MgO nanoparticle-catalyzed, solvent-free Hantzsch synthesis and antibacterial evaluation of new substituted thiazoles

Article abstract of DOI:10.1007/s13738-017-1052-x

Abstract: In this study, some novel 4-thiazolylpyrazoles were synthesized by modified Hantzsch method, under solvent-free conditions and in the presence of MgO nanoparticles as catalyst. Excellent yields in shorter reaction times were achieved under the n

Full text of DOI:10.1007/s13738-017-1052-x

J IRAN CHEM SOC
DOI 10.1007/s13738-017-1052-x
ORIGINAL PAPER
MgO nanoparticle‑catalyzed, solvent‑free Hantzsch synthesis
and antibacterial evaluation of new substituted thiazoles
Hamid Beyzaei1 · Reza Aryan1 · Hadi Molashahi1 ·
Mohammad Mehdi Zahedi2 · Alireza Samzadeh‑Kermani1 · Behzad Ghasemi3 ·
Mohammadreza Moghaddam‑Manesh4
Received: 13 September 2016 / Accepted: 2 January 2017
© Iranian Chemical Society 2017
Abstract In this study, some novel 4-thiazolylpyrazoles
were synthesized by modified Hantzsch method, under
solvent-free conditions and in the presence of MgO nano-
particles as catalyst. Excellent yields in shorter reaction
times were achieved under the new general protocol. Also,
the in vitro antibacterial effects of synthesized compounds
were evaluated against 21 gram-positive and gram-neg-
ative pathogenic bacterial strains and compared to antibi-
otics such as ceftriaxone and penicillin. The results were
reported as inhibition zone diameter, minimum inhibitory
concentration (MIC), and minimum bactericidal concentra-
tion (MBC) values. The compounds showed moderate to
good antibacterial activities. Among the newly synthesized
thiazoles, compounds 7b, f had inhibitory effects against
eight pathogenic bacteria; besides, thioamide 6 with MIC
and MBC values of 32 and 64 μg/mL against Streptococ‑
cus agalactiae was identified as the most effective antibac-
terial agent.
* Hamid Beyzaei
hbeyzaei@yahoo.com; hbeyzaei@uoz.ac.ir
1
Department of Chemistry, Faculty of Science, University
of Zabol, Zabol, Iran
2
Department of Chemistry, University of Saskatchewan, 110
Science Place, Saskatoon, SK S7N 5C9, Canada
3
Young Researchers and Elite Club, Neyshabur Branch,
Islamic Azad University, Neyshabur, Iran
4
Department of Chemistry, Faculty of Science, Kerman
Branch, Islamic Azad University, Kerman, Iran
1 3

J IRAN CHEM SOC
Graphical Abstract MgO nanoparticle was prepared and
successfully used as an efficient recyclable catalyst for
the Hantzsch thiazole synthesis; reaction times and prod-
uct yields were significantly improved in the presence of
nanocatalyst.
primary thioamids with α-halocarbonyl compounds [27].
This method works nicely in preparation of simple thia-
zole ring systems; however, the reaction is not efficient
when it applies to synthesis of polysubstituted thiazoles.
Keywords MgO nanocatalyst · Solvent-free condition ·
Thiazole · Hantzsch synthesis · Antibacterial activity
Various developments were achieved in order to improve
the reaction outcome such as the application of different
catalysts [28] or reactants [29–33]. More improvements
were observed when ionic liquids [34] and solvent-free
conditions [35] as reaction media, and ultrasound [36] or
microwave irradiations [37] as energy sources were used.
In recent years, nanoparticles have been widely used for
various organic transformations. Shorter reaction times,
higher yields, improved economy as well as the mini-
mization of the amount of chemical wastes are just a few
advantages of using nanocatalysts in organic synthesis [38].
These items were encouraged us to extend our experiences
on the synthetic applications of MgO nanoparticles. To the
best of our knowledge, there is no report in applying mag-
nesium oxide nanoparticles to Hantzsch thiazole synthesis.
