Asparagine functionalized Al2O3 nanoparticle as a superior heterogeneous organocatalyst in the synthesis of 2-aminothiazoles

Article abstract of DOI:10.1016/j.molstruc.2019.02.080

Asparagine functionalized aluminum oxide nanoparticles (Asp-Al₂O₃) have been prepared by a two-step procedure involving the grafting of Al₂O₃ with 3-chloropropyltrimethoxysilane (CPTMS) and subsequent organofunctionalization using asparagine amino acid. It is shown that Asp-Al₂O₃ exhibits as an active nanocatalyst for the preparation of 2-aminothiazoles is achieved by one-pot reaction of methylcarbonyls, thiourea and iodine. The structure of Asp-Al₂O₃ was characterized by fourier transform infrared radiation (FT-TR), thermal gravimetric analysis (TGA), X-ray diffraction (XRD), scanning electron microscopic (SEM), and energy-dispersive analysis of X-ray (EDAX) analyses. Advantages of this modified methodology include higher purity and excellent yield of products, greener and cleaner conditions, easy isolation of products and convenient manipulation. Moreover, immobilization of organocatalysts on the Al₂O₃ surface are stable under the catalytic reaction conditions resulting their efficient reuse.

Full text of DOI:10.1016/j.molstruc.2019.02.080

Accepted Manuscript
Asparagine functionalized Al O nanoparticle as a superior heterogeneous
2 3
organocatalyst in the synthesis of 2-aminothiazoles
Zohre Zarnegar, Zahra Shokrani, Javad Safari
PII:
S0022-2860(19)30210-8
DOI:
https://doi.org/10.1016/j.molstruc.2019.02.080
MOLSTR 26237
Reference:
To appear in: Journal of Molecular Structure
Received Date: 19 November 2018
Revised Date: 18 February 2019
Accepted Date: 20 February 2019
Please cite this article as: Z. Zarnegar, Z. Shokrani, J. Safari, Asparagine functionalized Al O
2 3
nanoparticle as a superior heterogeneous organocatalyst in the synthesis of 2-aminothiazoles, Journal
of Molecular Structure (2019), doi: https://doi.org/10.1016/j.molstruc.2019.02.080.
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ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT
Asparagine functionalized Al2O3 nanoparticle as a superior heterogeneous
organocatalyst in the synthesis of 2-aminothiazoles
Zohre Zarnegar,a Zahra Shokrani,b Javad Safarib٭
aResearch Affiliate, Department of Chemistry, University of Payame Noor, P.O. BOX 19395-4697,
Tehran-IRAN
bLaboratory of Organic Compound Research, Department of Organic Chemistry, College of Chemistry
and Biochemistry, University of Kashan, P.O. Box: 87317-51167, Kashan, I.R., Iran.
E-mail: safari_jav@yahoo.com,safari@kashanu.ac.ir
Abstract
Asparagine functionalized aluminum oxide nanoparticles (Asp-Al2O3) have been prepared by a
two-step procedure involving the grafting of Al2O3 with 3-chloropropyltrimethoxysilane
(CPTMS) and subsequent organofunctionalization using asparagine amino acid. It is shown that
Asp-Al2O3 exhibits as an active nanocatalyst for the preparation of 2-aminothiazoles is achieved
by one-pot reaction of methylcarbonyls, thiourea and iodine. The structure of Asp-Al2O3 was
characterized by fourier transform infrared radiation (FT-TR), thermal gravimetric analysis
(TGA), X-ray diffraction (XRD), scanning electron microscopic (SEM), and energy-dispersive
analysis of X-ray (EDAX) analyses. Advantages of this modified methodology include higher
purity and excellent yield of products, greener and cleaner conditions, easy isolation of products
and convenient manipulation. Moreover, immobilization of organocatalysts on the Al2O3 surface
are stable under the catalytic reaction conditions resulting their efficient reuse.
Keywords: Thiazoles, Al2O3 nanoparticles, Asparagine, One-pot synthesis, Organocatalyst.
