparticles
(74.3 emu/g), due to the coated shell [62]. In figure 4 (Left inset), we can also see that the
Mr and the Hc (Mr =0.45 emu gꢀ1and Hc = 0.03 Oe) could be ignored, thus the MNPꢀLꢀ
prolineꢀSO3H can be considered as superꢀparamagnetism. The strong magnetization of the
nanoparticles was also revealed by simple attraction with an external magnet (Fig. 4, Right
inset), suggesting that the obtained magnetic nanoparticles had an excellent magnetic
responsibility, which prevents composite microspheres from aggregating and enables them
to redisperse rapidly when the magnetic field is removed.
To evaluate the stability of the MNPꢀLꢀprolineꢀSO3H, and bond formation between
Fe3O4@Lꢀproline and sulfonic acid, the thermal gravimetric analysis is applied (Fig. 5).
Pursuant to TGA curve, the mass loss of MNPꢀLꢀprolineꢀSO3H nanoparticles until 230°C
is dedicated to deliver of adsorbed solvents and surface hydroxyl groups. Numerous weight
loss at roughly 250ꢀ650 °C, is attributed to evaporation and disintegration of organic
groups (proline and SO3H) grafted to the surface of Fe3O4 MNPs [62]. As can be seen from
the TGA curve, the amount of organic moiety was about 16.5 % against the total
heterogeneous catalyst. In accordance with this mass loss, it was calculated that 0.85 mmol
of Lꢀproline Nꢀsulfonic acid was loaded on 1 g of MNPꢀLꢀprolineꢀSO3H catalyst.
Furthermore, the DTG curve shows that the decomposition of the organic structure mainly
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occurred in one step, from 450 °C to 600 °C. Therefore, the MNPꢀLꢀprolineꢀSO3H is stable
around or below 300 °C.
Fig. 4. The magnetic hysteresis loops of MNPꢀLꢀprolineꢀSO3H. Left inset: the magnified
field from ꢀ3 to 3 Oe. Right inset: the picture displays the catalyst was dispersed in liquid
and captured by the outer magnet.
To assess the number of acidic sites of MNPꢀLꢀprolineꢀSO3H, the back titration method
was used [58]. To 0.05 g of heterogeneous catalyst, 5 ml of standardized 0.1N KOH
solution was added, and the resultant mixture was sonicated for 10 minutes. The magnetic
catalyst was separated using external magnet. Then, to obtained solution, 0.2 ml of
phenolphthalein solution was added as an indicator and unreacted base was titrated with
standardized 0.1 N HCl solution, until the pink color almost was disappeared. The number
of H+ sites in heterogeneous acidic catalyst was found to be 0.93 mmol/g. The agreement
between the acid amount of MNPꢀLꢀprolineꢀSO3H measured by back titration and the
organic group loading determined by TGA (0.85 mmol/g), is clear evidence that the Lꢀ
proline Nꢀsulfonic acid groups are principally located on the surfaces of MNP
nanoparticles, where they are accessible for adsorption and catalytic reaction processes.
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Fig. 5. TG–DTG analysis for MNPꢀLꢀprolineꢀSO3H
3.2. Synthesis of 3,4-dihydropyrimidine-2-(1H)-thiones using MNP-L-proline-SO3H
After characterization of the MNPꢀLꢀprolineꢀSO3H catalyst, we have focused to evaluate
its catalytic acting in multicomponent reaction for the preparation of 3,4ꢀ
dihydropyrimidineꢀ2ꢀ(1H)ꢀthiones (Scheme 2).
R
O
CHO
O
O
S
tꢀBuO
NH
MNPꢀLꢀprolineꢀSO3H
R
+
+
H2N
NH2
N
S
tꢀBuO
SolventꢀFree,
100 °C
H
2
1
3
4a-j
Scheme 2. Synthesis of 3,4ꢀdihydropyrimidineꢀ2ꢀ(1H)ꢀthiones
In an initial examination, a mixture of benzaldehyde (1 mmol), thiourea (1.5 mmol), tꢀ
butyl acetoacetate (1 mmol) and catalyst (0.1 g) in attendance of ethanol at reflux
conditions was stirred for a specified time as needed to complete the reaction (180 min). To
optimize the condition, the reaction was accomplished by applying diverse solvents,
different temperature and solventꢀ free condition to take satisfactory yield of products.