In the present article, a three-step pathway for the synthe-
sis of 4-thiazolylpyrazole derivatives using magnesium oxide
nanoparticles as catalyst under solvent-free conditions has
been described. A number of novel thiazole derivatives were
synthesized under the optimized conditions. The results were
compared to the classical Hantzsch method. The in vitro
antimicrobial activities of synthesized compounds were eval-
uated against a variety of gram-positive and gram-negative
pathogenic bacteria and reported as the minimum inhibitory
concentration (MIC), the minimum bactericidal concentra-
tion (MBC), and inhibition zone diameter (IZD) values.
Introduction
Thiazoles belong to an important class of heterocyclic
compounds that are found in many naturally occurring
compounds and biologically active molecules [1]. Thia-
zole core can be found in compounds such as thiamine
(vitamin B1), which plays a major role in the release of
energy from carbohydrates and the function of nervous
system, or luciferin, which is the main element in yel-
low light emission from fireflies [2]. Thiazole and its
analogs are present in the chemical structure of various
drugs such as meloxicam, ritonavir, sulfathiazole, tiazo-
furin, abafungin, bleomycine, niridazole, talipexole, rilu-
zole, archazolid A, telomestatin and pramipexole which
have known, respectively, as anti-inflammatory, antiret-
roviral, antimicrobial, antineoplastic, antifungal, antican-
cer, antischistosomal, antiparkinsonian, anticonvulsant,
antiproliferative, telomerase-inhibiting and antidepres-
sant agents [3–6]. Several methods have been developed
for the synthesis of thiazole derivatives [7–26], of which
Hantzsch approach is the most widely used method.
Hantzsch synthesis involves cyclocondensation of
1 3

J IRAN CHEM SOC
in ethanol (30 mL) was refluxed for 12 h. The reaction mix-
ture was cooled to room temperature, and the precipitates
were filtered, washed with cold ethanol, and recrystallized
from its ethanolic solution to give 6.54 g (83% yield) of the
product 4 as white needles, m.p. 166–168 °C.
Experimental
Chemicals
All chemicals and solvents were obtained from Merck and
Sigma-Aldrich and used without further purification. Anti-
biotics were purchased from Sigma-Aldrich. All yields
were referred to isolated products. Melting points were
recorded on a Kruss type KSP1 N melting point meter
and uncorrected. Monitoring progress of the reactions and
the purity of the products were affected by TLC on alu-
minum plates pre-coated by SiO2 gel (60, Merck) using
CHCl3:CH3OH (8:2, v/v) as mobile phase and visualized
with iodine vapor. The IR spectra of the products were
recorded on a Bruker Tensor 27 FT-IR spectrometer using
KBr disks, and only noteworthy absorptions were listed
Preparation of 5‑amino‑3‑methyl‑1‑phenyl‑1H‑
pyrazole‑4‑carbothioamide (5)
The thioamide 5 was synthesized according to the litera-
ture procedure [41] with slight modification as follows:
pyrazole 4 (1.98 g, 0.01 mol) was added to a solution of
P4S10 (4.44 g, 0.02 mol) in absolute ethanol (20 mL), and
the resulting mixture was stirred at room temperature for
2 h. The precipitated solid was filtered out, washed with
ethanol, and dried in an oven at 80 °C to afford com-
pound 5 without the need for further purification. White to
1
as well. The H and 13C-NMR spectra of DMSO-d6 solu-
1
light yellow solid, m.p. 119–121 °C, yield 98%; H NMR
tions were recorded on a Bruker FT-NMR Ultra Shield-400
spectrometer (400 and 100 MHz, resp.). Elemental analy-
ses were performed for C, H, N, and S on a Thermo Finni-
gan Flash EA microanalyzer. The concentration of bacterial
suspensions was determined by using Jenway 6405 UV–
Vis spectrophotometer. The X-ray diffraction (XRD) anal-
ysis was conducted by using a Bruker D8 X-ray diffrac-
tometer with cu-kα radiation (λ = 1.5418 Å) in the range
of 10°–70° and the scanning rate of 1.5°/min. A scanning
electron microscope (SEM) was applied to observe the sur-
face morphology of nanoparticles using a Hitachi S4160
instrument.