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1. Introduction
Aluminum oxide (Al2O3) nanoparticles are utilized for various applications in industry and
chemistry. such as catalysis in petroleum refining, ceramic composites, optoelectronics,
electronics, hydrogenation, automotive emission control, metallurgy, refractories, and wear
protection [1-6]. Notably, ꢀ-Al2O3 nanoparticles as a catalytic support and nanocatalyst has been
explored for diverse organic reactions [7-10]. In practical applications, the use of modified nano
ꢀ-Al2O3 with organic and inorganic materials led to the development of their superior catalytic
activities due to some of advantages for example large surface area, pore-size distribution, pore
volume, facile surface modification, and acid/base characteristics [9,10]. To the best of our
knowledge, there is no amino acid functionalized Al2O3 nanoparticles as catalytic systems for the
organic conversions.
Nowadays, the use of organocatalysts have attracted great attention in modern chemistry. They
can catalyze chemical processes as Brønsted acids, Brønsted bases, Lewis acids, and Lewis
bases. Organic based catalysts are often based on nontoxic organic compounds originating from
biological materials like amino acids [11,12]. Recently, amino acids are widely used in organic
transformations such as proline in Michael reaction [13] and Robinson annulation [14], various
amino acids in the Biginelli dihydropyimidone synthesis [15], valine for synthesis of substituted
pyrrolidines [16], tryptophan for the Mannich reaction and aldol reaction [17], phenylalanine in
synthesis of imidazolines [18], and etc [19]. However, in the homogeneous catalytic conditions
have limited their application because of their difficult separation from the reaction environment.
In recent years, heterogeneous organocatalysts have caused the extensive attention due to their
recyclable and environmental friendly property. Therefore, in this research, we report the
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efficient activity of asparagine catalyst supported on aluminum oxide nanoparticles (Asp-Al2O3)
as an effective catalyst to produce 2-aminothiazole scaffolds.
Thiazoles are important branches of the azole heterocycles that contain both nitrogen and
sulfur in their aromatic rings. Thiazole and their substituted analogues as biologically active
compounds have been extensively used as sulfur drugs [20-23]. The first report for the synthesis
of thiazole is proposed by Hantzsch and Weber in 1887. The Hantzsch thiazole synthesis is a
reaction between haloketones and thioamides or thiourea [24]. Among the important thiazoles, 2-
aminothiazole and their derivatives have attracted increasing attention from synthetic chemists
due to their potential biological properties and pharmacological importance such as anticancer
and antitumor activity [25], antihypertensive activity [26], antileishmanial [27,] antiviral agent
[28], antimicrobial activities [29], antidiabetic [30], anti-inflammatory [31], anticonvulsant
activity [32], and etc [33]. Moreover, some organocatalysts have been used for the synthesis of
2-aminothiazoles such as NEt3 [34], TsOH [35], (bmim)BF4 [36], asparagine [37], 1,3-di-n-
butylimidazolium tetrafluoroborate [38], and ammonium 1,2-molybdophosphate [39]. Although
some of these protocols have certain merits, but there are some of disadvantages for reported
methods, including harsh reaction conditions, difficult to recycle of catalyst, poor atom-
efficiency, long reaction time, unsatisfactory yields, and complex work-up procedure. Thus, due
to the importance of 2-aminothiazole heterocycles and fixing the limitations of synthetic routes,
there is still the need to develop new modified procedures and the use of effective
organocatalysts for the synthesis of these heterocycles.
In this project, we report the highly efficient activity of Asp-Al2O3 as an effective heterogeneous
organocatalyst to prepare 2-aminothiazoles. First, the Al2O3 nanoparticles were synthesized by
precipitation method and modified with 3-chloropropyltrimethoxysilane (CPTMS). Then, Asp-
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Al2O3 are prepared through covalent functionalization the chloropropyl grafted Al2O3 with
asparagine. The Asp-Al2O3 is then used as highly active, reusable and stable organocatalyst
for the synthesis of 2-aminothiazoles by one pot condensation of various methylcarbonyls and
thiourea as precursors using iodine as oxidant reagent at 85°C in DMSO (Scheme 1). The amino
acid functionalized nanoparticles have not yet been used as heterogeneous organocatalysts in the
synthesis of heterocycles.
Scheme 1. The synthesis of 2-aminothiazole using Asp-Al2O3.
