Mechanochemical synthesis of 5-acetylthiazole: A step toward green and sustainable chemistry

Article abstract of DOI:10.1002/jhet.4079

Mechanochemical synthesis of 5-acetylthiazole derivatives by one-pot three-component procedure over Silica Sulfuric acid under solvent-free conditions, has been developed. The durability of the catalyst was tested. The environmentally benign protocol introduced herein characterized by no hazardous organic solvent used, recyclability of the catalyst up to five runs without loss of its catalytic activity and high yields of products that confirm the utilization of some green chemistry principles in the mentioned protocol.

Full text of DOI:10.1002/jhet.4079

Mechanochemical synthesis of 5-acetylthiazole: A step toward green and sustainable chemistry
Abdullah S. Al-Bogamia,*, Tamer S. Saleha,b,*, and Adel H. El-Shareefa
a University of Jeddah, College of Science, Department of Chemistry, Jeddah, Saudi Arabia
b Green Chemistry Department, National Research Centre, Dokki, Giza 12622, Egypt
Email: aalbogami@uj.edu.sa, chem_org@hotmail.com
tssayed@uj.edu.sa, tamsaid@yahoo.com
Abstract Mechanochemical synthesis of 5-acetylthiazole derivatives by one-pot
three-component procedure over Silica Sulfuric acid (SSA) under solvent-free
conditions, has been developed. The durability of the catalyst was tested. The
environmentally benign protocol introduced herein characterized by no hazardous
organic solvent used, recyclability of the catalyst up to five runs without loss of its
catalytic activity and high yields of products that confirm the utilization of some
green chemistry principles in the mentioned protocol.
Keywords: Ball milling, 5-acetylthiazole, mechanochemistry, X-ray
crystallography.
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Introduction
The focal point of current green organic chemistry research is the development of
nonhazardous alternatives for the sustainable growth of chemical endeavor that
includes solventless organic synthesis, multicomponent reactions etc. There are
various advantages for the green organic process not only reduce the consumption
of environmentally perilous solvents but also minimize the formation of other
waste materials [1].
Organic chemists nowadays search for utilization of different green chemistry tools
one of the recent spread tools that attain solvent free condition is
“Mechanochemistry" [2-6]. Mechanochemistry can be done either hand grinding
or mechanical milling [7]. Ball milling is a tool that performs the Mechanical
milling with the aid of milling ball(s). A plethora of applications in material
science have been done via Ball mills. Ball mills used to grind and homogenize,
minerals, or in the manufacturing of catalysts and nanoparticles [8-10]. However,
ball mills have recently become interesting tools for contemporaneous research in
organic synthesis in which they offer development of rapid and selective synthetic
routes toward functionalized heterocyclic building blocks [11,12].
Thiazoles are important class of heterocyclic compounds, found in many potent
biologically active molecules such as Sulfathiazol (antimicrobial drug), Ritonavir
(antiretroviral drug), Abafungin (antifungal drug) with trade name Abasol cream
and Bleomycine and Tiazofurin (antineoplastic drug) [13].
In recent times, the applications of thiazoles were found in drug development for
the treatment of allergies [14], hypertension [15], inflammation [16], schizophrenia
[17], bacterial [18], HIV infections [19], hypnotics [20] and more recently for the
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treatment of pain [21], as fibrinogen receptor antagonists with antithrombotic
activity [22] and as new inhibitors of bacterial DNA gyrase B [23].
Moreover, the presence of (S-C=N) toxophoric unit in thiazole ring system is the
cause for its antimicrobial importance because of this unit enhanced lipid solubility
with hydrophilicity and also easily metabolized by routine biochemical reactions
and are non-carcinogenic in nature [24].
Among substituted thiazoles, 5-acetylthiazoles represent an interesting building
blocks for the construction of several bioactive compounds. A variety of protocols
[25-33] have been reported for the synthesis of 5-acetylthiazoles derivatives.
However, these methods show varying degrees of success as well as limitations
such as high temperatures, prolonged reaction times, unsatisfactory yield, use of
toxic solvents and catalysts, tedious steps for the preparation of catalyst, lack of
catalyst reusability, laborious work-up procedures, harsh reaction conditions and
lack of generality. Recently, few reports have been published regarding utilizing of
mechanochemistry for synthesis of thiazole ring [34,35]. Thus, the development of
an alternate milder, clean as well as environmentally friendly procedure is highly
demanding for the synthesis of substituted 5-acetylthiazoles, which surpasses those
limitations. As a part of our ongoing efforts to develop cost-effective and simpler
green methodologies for the synthesis of hybrid pharmacophores [36-38], we
report herein, a simple, convenient, and green synthesis of substituted 5-
acetylthiazoles using ball mill technique.
Results and discussion
Initially, we optimized the one-pot three component reaction of equimolar amounts
of 4-trifluromethyl aniline (1a), 3-chloro-2,4-pentanedione (2) and potassium
thiocyanate (3) in presence of different solid catalysts utilizing ball mill technique
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to generate 1-(4-methyl-2-((4-(trifluoromethyl)phenyl)amino)thiazol-5-yl)ethanone
(4a) (Scheme 1).