(DMSO-d6, 400 MHz) δ: 2.38 (3H, s, CH3), 7.41 (2H, m,
NH2) 7.53 (5H, d, J = 4.3 Hz, Ph), 7.85, 8.94 (1H, s, 1H,
s, CSNH2); 13C NMR (DMSO-d6, 100 MHz) δ: 174.70
(C=S), 165.60 (C-5 pyrazole), 145.52 (C=N), 143.97 (C-1
Ph), 129.05 (C-3,5 Ph), 128.17 (C-4 Ph), 126.87 (C-2,6
Ph), 101.17 (C-4 pyrazole), 14.49 (CH3); IR (KBr) ν: 3317,
3268 (NH2), 1620 (C=N), 1549 (C=C), 1392 (N–N), 1203
(C–N), 1086 (C=S) cm−1. Anal. Calcd for C11H12N4S: C
56.87, H 5.21, N 24.12, S 13.80; found C 56.85, H 5.23, N
24.14, S 13.78.
General procedure for the synthesis
of 4‑thiazolylpyrazoles 7a–f
Preparation of MgO nanoparticles
The classical Hantzsch conditions
The MgO nanoparticles were prepared by wet chemical
method according to the previously reported procedure
[39], as follows: a suspension of starch (0.1 g) and mag-
nesium nitrate (12.83 g, 0.1 mol) were mixed in 100 mL
distilled water. Then, sodium hydroxide solution (25 mL,
0.008 M) was added slowly to the mixture while it was stir-
ring vigorously over 2 h. The reaction mixture was left at
room temperature for 24 h without stirring. The suspension
was centrifuged at 10,000 rpm for 10 min. Centrifugate
was washed three times using distilled water. The resulting
magnesium hydroxide nanoparticles were placed in the fur-
nace at 300 °C for 4 h to yield nanoparticles of MgO.
A suspension of thioamide 5 (0.23 g, 1 mmol), the appro-
priate α-bromocarbonyl compounds (1 mmol) and sodium
bicarbonate (0.08 g, 1 mmol) in DMF (1 mL) was stirred
at room temperature for 24–46 h. Then, the mixture was
poured gradually onto crashed ice; the solid obtained was
filtered out, washed with water and ethanol, oven-dried,
and finally purified by recrystallization from methanol to
produce thiazoles 7a–f.
The modified Hantzsch conditions (MgO‑catalyzed
process)
Preparation of 5‑amino‑3‑methyl‑1‑phenyl‑1H‑
A few drop of DMF was added to a suspension of thioamide
5 (0.23 g, 1 mmol) and the appropriate α-bromocarbonyl
compounds (1 mmol) in the presence of MgO nanoparti-
cles (5% molar), and the reaction mixture was stirred at
room temperature about 5 min before heating to 100 °C for
5–11 h. After the reaction was complete, acetone (5 mL)
was added to the mixture at room temperature, and the
pyrazole‑4‑carbonitrile (4)
Pyrazole 4 as the starting material was prepared according
to the procedure reported by Allouche et al. [40] as follows:
a solution of malononitrile (1) (2.18 g, 33 mmol), triethyl
orthoacetate (2) (5.52 g, 34 mmol), phenylhydrazine (3)
(3.57 g, 33 mmol) and few drops of acetic acid as catalyst
1 3

J IRAN CHEM SOC
MgO nanocatalyst was filtered off. The recovered MgO
was rinsed with more water and acetone and dried in an
oven at 100 °C. The desired product was crashed out once.
The filtrate was added to an ice-water mixture. The solid
residue was filtered, oven-dried at 80 °C, and recrystallized
from its methanolic solution to yield thiazoles 7a–f.
C17H18N4O2S: C 59.63, H 5.30, N 16.36, S 9.36; found C
59.65, H 5.28, N 16.38, S 9.37.