2. Experimental
Chemical substances in high purity were purchased from the Merck, Fluka and Aldrich with
commercial grade. Melting points (°C) were determined in an open-glass capillary using an
electro-thermal digital melting point apparatus and are uncorrected. Progress of the catalytic
process was monitored by thin layer chromatography (TLC) using silica gel plates in the solvent
system (ethyl acetate/n-hexane, 4:2). FT-IR spectra of all the compounds were measured on a
1
13
Perkin-Elmer 550 spectrometer in the range 400-4000 cm–1 with KBr pellets. H NMR and C
NMR spectra were recorded with a Bruker DRX-400 spectrometer at 400 and 100 MHz
respectively. NMR spectra were obtained in DMSO-d6 solutions and are reported as parts per
million (ppm) downfield from Me4Si as internal standard. Modified nano ꢀ-Al2O3 were
characterized using a Holland Philips Xpert X-ray powder diffraction (XRD) diffractometer
(CuK, radiation, λ= 0.154056 nm), at a scanning speed of 2°/min from 10° to 100° (2θ).
Scanning electron microscopic (SEM) images were performed on a Zeiss EM10C SEM that it
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equipped with energy dispersive X-ray spectrometer (EDAX). Thermal gravimetric analysis
(TGA) was performed on a mettler STA4000 system at a heating rate of 10 K min-1 under N2
atmosphere.
2.1. Preparation of the Asp-Al2O3 nanoparticles
0.5 g of aluminum chloride (AlCl3) was dissolved in 150 mL of ethanol under vigorous stirring.
Subsequently, a little amount of distilled water was added to it and a transparent solution was
obtained. Then, 60 mL NH3 as precipitant agent was slowly added to the stirred solution until the
white Al(OH)3 was precipitated. After filtering in vacuum system, the resultant sample was dried
at 200 °C for 2h in oven and heated at 1250 °C for 1h to afford white ꢀ-Al2O3 nanoparticles [40].
The chloropropyl grafted Al2O3 (Cl-Al2O3) was prepared using CPTMS as the asparagine
functional group precursor. In a typical procedure, in 50 ml round-bottom flask, 5 g (49 mmol)
of ꢀ-Al2O3 was dispersed in 15 mL of toluene. Next, 2 mL (10 mmol) of CPTMS were added to
the reaction mixture and refluxed for 24 h. After this time, was collected by filtration and washed
three times with ethanol to remove the precursor residue. Cl-Al2O3 was then dried at temperature
of 70 ºC for 12 h. Finally, for immobilization of asparagine amino acid on functionalized ꢀ-
Al2O3, 1 g of Cl-Al2O3 was dispersed in 30 ml of toluene and 1.5 g (11 mmol) of asparagine was
added to solution in the presence of NEt3 (1.2 mmol) and stirred under reflux conditions for 48 h.
The mixture was filtered, washed with toluene and chloroform and dried in oven at 80 °C for 12
h to produce the Asp-Al2O3.
2.2. General procedure for the catalytic synthesis of 2-aminothiazoles
A mixture of methylcarbonyl (5 mmol), thiourea (7.5 mmol), I2 (5 mmol), and nano Asp-Al2O3
(0.2 g) in DMSO was stirred at 85 °C for desired time. After the completion of reaction
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(monitored by TLC), the heterogeneous organocatalyst was separated by simple filtration and the
solvent was removed under reduced pressure. The crude product was dissolved in hot water,
extracted with ether (3×30 mL), and adjusted to pH = 9–10 by ammonia to give the solid
products. Finally, the pure product was recrystallized by ethanol in high yield. All corresponding
products are known and were characterized by comparison of their physical (Mp) and spectral
data (IR and 1H NMR) with those of authentic samples.
4-(4-Phenyl)thiazol-2-amine
Yellow powder; IR (KBr, cm-1): 3435 and 3254 (NH2), 3114 (aromatic C–H), 1598 (C=C), 1517
1
(C=N), 1337 (N-H Bending aromatic), 773 (S-C=N); H NMR (DMSO-d6, 400 MHz) δ (ppm):
δH 6.92 (s, 1H, thiazole), 7.22 (s, 2H, NH2, D2O exchangeable), 7.32 (t, J = 7.9 Hz, 1H, Ar-H),
7.69 (t, J = 7.9 Hz, 2H, Ar-H), 7.71 (m, 2H, Ar-H).