Evaluation of reaction under kind of solvents, indicated, the ethanol is the most favor
solvent because of its considerable efficiency and environmental compatibility. We also
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optimized the quantity of catalyst. In nonattendance of MNPꢀLꢀprolineꢀSO3H, no product
was detected and starting materials retrieved without alteration, but using solid acid
catalyst, satisfactory yield of favored product was apperceived. According to Table1
(entry10), it is noticeable that increasing of quantity of catalyst didn’t affirmative efficacy
on the yield of products. It was found that 75 mg value of MNPꢀLꢀprolineꢀSO3H had the
best result in the yield. Moreover, the effect of diverse temperatures was tested on the
improvement of the reaction in evidence of 75 mg quantity of MNPꢀLꢀprolineꢀSO3H under
solventꢀfree condition (Table 1). The best temperature on the progressing of the reaction
was choosing 100 °C. It should be pointed out, that the progressing of threeꢀcomponent
reaction under solventꢀfree condition rather than different solvents, exhibited excellent
yield for product. So, as a final result from Table 1, synthesis of dihydropyrimidine
derivatives by using 75 mg of catalyst, under 100 °C and solventꢀfree condition has the
evident effect in the efficiency (90.0 %).
Table 1. The oneꢀpot three component reaction of benzaldahyde (1mmol), thiourea(1.5mmol) and
tꢀbutyl acetoacetate (1mmol) in the presence of MNPꢀLꢀprolineꢀSO3H under different condition.
Entry Catalyst (g)
Solvent
EtOH
Condition
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
120 °C
Time (min)
180
Yield (%)a
78
0
1
2
3
4
5
6
7
0.1
ꢀ
EtOH
300
0.1
0.1
0.1
0.1
0.075
CH3CN
MeOH
Water
180
70
76
0
180
240
EtOHꢀH2O (1:1)
ꢀ
240
35
90
180
8
9
10
0.075
0.075
0.125
ꢀ
ꢀ
ꢀ
100 °C
80 °C
100 °C
180
180
180
90
79
90
11
12
13
0.075
0.05
ꢀ
ꢀ
ꢀ
100 °C
100 °C
120 °C
180
180
180
90
66
23
0.025
a Isolated yields.
With regard to optimized reaction conditions, various substituted aromatic aldehydes
reacted with thiourea and tꢀbutyl acetoacetate in presence of MNPꢀLꢀprolineꢀSO3H under
solventꢀfree conditions (Table 2). As shown in Table 2, the aromatic aldehydes with both
electronꢀwithdrawing and electronꢀreleasing groups take part in multiꢀcomponent reaction
to provide the corresponding product in superb efficiency.
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Table 2. Solventꢀfree preparation of 3,4ꢀdihydropyrimidineꢀ2ꢀ(1H)ꢀthiones by using MNPꢀLꢀ
prolineꢀSO3H.
M.P. (°C)
Reported [Lit.]
Yield
(%)a
Entry
Aldehyde
Product
Found
1
89
204ꢀ206
4a
4b
206ꢀ207[63]
214ꢀ215[63]
2
91
213ꢀ215
3
4
89
89
184ꢀ186
199ꢀ201
4c
183ꢀ185[63]
ꢀ
4d
5
6
88
87
193ꢀ195
251ꢀ253
ꢀ
ꢀ
4e
4f
7
8
90
88
175ꢀ177
179ꢀ181
ꢀ
ꢀ
4g
4h
tꢀBuO
O
9
89
91
161ꢀ163
239ꢀ241
4i
4j
HN
S
ꢀ
ꢀ
NH
O2N
10
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a Isolated yields.
In order to show the merit of the present work, a comparison of the use of MNPꢀLꢀprolineꢀ
SO3H with some of the other reported catalysts for the synthesis of tꢀButylꢀ6ꢀmethylꢀ4ꢀ
phenylꢀ2ꢀthioxoꢀ1,2,3,4ꢀtetrahydropyrimidineꢀ5ꢀcarboxylate (Table 2, entry 1) has been
shown in Table 3. These results demonstrate that MNPꢀLꢀprolineꢀSO3H promote the
reaction more effectively in terms of short reaction times and simple conditions.