Ethyl 2-(5-amino-3-methyl-1-phenyl-1H-pyrazol-4-yl)thi-
azole-4-carboxylate (7d): Light yellow crystals, m.p. 165–
1
167 °C; H NMR (DMSO-d6, 400 MHz) δ: 1.33 (3H, t,
J = 7.1 Hz, CH2CH3), 2.40 (3H, s, CH3 pyrazole), 4.33 (2H,
q, J = 7.1 Hz, CH2CH3), 6.85, 7.41 (1H, d, J = 8.1 Hz, 1H,
t, J = 7.2 Hz, NH2), 7.55 (3H, t, J = 7.4 Hz, H-3,4,5 Ph),
7.62 (2H, d, J = 7.8 Hz, H-2,6 Ph), 8.32 (1H, s, CH thia-
zole); 13C NMR (DMSO-d6, 100 MHz) δ: 162.95 (C=O),
161.17 (C-2 thiazole), 146.97 (C-4 thiazole), 146.52 (C-5
pyrazole), 145.26 (C-3 pyrazole), 138.56 (C-1 Ph), 129.86
(C-3,5 Ph), 127.40 (C-4 Ph), 123.45 (C-2,6 Ph), 123.96 (C-5
thiazole), 97.68 (C-4 pyrazole), 61.21 (CH2CH3), 14.65
(CH3 pyrazole, CH2CH3); IR (KBr) ν: 3434, 3314 (NH2),
1729 (C=O), 1602 (C=N), 1563 (C=C), 1394 (N–N), 1221
(C–N), 639 (C–S) cm−1. Anal. Calcd for C16H16N4O2S: C
58.52, H 4.91, N 17.06, S 9.76; found C 58.54, H 4.88, N
17.09, S 9.75.
2-(5-Amino-3-methyl-1-phenyl-1H-pyrazol-4-yl)thia-
zol-4(5H)-one (7e): Light pink crystals, m.p. 238–240 °C;
1H NMR (DMSO-d6, 400 MHz) δ: 2.42 (3H, s, CH3), 4.01
(2H, s, CH2), 7.46, 7.55 (1H, m, 1H, m, NH2), 7.56–760
(5H, m, Ph); 13C NMR (DMSO-d6, 100 MHz) δ: 189.87
(C=O), 165.60 (C-2 thiazole), 149.92 (C-5 pyrazole),
149.70 (C-3 pyrazole), 137.48 (C-1 Ph), 130.07 (C-3,5
Ph), 128.36 (C-4 Ph), 124.23 (C-2,6 Ph), 99.45 (C-4 pyra-
zole), 36.31 (CH2), 15.17 (CH3); IR (KBr) ν: 3342, 3272
(NH2), 1732 (C=O), 1627 (C=N), 1540 (C=C), 1402
(N–N), 1203 (C–N), 639 (C–S) cm−1. Anal. Calcd for
C13H12N4OS: C 57.34, H 4.44, N 20.57, S 11.77; found C
57.31, H 4.47, N 20.53, S 11.79.
3-Methyl-4-(4-methylthiazol-2-yl)-1-phenyl-1H-pyra-
1
zol-5-amine (7a): White crystals, m.p. 170–172 °C; H
NMR (DMSO-d6, 400 MHz) δ: 2.37 (3H, s, CH3 pyrazole),
2.40 (3H, s, CH3 thiazole), 6.71, 7.39 (1H, d, J = 9.5 Hz,
1H, m, NH2), 7.04 (1H, s, CH thiazole), 7.54–7.56 (3H,
m, H-3,4,5 Ph), 7.62 (2H, d, J = 7.8 Hz, H-2,6 Ph); 13C
NMR (DMSO-d6, 100 MHz) δ: 161.92 (C-2 thiazole),
151.14 (C-4 thiazole), 146.52 (C-5 pyrazole), 146.32 (C-3
pyrazole), 138.79 (C-1 Ph), 129.84 (C-3,5 Ph), 127.21 (C-4
Ph), 123.29 (C-2,6 Ph), 109.14 (C-5 thiazole), 98.17 (C-4
pyrazole), 17.30 (CH3 thiazole), 14.49 (CH3 pyrazole); IR
(KBr) ν: 3314, 3262 (NH2), 1620 (C=N), 1556 (C=C),
1401 (N–N), 1200 (C–N), 641 (C–S) cm−1. Anal. Calcd for
C14H14N4S: C 62.20, H 5.22, N 20.72, S 11.86; found C
62.23, H 5.23, N 20.70, S 11.84.