4-(4-Chlorophenyl)thiazol-2-amine
White solid; IR (KBr, cm-1): 3437 and 32284 (NH2), 3111 (aromatic C–H), 1632 (C=C), 1532
(C=N), 1475 (N-H Bending aromatic), 729 (S-C=N); 1H NMR (DMSO-d6, 400 MHz) δ (ppm):
δH 7.27 (s, 1H, ) 7.55 (d, J= 8.4 Hz, 2H, Ar-H), 7.73 (d, J= 8.4 Hz, 2H, Ar-H), 8.43 (s, 2H, NH2,
D2O exchangeable).
4-(4-Bromophenyl)thiazol-2-amine
Brown solid; IR (KBr, cm-1): 3428 and 3281 (NH2), 3110 (aromatic C–H), 1632 (C=C), 1532
(C=N), 1471 (N-H Bending aromatic), 725 (S-C=N); 1H NMR (DMSO-d6, 400 MHz) δ (ppm):
δH 7.07 (s, 1H, thiazole), 7.10 (s, 2H, NH2), 7.53 (d, J= 6.8 Hz, 2H, Ar-H), 7.74 (d, J= 6.8 Hz,
2H, Ar-H).
4-(4-Hydroxyphenyl)thiazol-2-amine
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Yellow crystal; IR (KBr, cm-1): 3448 and 3304 (NH2), 3197 (aromatic C–H), 1613 (C=C), 1536
1
(C=N), 1434 (N-H Bending aromatic), 832 (S-C=N); H NMR (DMSO-d6, 400 MHz) δ (ppm):
δH 6.68 (d, J= 8.5 Hz, 2H, Ar-H), 6.72 (s, 1H, thiazole), 6.98 (d, 2H, NH2), 7.60 (d, J= 8.5 Hz,
2H, Ar-H), 9.48 (s, OH).
4-(2-Hydroxyphenyl)thiazol-2-amine
Yellow powder; IR (KBr, cm-1): 3249 and 31180 (NH2), 3064 (aromatic C–H), 1635 (C=C),
1
1569 (C=N), 1460 (N-H Bending aromatic), 743 (S-C=N); H NMR (DMSO-d6, 400 MHz) δ
(ppm): δH 6.90 (t, 1H, J = 7.6 Hz, 1H, ArH), 6.99 (d, J = 8.24 Hz, 1H, ArH), 7.18 (s, 1H), 7.27 (t,
J = 8.24 Hz, 1H, ArH), 7.53 (d, J = 7.6 Hz, 1H, ArH), 8.82 (s, 1H, OH, D2O exchangeable), 6.62
(s, NH2).
4-(3-Methyl phenyl)thiazol-2-amine
Cream powder; IR (KBr, cm-1): 3423 and 3304 (NH2), 3148 (aromatic C–H), 1607 (C=C), 1520
1
(C=N), 1480 (N-H Bending aromatic), 715 (S-C=N); H NMR (DMSO-d6, 400 MHz) δ (ppm):
δH 6.85 (s, 1H, thiazole), 7.59 (d, J= 8.6 Hz, 2H, Ar-H), 7.66 (d, J= 8.6 Hz, 2H, Ar-H), 8.00(s,
NH2).
4-(4-Methylphenyl)thiazol-2-amine
Yellow powder; IR (KBr, cm-1): 3438 and 3365 (NH2), 3282 (aromatic C–H), 1609 (C=C), 1515
1
(C=N), 1468 (N-H Bending aromatic), 724 (S-C=N); H NMR (DMSO-d6, 400 MHz) δ (ppm):
δH 2.31 (s, 3H, CH3), 6.91 (s, 1H, thiazole), 7.15 (s, 2H, NH2), 7.32 (d, J= 7.8 Hz, 1H, Ar-H),
7.52 (t, 1H, J= 7.9 Hz, Ar-H), 7. 61 (d, J= 7.9 Hz, 1H, Ar-H), 7. 66 (s, 1H, Ar-H).