Furthermore, the yield of product in the presence of MNPꢀLꢀprolineꢀSO3H is comparable
to the reported catalysts.
Table 3. Comparison of MNPꢀLꢀprolineꢀSO3H with other catalysts reported in the literature for the
synthesis of tꢀButylꢀ6ꢀmethylꢀ4ꢀphenylꢀ2ꢀthioxoꢀ1,2,3,4ꢀtetrahydropyrimidineꢀ5ꢀcarboxylate (4a).
Entry
Catalyst (amount)
PPE (300 mg)
Indionꢀ130 (500 mg)
Ytterbium Complex (10 mol%)
MNPꢀLꢀprolineꢀSO3H (75 mg)
Condition
microwave
EtOH (Reflux)
THF (25°C)
Solventꢀfree (100 °C)
Time
3 min
3 h
60 h
3 h
Yield (%)a Ref.
1
2
3
4
85
87
54
94
[63]
[64]
[65]
This work
a Isolated yields.
At this study, we evaluated the recoverability and reusability of the magnetic catalyst,
according to green chemistry viewpoint. After fulfillment of the reaction, ethanol as a
secure solvent surcharged to the reaction mixture and the catalyst was retrieved using an
external magnet. The MNPꢀLꢀprolineꢀSO3H washed two times with ethanol and dried at 60
°C for 1h. The isolated catalyst was reused in subsequent reaction mixture under similar
conditions. The catalyst retrieved up to four times without tolerating any considerable
decline in its catalytic activity or the efficiency of the reaction (Fig. 6). Unfortunately,
using catalyst more than four times was afforded to remarkable decrease the catalytic
activity of catalyst. The reason for the decrease of the catalytic activity may be which some
of MNPꢀLꢀprolineꢀSO3H nanoparticles are not fully recovered using an external magnet or
might be the result of chemical poisoning of the surface of the catalyst during the reaction.
Generally speaking, the privileges of our study are remarkable yield, reusability, facile
separation, ecoꢀfriendly of the catalyst and solventꢀfree reaction.
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Fig. 6. Recyclability of MNPꢀLꢀprolineꢀSO3H in the reaction of benzaldehdye (1 mmol), tꢀbutyl
acetoacetate (1 mmol), thiourea (1.5 mmol) and catalyst (0.075 g) under solventꢀfree conditions
4. Conclusion
In this research, a novel nanoꢀmagnetic solid acid catalyst was successfully prepared and
specified with XRD, TGA, VSM, SEM and EDAX analyses. LꢀProline Nꢀsulfonic acidꢀ
functionalized magnetic nanoparticles (MNPꢀLꢀprolineꢀSO3H) were synthesized during
two stages: imprimis, Fe3O4@Lꢀproline magnetic nanoparticles (MNPꢀLꢀproline) were
obtained by coꢀprecipitation method, henceforth chlorosulfonic acid (ClSO3H) was
covalently grafted to the surface of magnetic nanoparticles. Performance and reusability of
catalyst was figured out for the first time in oneꢀpot synthesis of 3,4ꢀdihydropyrimidineꢀ2ꢀ
[1H] thione derivatives from an thiourea, βꢀketoester, and diverse aromatic aldehydes
under solventꢀfree condition at 100°C. Marvelous specifications of this catalyst include,
short reaction time, superb yield, inexpensive, great catalytic activity, facile recovery from
the mixture, easy workup of product under solventꢀfree condition and environmentally
secure. Moreover, the catalyst can be simply regained by an external magnet and reused 4
times without a noticeable decline in its activity.
Acknowledgement
We thank the Emad Darman Pars Pharmaceutical Company for financial support.
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Graphical Abstract:
L-Proline N-sulfonic acid-functionalized magnetic nanoparticles: A novel and
magnetically reusable catalyst for one-pot synthesis of 3, 4-dihydropyrimidine-2-
(1H)-thiones under solvent-free conditions
M. Afradi, N. Foroughifar,* H. Pasdar and H. Moghanian