Scheme 1: Optimization the reaction conditions for the three-component reaction.
First, the presence of solid catalyst such as silica, Silica sulfuric acid, acidic
alumina and Montmorillonite K10 (Table 1) not only to study its catalytic effect
but also, to counter the liquid nature of the used reactants.
As we clarify above, the reaction depicted in Scheme 1 was taken as a model
reaction for synthesis of 5-acetylthiazole derivative 4a utilizing ball mill “a
solvent-free technique”. It is clear from the results cited in Table 1 that no product
formed in the absence of catalyst even after 3h (entry 1). In addition, utilizing of
SSA catalyst the best yield attained 99% of the desired product 4a in 25 min.
(entry 3). Furthermore, a relatively lower product’s yield in longer period of time
(89%, 45 min and 82%, 90 min) was attained using montmorillonite K10 and
acidic alumina catalysts, respectively (entries 4,5). Moreover, when using silica as
catalyst the obtained yield 42% in 120 min. (entry 2).
Table 1: Different catalysts screening for synthesis of compound 4a under ball
milling technique
Entry
1
Catalyst
Time (min.)
Yield (%)
None
180
0
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Silica
120
25
42
99
89
82
2
3
4
5
Silica sulfuric acid
Montmorillonite K10
Acidic alumina
45
90
In order to get the best optimized reaction conditions for the best solid catalyst
“Silica sulfuric acid”, a run of tests was performed under different parameters and
the reaction progress was monitored by using thin-layer chromatography (TLC) for
a representative reaction (Scheme 1) under ball milling. The results obtained from
the catalytic test reaction are cited in Table 2, by studying the following
parameters: The reaction time, milling frequency, and impact force (controlled in
ball milling by varying the number and size of milling balls) (Table 2).
Table 2: optimizing the reaction condition* for synthesis of 4a (effect of frequency
and number of milling balls on reaction time and Yield).
Entry Frequancy (Hz) Number of milling balls** Reaction time (min.) Yield(%)
1
2
3
4
5
6
7
30Hz
30Hz
30Hz
30Hz
15Hz
20Hz
25Hz
1
2
3
4
2
2
2
120
25
traces
99
25
95
25
95
120
40
traces
83
35
87
*Reaction conditions: Equimolar amounts of 4-trifluromethyl aniline (1a), 3-chloro-2,4-
pentanedione (2) and potassium thiocyanate (3) in presence of 0.5 g
silica sulfuric acid
**Ball diameter 12 mm.
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From table 2, we found that, for the above-mentioned reaction the best time was 25
min., as evidenced by TLC, when carrying out the reaction at frequency 30Hz and
using of 2 balls of diameter 12 mm. also, we obtained excellent yield (99%) for the
mentioned conditions (entry 2). The number of milling balls varying from 1 to 4
(entry 1-4), it has to be stated expressly that a minimum of 2 milling balls are
necessary to get a quantitative yield of product 4a. Also, the best reaction time and
yield attained at frequency 30 Hz but other frequencies 15, 20, 25 Hz (entries 5-7)
exhibit lower yield and long time.
The spectroscopic data of the obtained product is in complete agreement with the
structure 1-(4-methyl-2-((4-(trifluoromethyl)phenyl)amino)thiazol-5-yl)ethanone
1
(4a). The H NMR of compound 4a show that two singlet signals at δ 2.50 and
2.51 due to methyl and acetyl protons, two doublets signals at δ 7.93 and δ 7.99
due to the four aromatic protons in addition to the D2O exchangeable signal at δ
11.8 due to NH protons.
A further sharp evidence for the proposed structure of compound 4a was presented
in Figure 1, in which the structure of the compound 4a was confirmed using X-ray
crystallography. Supplementary crystallographic data for this paper are available
free of charge from the Cambridge Crystallographic Data Centre under CCDC-
1580012.
Figure1: Single crystal X-ray of 4a
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The scope and generality of the reaction depicted in Scheme 1 are illustrated by a
series of 5-acetylthiazole derivatives as can be seen in Scheme 2. A wide range of
aromatic amines were employed and all 5-acetylthiazole derivatives were obtained
in excellent yields (Scheme 2). The reactions worked-up very well with all
products.
Entry
Amine
Product
Reaction time Yield
(min.)
25
(%)
99
1
1b
4b
25
20
99
99
2
3
1c
4c
1d
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4d
25
99
4
1e
4e
35
98
5
1f
4f
4g
4h
30
40
98
91
6
7
1g
1h
Scheme 2: Reaction of aniline derivatives (1b-h), 3-chloro-2,4-pentanedione (2)
and potassium thiocyanate (3) under optimized conditions utilizing
ball mill technique.