4-(4-Nitrophenyl)thiazol-2-amine
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Yellow crystal; IR (KBr, cm-1): 3421 and 3318 (NH2), 3116 (aromatic C–H), 1640 (C=C), 1597
(C=N), 1512 and 1343 (NO2), 701 (S-C=N); 1H NMR (DMSO-d6, 400 MHz) δ (ppm): δH 7.45 (s,
1H, thiazole), 8.04 (d, J= 8.6 Hz, 2H, Ar-H), 8.27 (d, J= 8.6 Hz, 2H, Ar-H), 8.40 (s, NH2).
4-(4-Methoxyphenyl)thiazol-2-amine
Yellow powder; IR (KBr, cm-1): 3417 and 3352 (NH2), 3119 (aromatic C–H), 1607 (C=C), 1519
1
(C=N), 1462 ((N-H Bending aromatic), 732 (S-C=N); H NMR (DMSO-d6, 400 MHz) δ (ppm):
δH 6.85 (s, 1H, thiazole), 7.59 (d, J= 8.6 Hz, 2H, Ar-H), 7.66 (d, J= 8.6 Hz, 2H, Ar-H), 8.00(s,
NH2).
4-Methyl-5(ethoxycarbonyl)thiazol-2-amine
White powder; IR (KBr, cm-1): 3373 and 3300 (NH2), 3083 (aromatic C–H), 1675 (C=C), 1516
1
(C=N), 1373 (N-H Bending aromatic), 757 (S-C=N); H NMR (DMSO-d6, 400 MHz) δ (ppm):
δH 1.22 (t, J= 7.1, 3H, CH3), 2.36 (s, 3H, CH3), 4.14 (q, 2H, CH2), 7.72 (s, 2H, NH2).
4-Methyl-5(Methoxycarbonyl)thiazol-2-amine
Pale pink powder; IR (KBr, cm-1): 3371 and 3292 (NH2), 3095 (aromatic C–H), 1676 (C=O),
1
1644 (C=C), 1509 (C=N), 1322 (N-H Bending aromatic), 759 (S-C=N); H NMR (DMSO-d6,
400 MHz) δH 2.36 (s, 3H, CH3), 3.66 (s, 3H, CH3), 7.75 (S, 2H, NH2).
4-(4-Morpholinophenyl)thiazol-2-amine
Yellow powder; IR (KBr, cm-1): 3315 and 3188 (NH2), 3057 (aromatic C–H), 1600 (C=C), 1535
1
(C=N), 1379 (N-H Bending aromatic), 1236 (C-O), 739 (S-C=N); H NMR (DMSO-d6, 400
MHz) δH 3.09 (2H, CH2), 3.71 (2H, CH2), 6.73-6.89 (m, 3H, Ar-H)), 7.64-7.80 (m, 2H, Ar-H),
9.02 (s, NH2).
3. Results and discussion
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The nanocatalyst Asp-Al2O3 was prepared according to the Scheme 2. The Al2O3 nanoparticles
were synthesized by precipitation of aluminum trichloride in ethanol solution using as a
precursor and ammonia as the precipitating agent [40]. This reaction is performed according to
the following reaction [10]. Next, Al2O3 was functionalized with organosilane precursor CPTES
to produce Cl-Al2O3. Then this chloropropyl grafted Al2O3 is refluxed with asparagine to prepare
Asp-Al2O3 nanoparticles. The structure of amino acid functionalized Al2O3 is identified by types
of techniques such as FT-IR, SEM, EDAX, TGA, and XRD. Then, the catalytic behavior of Asp-
Al2O3 is evaluated for the synthesis of 2-aminothiazole scaffolds.
AlCl3 + 3NH4OH → Al(OH)3↓ + 3 NH4Cl
2Al(OH)3→Al2O3+3H2O
Scheme 2. Schematic illustration to prepare Asp-Al2O3 nanoparticles.