1-(2-(5-Amino-3-methyl-1-phenyl-1H-pyrazol-4-yl)-
4-methylthiazol-5-yl)ethan-1-one (7b): Brown crystals,
m.p. 118–120 °C; 1H NMR (DMSO-d6, 400 MHz) δ: 2.38
(3H, s, CH3 pyrazole), 2.54 (3H, s, COCH3), 2.69 (3H, s,
CH3 thiazole), 6.97, 7.42 (1H, s, 1H, t, J = 7.1 Hz, NH2),
7.54–7.61 (5H, m, Ph); 13C NMR (DMSO-d6, 100 MHz)
δ: 164.57 (C=O), 161.92 (C-2 thiazole), 159.56 (C-4
thiazole), 147.70 (C-5 pyrazole), 147.08 (C-3 pyrazole),
138.36 (C-1 Ph), 129.88 (C-3,5 Ph), 127.58 (C-4 Ph),
123.66 (C-2,6 Ph), 115.33 (C-5 thiazole), 97.75 (C-4 pyra-
zole), 17.54 (COCH3), 14.77 (CH3 thiazole), 14.70 (CH3
pyrazole); IR (KBr) ν: 3442, 3296 (NH2), 1653 (C=O),
1617 (C=N), 1548 (C=C), 1397 (N–N), 1237 (C–N), 656
(C–S) cm−1. Anal. Calcd for C16H16N4OS: C 61.52, H
5.16, N 17.94, S 10.26; found C 61.49, H 5.18, N 17.93,
S 10.29.
2-(5-Amino-3-methyl-1-phenyl-1H-pyrazol-4-yl)-
5-methylthiazol-4(5H)-one (7f): Yellow crystals, m.p.
1
137–139 °C; H NMR (DMSO-d6, 400 MHz) δ: 1.55 (3H,
d, J = 7.2 Hz, CH3 thiazole), 2.41 (3H, s, CH3), 3.85 (1H,
m, CH), 7.46, 7.63 (1H, m, 1H, m, NH2), 7.55–760 (5H,
m, Ph); 13C NMR (DMSO-d6, 100 MHz) δ: 190.13 (C=O),
164.50 (C-2 thiazole), 147.78 (C-5 pyrazole), 147.15 (C-3
pyrazole), 138.53 (C-1 Ph), 129.86 (C-3,5 Ph), 127.54 (C-4
Ph), 123.61 (C-2,6 Ph), 97.85 (C-4 pyrazole), 65.17 (CH),
30.58 (CH3 thiazole), 14.78 (CH3 pyrazole); IR (KBr)
ν: 3329, 3265 (NH2), 1736 (C=O), 1629 (C=N), 1534
(C=C), 1396 (N–N), 1194 (C–N), 659 (C–S) cm−1. Anal.
Calcd for C14H14N4OS: C 58.72, H 4.93, N 19.57, S 11.20;
found C 58.73, H 4.96, N 19.55, S 11.17.
Ethyl 2-(5-amino-3-methyl-1-phenyl-1H-pyrazol-4-yl)-
4-methylthiazole-5-carboxylate (7c): Light yellow crys-
1
tals, m.p. 144–146 °C; H NMR (DMSO-d6, 400 MHz) δ:
1.31 (3H, t, J = 7.1 Hz, CH2CH3), 2.38 (3H, s, CH3 pyra-
zole), 2.67 (3H, s, CH3 thiazole), 4.28 (2H, q, J = 7.1 Hz,
CH2CH3), 6.93, 7.42 (1H, d, J = 7.3 Hz, 1H, t, J = 7.1 Hz,
NH2), 7.54–7.61 (5H, m, Ph); 13C NMR (DMSO-d6,
100 MHz) δ: 192.23 (C=O), 183.80 (C-4 thiazole), 171.45
(C-2 thiazole), 150.11 (C-5 pyrazole), 149.70 (C-3 pyra-
zole), 137.50 (C-1 Ph), 130.01 (C-3,5 Ph), 128.28 (C-4
Ph), 124.18 (C-2,6 Ph), 123.28 (C-5 thiazole), 99.45 (C-4
pyrazole), 64.51 (CH2CH3), 18.80 (CH3 thiazole), 15.12
(CH2CH3) 14.32 (CH3 pyrazole); IR (KBr) ν: 3378, 3287
(NH2), 1670 (C=O), 1619 (C=N), 1545 (C=C), 1396
(N–N), 1263 (C–N), 649 (C–S) cm−1. Anal. Calcd for
Antibacterial activity
The antibacterial activity of all newly synthesized com-
pounds was evaluated against 21 pathogenic bacteria
including gram-negative strains Pseudomonas aeruginosa
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J IRAN CHEM SOC
Scheme 1 Total synthesis of
4-thiazolylpyrazoles 7a–f
Table 1 Synthesis of Hantzsch
thiazole derivatives under two
different conditions
Thiazoles
α-Bromocarbonyls
Classical conditions
Modified conditions
Time (h)
Yield (%)
Time (h)
Yield (%)
7a
7b
7c
7d
7e
7f
Bromoacetone
24
41
41
46
24
46
76
60
77
52
77
85
5
10
10
11
5
90
75
91
68
92
97
3-Bromoacetylacetone
Ethyl 2-bromoacetoacetate