In order to show the functional groups of nanostructures, FT-IR spectra of unmodified and
modified Al2O3 have been analyzed. The FT-IR analysis of the of ꢀ-Al2O3 nanoparticles is shown
in Fig. 1(a). The vibration bands at 3457 and 1640 cm−1 are corresponded to asymmetrical
stretching of O–H and the bending vibration of adsorbed water or alcohol, respectively. The wide
band appearing between 500 and 900 cm−1 is attributed to the stretching vibration of co-ordinate
O–Al–O bond, showing nano amorphous Al2O3 [40,41]. Asparagine spectrum in Fig. 1(b) has
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signals at 3382 and 3110 cm−1 that they confirm the existence of the NH2 and O–H stretching
vibrations in the amino acid. The band stretching near 2925 cm−1 can be attributed to the
presence of C–H groups. The signal appeared at 1683 cm−1are attributed to the COO- stretching
vibrations. The FT-IR spectrum of Asp-Al2O3 in Fig. 1(c) shows aluminum oxide and asparagine
of absorption behavior in its structure. Therefore, these results confirm that asparagine have
attached to the Al2O3.
(c)
(b)
(a)
Fig. 1. The comparative FT-IR spectra for (a) ꢀ-Al2O3, (b) asparagine and (c) Asp-Al2O3.
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The structures and morphology of nanoparticles was investigated by SEM technique and their
images were shown in Fig. 2. It can be seen in Fig. 2(a) that Al2O3 nanoparticles has a nearly
spherical or irregular hexagonal structure. The SEM micrograph in Fig. 2 (b) shows surface
morphology of Asp-Al2O3 nanocatalyst and it was revealed a homogeneous surface remained
intact after modification.
(a)
(b)
Fig. 2. Images of (a) ꢀ-Al2O3 and (b) Asp-Al2O3.
The EDAX of the ꢀ-Al2O3 nanoparticles has been presented in Fig. 3 (a). These results indicate
that Al2O3 nanoparticles were successfully synthesized. The EDAX analysis in Fig. 3(b)
confirms the presence of C, O, N and Si elements for Asp- Al2O3.
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(b)
(a)
Fig. 3. The EDS spectra of (a) ꢀ-Al2O3 and (b) Asp-Al2O3.
The thermal stability of the uncoated Al2O3 and Asp-Al2O3 was evaluated by TGA analysis as
shown in Fig. 4. The initial weight loss from the Al2O3 up to 100-250 ºC is due to the removal of
absorbed water and surface hydroxyl groups. the TGA curve for Asp-Al2O3 shows the weight
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loss about 6.1% between 400 and 600 ºC, which is contributed to the thermal decomposition of
the organic section.
Fig. 4. TGA diagram of ꢀ-Al2O3 and Asp-Al2O3.
Furthermore, Fig. 5 shows the XRD patterns of ꢀ-Al2O3 and modified aluminum oxide
nanoparticles. The characteristic XRD peak of ꢀ-Al2O3 in Fig. 5(a) was displayed at 2θ 37.75º,
39.32º, 46.07º, 61.44º, and 67.19º which are assigned to the diffractions of the (110), (111),
(210), (210), and (211) reflections, respectively. These peaks were related to the Al2O3
nanoparticles which were in accordance with aluminum oxide (JCDPS card no. 01-1303) [40].
The XRD analysis in Fig. 5(b) is for the Cl-Al2O3 show that organosilane grafted on aluminum
oxide are similar to that of the unmodified Al2O3. This analysis proves that there is no change in
the morphology of nanoparticle structure created during the functionalization process. The
characteristic peak of Al2O3 are observed in the Asp-Al2O3 in Fig. 5(c). The weaker diffraction
lines of its structure indicate that the Asp-Al2O3 were successfully coated by amino acid on the
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surface of modified aluminum oxide. Also, the sharp bands in the range of 10°–30° can show the
new orientation of the plates of particles.
(c)
(b)
(a)
Fig. 5. XRD analysis of (a) ꢀ-Al2O3, (b) Cl-Al2O3, and (c) Asp-Al2O3.
The synthesized Asp-Al2O3 was assessed for its activity for the preparation of 2-amino-thiazole
derivatives. In a model reaction, acetophenone, thiourea, and iodine were chosen as model
substrates in DMSO solvent. As shown in Table 1, the influence of quantity of nanocatalyst, the
effect of temperature and solvent were studied to optimize the reaction conditions. The model
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reaction in the absence of the catalyst resulted in the formation of product with 75% yield for 4h
(Entry 1). Determining the minimum amount of catalyst is necessary for maximum formation of
desired product. The reaction yield improved with increasing the amount of nanocatalyst from
0.10 to 0.30 g in shorter reaction time. When Asp-Al2O3 was used 0.20 g, the product formation
enhanced rapidly with 96% yield 3h (Entry 4). To select the appropriate temperature, the reaction
was checked in the temperature range from 60 to 90 °C. It was observed that the optimized yield
was obtained at 85 °C in DMSO as the best solvent. The efficiencies of pure Al2O3 and
asparagine as the catalyst toward the model reaction were compared s shown in this table, the
Asp-Al2O3 was more efficient than the other ones (entries 16 and 17).
Table 1. Optimization of reaction conditions in the reaction of acetophenone, thiourea, I2 with the
catalysts in the solvent.a
Entry
Catalyst (g)
Solvent
Time (h)
Yield (%)b
Temperature (°C
)
-
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
EtOH
85
85
4
3.5
3.5
3
75
89
91
96
96
93
78
85
90
94
92
35
1
2
0.10
0.15
0.20
0.25
0.30
0.20
0.20
0.20
0.20
0.20
0.20
85
3
85
4
85
3
5
85
3
6
60
4
7
70
4
8
80
3
9
90
3
10
11
12
reflux
reflux
3
MeOH
4
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0.20
0.20
H2O
CH3CN
THF
reflux
reflux
reflux
85
4
3
4
4
4
34
90
90
80
82
13
14
15
16
17
0.20
0.20 (Al2O3)
0.20 (Asp)
DMSO
DMSO
85
a Reaction conditions: acetophenone (5 mmol), thiourea (7.5 mmol), I2 (5 mmol) and solvent (5 ml).
bIsolated yield.
After optimization study, in order to determine the generality and efficacy of the nanocatalyst,
different types of methylcarbonyls carrying either electron-donating or electron- withdrawing
groups were evaluated under the optimized reaction condition. The results are depicted in Table
2. The catalytic reaction proceeded with a variety of methylcarbonyls in the presence of Asp-
Al2O3 at 85°C and the desired products were obtained in good to excellent yields (90–98%). The
procedure was highly effective and the nature of substituent on the aromatic ring of
methylcarbonyls did not show obvious effects in terms of yields and times under the optimized
conditions.
Table 2. Synthesis of 2-aminothiazoles using different substrates using Asp-Al2O3 at 85 °C in DMSO.
Time TONa TOFb
(h)
Mp (°C)
(Ref)
Entry
1
Substrate
Product
Yield
(%)c
3
960
320
149-151 (151-
153) [37]
96
3.5
960
274
162-163 (160-
162) [37]
96
2
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O
3.5
4.5
970
930
277
207
182-183 (180-
182) [37]
97
93
3
4
CH3
Br
HO
198-199 (197-
200) [37]
N
NH2
S
5
4
930
940
186
235
139-140 (138-
140) [37]
93
94
5
6
88-90 (88-90)
[37]
4
940
235
150-151 (152)
[42]
94
7
4
900
900
225
200
286-287 (285-
287) [37]
90
90
8
9
4.5
141-142 (141)
[42]
3.5
960
274
177-179 (178-
179) [37]
96
10
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ACCEPTED MANUSCRIPT
3.5
3
910
980
260
327
224-225 (224-
226) [37]
91
98
11
12
278-281 (277-
280) [43]
a TON: (turnover number, yield of product/ per g of Asp-Al2O3).
b TOF: (turn over frequency, TON/time of reaction (hour))
c Isolated yield
A plausible mechanism for the formation of 2-aminothiazoles is exemplified in Scheme 3. The
Asp-Al2O3 as heterogeneous bi-functional organocatalyst facilitates this cyclocondensation due
to the existence of both Lewis base (NH2) and Lewis acid-Brønsted acidic (Al+3, COOH) sites. In
the suggested mechanism, In the suggested mechanism, amino acid and nanoalumina as a
Brønsted and Lewis acid polarizes the carbonyl group of acetophenone and asparagine as a
Lewis base serves the formation of enolate to produce α-iodoacetophenone. Moreover, thiourea
is converted to enol under basic conditions and react with the iodinated acetophenone for the
synthesis of carbamimidothioic acid species. Next, asparagine-promoted dehydrogenation gives
2-aminothiazoles [37, 43].