Ethyl bromopyruvate
Ethyl bromoacetate
Ethyl 2-bromopropionate
11
(PTCC 1310), Klebsiella pneumoniae (PTCC 1290),
Escherichia coli (PTCC 1399), Shigella flexneri (PTCC
1234), Shigella dysenteriae (PTCC 1188), Proteus mira‑
bilis (PTCC 1776), Proteus vulgaris (PTCC 1079), Salmo‑
nella enterica subsp. enterica (PTCC 1709), Salmonella
typhi (PTCC 1609), Enterococcus faecalis (PTCC 1778)
and gram-positive strains Streptococcus pyogenes (PTCC
1447), Streptococcus agalactiae (PTCC 1768), Strepto‑
coccus equinus (PTCC 1445), Streptococcus pneumoniae
(PTCC 1240), Listeria monocytogenes (PTCC 1297),
Staphylococcus aureus (PTCC 1189), Staphylococcus
epidermidis (PTCC 1435), Bacillus cereus (PTCC 1665),
Bacillus subtilis subsp. spizizenii (PTCC 1023), Bacillus
thuringiensis subsp. kurstaki (PTCC 1494), and Rhodo‑
coccus equi (PTCC 1633) which were prepared from the
Persian Type Culture Collection (PTCC), Tehran, Iran.
Antibacterial activities were tested according to Clinical
and Laboratory Standards Institute (CLSI) broth microdi-
lution and disk diffusion methods described in guidelines
M07-A9, M26-A and M02-A11 [42], repeated three
times, and expressed as the average of three independent
experiments.
Solution of all derivatives and antibiotics were prepared
in DMSO and double-distilled water at initial concentra-
tions of 9011 and 17.6 μg/mL, respectively, and these con-
centrations were also used to measure IZDs. In all tests,
DMSO and antibiotics were used as negative and positive
controls.
Results and discussion
Synthesis and spectroscopic characterization
of thiazoles 7a–f
In this study, 4-thiazolylpyrazoles 7a–f were synthesized
in a three-step process (Scheme 1). Pyrazole 4 was pre-
pared via an acid-catalyzed reaction of malononitrile (1),
1 3

J IRAN CHEM SOC
triethyl orthoacetate (2), and phenylhydrazine (3). Thiona-
tion of pyrazole 4 by phosphorus pentasulfide (P4S10) was
resulted in the formation of 5-amino-3-methyl-1-phenyl-
1H-pyrazole-4-carbothioamide (5). Our efficient two-step
synthesis of the desired compound (5) was resulted in
higher yield than the four-step procedure reported by Giori
et al. [43]. Finally, cyclocondensation of thioamide 5 with
α-bromoketones 6a–f formed 4-thiazolylpyrazoles 7a–f.
Through our optimization process, two different conditions
were tested (classical Hantzsch vs. MgO-catalyzed reac-
tion). Furthermore, we found that using MgO nanoparticles
was resulted in higher yields and shorter reaction times as
shown in Table 1.
Similar thiazoles 7a–f were synthesized using the
classical Hantzsch protocol in order to compare with
our novel procedure and demonstrated the generality
of the new method. Thioamide 5 has been reacted with
α-bromoketones 6a–f in DMF at room temperature for
24–46 h under the classical Hantzsch protocol to form thia-
zoles 7a–f in 52–85% yields. Besides, same products were
obtained in higher yields (68–97%) under solvent-free con-
ditions and shorter reaction times by using MgO nanocata-
lyst. The comparative results are shown in Table 1.
Table 2 Optimization of the model reaction conditions
Entry
Solvent T (°C) Molar% MgOa Time (h) Yield (%)
1
DMF
rt
–
–
–
–
1
3
4
5
–
–
–
–
–
1
1
1
1
1
1
3
4
5
6
24
20
18
15
22
19
17
17
19
16
14
12
12
13
11
10
8
76
69
63
59
78
81
84
84
46
53
61
70
70
52
61
70
76
81
81
83
87
90
90
Higher yields, shorter reaction times as well as using an
eco-friendly procedure are some benefits of our new proce-
dure. It is important to notice that the MgO nanoparticles
can be recycled at least three times with almost no loss of
reactivity.
The reaction of thioamide 4 with bromoacetone (6a) in
a 1:1 molar ratio was selected in order to roll out the effect
of parameters such as temperature, presence or absence of
solvent, and the amount of the catalyst (Table 2).
It was observed that a slightly increase in the reaction
temperature decreased the product yield drastically under
the classical conditions. Based on the Le Chatelier’s prin-
ciple, this might happen due to the increase in the solubil-
ity of the product in DMF at higher temperatures which in
turn decreased the conversion of the reactants to the desired
products (Entries 1–4). The yield was improved when MgO
nanoparticles were added to the reaction mixture in DMF at
room temperature (Entries 5–8). Under solvent- and cata-
lyst-free conditions, an increase in the temperature to 80 °C
led to increase in the yield and decrease in the reaction time
(Entries 9–13). It was shown that eliminating the solvent
and increasing the reaction temperature in the presence of
1 mol% of the catalyst improved the yield and shortened
the reaction time as well (Entries 14–19). Further increase
2
DMF
40
50
60
rt
3
DMF
4
DMF
5
DMF
6
DMF
rt
7
DMF
rt
8
DMF
rt
9
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
rt
10
11
12
13
14
15
16
17
18
19
20
21
22
23
40
60
80
90
rt
40
60
80
100
110
100
100
100
100
7
7
7
6
5
5
a
In the form of nanoparticles
Scheme 2 A proposed mecha-
nism for the Hantzsch thiazole
synthesis in the presence of
MgO nanoparticles
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J IRAN CHEM SOC
Fig. 1 Formation of intramolecular hydrogen bonding in thiozoles
in the reaction temperature as well as the amount of the
catalyst improved the yield to 90% (Entry 22). The highest
yield with the shortest time was obtained under solvent-free
conditions and in the presence of 5 molar% MgO nanopar-
ticles at 100 °C and considered as the optimal condition.
The role of the MgO nanoparticle in this reaction has
been illustrated by a plausible mechanism in Scheme 2.
The dual nature of acidic and basic MgO has helped to cat-
alyze different stages of this reaction.
Fig. 3 SEM image of prepared MgO nanoparticles
system. In the FT-IR spectra of thiazole derivatives, absorp-
tion bands within ν = 3262–3314 and 3314–3442 cm−1 were
determined to correspond to symmetric and asymmetric
stretching vibrations of the amino groups. The microanalyti-
cal data also confirmed the purity of all products.
Structure of applied MgO nanoparticles was character-
ized using XRD and SEM techniques and illustrated in
Figs. 2 and 3, respectively. In XRD pattern, the sharp and
intense main peaks were found around 2θ values of 42.7
and 62.06 with (110) and (200) crystal planes, confirmed
crystalline structure of MgO [39]. The average crystallite
size of nanoparticles is estimated from Scherrer equation
as to be 23.7 and 25.7 nm. The morphology of the synthe-
sized nanocrystals was determined by SEM and their par-
ticle size found to be in the range 30–50 nm. Dense flakes
form of nanoparticles is also obvious in Fig. 3.
The chemical structures of compounds 6 and 7a–f were
1
confirmed based on their H, 13C-NMR, and other analyti-
cal data. Methyl and phenolic proton signals of pyrazole
ring system in compounds 7a–f were, respectively, appeared
within δ = 2.37–2.42 and 7.54–7.80 ppm. The two hydro-
gens of the amino group (NH2) were appeared in different
chemical shifts probably due to intramolecular hydrogen
bonding with nitrogen of thiazole ring as shown in Fig. 1.