18

ACCEPTED MANUSCRIPT
CONH2
COOH
CONH2
H
H
N
N
COOH
O
O
O
I2
CH2I
CH2
CONH2
COOH
H
N
S
S-
S
H2N
NH2
NH-
H2N
NH
H2N
CONH2
H
N
COOH
O
HN
..
NH2
O
S-
S
I
CH2
+
H2N
NH
HI
-H2O
(I)
N
NH3
NH I
N
-
4
S
NH2.HI
S
NH2
Scheme 3. Plausible Mechanism for the synthesis of 2-aminothiazoles.
After completion of the catalytic reaction, the Asp-Al2O3 was removed from the reaction
medium using filtration. It was washed with ethyl acetate several times and dried at 80 °C. The
organocatalyst was found to be reusable for five cycles for model reaction (Fig. 6).
Fig. 6. Reusability of Asp-Al2O3 for the model reaction.
Moreover, the catalytic activity of the Asp-Al2O3 was compared with other reported catalysts in
the literature for the preparation of 4-(4-phenyl)thiazol-2-amine. The results are presented in
19

ACCEPTED MANUSCRIPT
Table 3. It can be clearly observed from the table that the synthesis of 2-aminothiazoles by using
Asp-Al2O3 as an effective heterogenized catalyst is performed with a better catalytic activity and
high yield compared to catalysts like valine and TsOH, the use of nontoxic and heterogeneous
nanocatalyst with good reusability compared to catalysts such as NEt3, pyrrolidine,
diethanolamine, HI-DMSO, HBr-DMSO, asparagine and valine, less reaction time and milder
reaction conditions compared to catalyst-free technique and KI/NH4NO3 catalyst.
Table 3. Comparison Asp-Al2O3 nanocatalyst with other catalysts in the literature to synthesize
4-(4-phenyl)thiazol-2-amine.
Entry
Conditions
Time
(h)
Temperature
(°C)
Yield (%)
[Ref.]
1
2
Fe3O4@SiO2-TiO2 (10 mol%) (PEG-200)
NEt3 (0.2 mL), EtOH
5
4
r.t
80
90
90
60
60
85
85
80
40
98 [44]
96 [34]
70 [34]
70 [34]
93 [45]
90 [45]
95 [37]
75 [37]
55 [35]
95 [46]
3
Pyrrolidine (0.2mL), EtOH
Diethanolamine (0.2mL), EtOH
HI-DMSO (0.6 eq), EtOAc
HBr-DMSO (0.6 eq), EtOAc
Asparagine (7.5 mol%), DMSO
Valine (7.5 mol%), DMSO
TsOH (0.25 mmol), DMSO
4
4
4
5
2
6
2
7
4
8
4
9
12
4
10
KI/NH4NO3 (20 mol%), H2SO4 (1 eq), O2,
[Bmim]OTf/H2O
11
Catalyst-free, PEG-400
6
r.t
90 [47]
20

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12
Asp-Al2O3 (0.1 g), DMSO
3
96
96 (This
research)
4. Conclusions
Finally, we have prepared Asp-Al2O3 nanoparticles by grafting of Al2O3 with CPTMS and
functionalization using asparagine. After characterization, the Asp-Al2O3 was used for the
catalytic synthesis of 2-aminothiazoles. The present protocol offers some of advantages such as
excellent isolated yields, short reaction times, the use of green catalytic system, reusability of the
nanocatalyst, the environmental safety of the process, the simplicity of performance and ease of
separation. Further applications of immobilized amino acids as effective catalysts to other
organic reactions are currently under investigation.
Acknowledgments
We gratefully acknowledge the financial support from the Research Council of the University of
Kashan for supporting this work by Grant (No. 256722/27).
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Scheme 2. Schematic illustration to prepare Asp-Al2O3 nanoparticles.