The 13C-NMR spectra of these products were exhibited
signals within δ = 14.32–15.17, 123.29–138.79, 97.68–
99.45, 145.26–149.70, 146.52–150.11 ppm which attrib-
uted, respectively, to methyl, phenyl, 4-, 3-, and 5-carbons
of pyrazole ring system. Also, signals within δ = 161.17–
185.41 ppm were assigned to the 2-carbons of thiazole ring
Fig. 2 XRD spectrum of the
chemically synthesized MgO
nanoparticles
1 3

J IRAN CHEM SOC
Table 3 Screening of IZD,
MIC, and MBC of the newly
synthesized derivatives and
antibiotics against some gram-
positive and gram-negative
bacteria
Bacteria
Products/Antibiotics
6
7a
7b
7c
7d
7e
7f
Ceftriaxone
Penicillin
1310
IZD
12.23
1024
2048
19.16
1024
2048
11.57
512
18.25
1024
2048
15.61
1024
2048
18.34
1024
2048
16.27
1024
2048
16.2
0.5
1
–
–
–
MIC
MBC
1665
IZD
1024
–
–
–
8.78
1024
4096
9.40
1024
2048
–
–
–
–
–
–
–
–
–
11.08
512
–
–
–
–
–
–
MIC
MBC
1079
IZD
2048
–
–
–
–
–
–
18.33
1024
1024
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
12.82
8
MIC
MBC
1399
IZD
32
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
10.92
1024
2048
31.49
–
–
–
MIC
MBC
1240
IZD
8
8
–
–
–
12.85
128
15.39
512
13.47
256
17.03
2048
4096
16.26
256
15.09
256
–
–
–
12.20
8
MIC
MBC
1189
IZD
256
512
512
512
512
16
–
–
–
–
–
–
18.06
1024
2048
13.54
2048
4096
10.28
2048
4096
–
–
–
18.62
256
15.36
4
18.32
8
MIC
MBC
1778
IZD
512
16
32
–
–
–
–
–
–
8.93
512
10.65
512
–
–
–
–
–
–
–
–
–
18.38
23.64
8
MIC
MBC
1297
IZD
1
2
1024
1024
16
10.48
1024
2048
–
–
–
–
–
–
4.74
2048
4096
–
–
–
–
–
–
–
–
–
8.27
8
22.11
8
MIC
MBC
1768
IZD
8
16
13.89
32
11.29
64
11.57
1024
2048
20.14
512
8.06
512
7.73
256
16.37
128
–
–
–
–
–
–
MIC
MBC
1435
IZD
64
64
1024
4096
1024
256
12.86
512
7.58
256
512
10.06
256
16.43
256
8.18
512
–
–
–
9.64
1024
1024
18.54
0.5
2
23.58
0.5
1
MIC
MBC
1445
IZD
1024
512
512
1024
8.74
1024
2048
7.86
256
512
–
–
–
–
–
–
–
–
–
7.82
512
10.22
1024
2048
8.09
8
13.61
8
MIC
MBC
2048
16
32
IZD (mm), MIC (μg/mL), MBC (μg/mL)
–, no noticeable antibacterial effect at selected highest concentration
1 3

J IRAN CHEM SOC
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Antibacterial evaluation of the newly synthesized
compounds
The in vitro antibacterial effects of the newly synthesized
derivatives in comparison to antibiotics such as ceftriaxone
and penicillin were evaluated and presented as IZD, MIC,
and MBC values in Table 3. Since the synthesized deriva-
tives at the initial concentrations were ineffective against
some bacteria, their data has not been given in this table.
The derivatives had an inhibitory activity against various
bacterial families of both gram-positive and gram-negative
strains. All 4-thiazolylpyrazoles 7a–f showed inhibitory prop-
erties toward P. aeruginosa, S. pneumoniae, and S. agalac‑
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eight pathogenic bacteria, as the result they came out as the
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effective compounds against E. coli. The best inhibitory effect
was observed in thioamide 6 with MIC and MBC values of
32 and 64 μg/mL, respectively, against S. agalactiae.
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time, and higher product yield over the classical condition.
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synthesized compounds were examined against a variety
of pathogenic bacteria. Moderate to good activities were
observed for all derivatives. The inhibitory effects of all
synthesized compounds against S. agalactiae were success-
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Acknowledgement The authors would like to thank members of the
University of Zabol especially Dr. Mansour Ghaffari-Moghaddam,
dean of the faculty of science, for their support and assistance at the
various stages of this project.
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1 3