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Also, as we refer that the low impact of the used catalyst on environment due to
availability to reuse. Therefore, the sustainability of the Silica sulfuric acid was
tested for several reaction runs (taking the synthesis of 4a as example under the
optimized reaction conditions) i.e., the catalyst was removed after the completion
of the reaction by filtration, then catalyst was taken in hot ethanol in ultrasonic
cleaning bath, then filtered and dried under vacuum. The recovered catalyst was
reused for five times using the same reaction conditions. Figure 2 shows that the
regenerated catalyst performs the reactions efficiently under the same reaction
conditions even after being used till the fifth times. The slight decay observed in
the catalytic activity of the silica sulfuric acid catalyst on the fifth time could be
attributed to the weight loss of the catalyst during the working up in each time.
99
99
99
99
95
100
90
80
70
60
50
40
30
20
10
0
1
2
3
4
5
Number of runs
Figure 2. Re-usability of SSA catalyst for the formation of 4a.
Conclusions
We have developed a facile and efficient method for the syntheses of 5-
acetylthiazole derivatives catalyzed by SSA utilizing ball mill technique. This
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methodology provides an easy access to build up the library of 5-acetylthiazoles.
The major advantages of this protocol are (i) economic and relatively
environmentally benign SSA catalyst, (ii) mild reaction conditions and (iii) ease of
isolation of product in excellent yield.
Experimental
General
All organic solvents were purchased from commercial sources and used as
received unless otherwise stated. All other chemicals were purchased from Merck
(Darmstadt, Germany), Sigma-Aldrich (St. Louis, MO) or Acros Organics (part of
Thermo Fisher Scientific, Waltham, MA) and used without further purification.
Thin-layer chromatography was performed on precoated Merck 60 GF254 silica
gel plates with a fluorescent indicator, and ultraviolet irradiation at 254 and 360
nm was used for detection. The melting points were measured on a Stuart melting
point apparatus and not corrected. IR spectra were recorded on a Smart iTR, which
is an ultrahigh-performance, versatile attenuated total reflectance sampling
accessory on the Nicolet iS10 FT-IR spectrometer (Thermo Fisher Scientific).
NMR spectra were recorded at 298 K on a Bruker Avance III 400 (9.4 T, 400.13
1
13
MHz for H, 100.62 MHz for C) spectrometer (Bruker, Billerica, MA) with a 5-
mm BBFO probe. Chemical shifts ( in ppm) are relative to internal standard
1
DMSO-d6 ( 2.50) for H NMR. Mass spectra were recorded on a Thermo Fisher
Scientific ISQ single-quadrupole GC–MS. Elemental analyses were carried out on
a Euro Vector C, H, N, S analyzer (EA3000 series). Single-crystal X-ray
diffraction analysis was performed using a Bruker APEX2. The ball mill was a
Retch MM2000 (Hanna, Germany). Silica sulfuric [39] was prepared according to
the reported literature
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2.2 General procedure for the synthesis of 1-(4-methyl-2-aryl)amino)thiazol-5-
yl)ethanone (5-acetylthiazole derivatives) (4a–h)
SSA catalyst (0.5 g), were added to a mixture of 4-trifluromethyl aniline (1a) (10
mmol), 3-chloro-2,4-pentanedione (2) (10 mmol) and potassium thiocyanate (10
mmol) in a mortar, the grinded blend, utilizing a pestle at ambient temperature,
inserted in the 50 mL stainless steel jar equipped with two stainless steel balls (12
mm in diameter). The jar was locked and milling was carried out at the frequency
illustrated in Table 2. After 5 min, thin layer chromatography (TLC) was applied to
follow up the reaction progress. If necessary, the milling cycle was repeated until
the reaction was complete. The product was isolated by simple washing of the
crude reaction residue with hot ethyl acetate and sonicated for 5 min. to desorb all
adsorbed product on the surface of catalyst then remove the catalyst by filtration.
Then the filtrate was concentrated in vacuo under reduced pressure and the residual
solid was taken in ethanol and filtered as pure product.
Washing of the pre-used catalyst with ethyl acetate and drying prior to new
catalytic test was systematically followed. Compound 4a was attained utilizing
different catalysts (Silica, montmorillonite K10, acidic alumina) using ball mill
technique. All the tested catalysts showed reasonable efficiency but SSA provided
excellent effectiveness with high yield in short period (Table 1).
In addition to, the reaction was also performed on the same scale described above
without any catalyst to afford no isolable product.
Representative spectral and analytical data:
1-(4-methyl-2-((4-(trifluoromethyl)phenyl)amino)thiazol-5-yl)ethan-1-one
(4a):
1
m.p. 210-212oC; Yield 99%; IR (KBr) v/cm−1:1641(C=O), 1593 (C=N). H NMR
(400 MHz, DMSO), δ: 2.50 (s, 3H, CH3), 2.57 (s, 3H, CH3), 7.18 (d, J= 8.7 Hz,
2H, Ar-H), 8.04 (d, J= 8.8 Hz, 2H, Ar-H), 11.06 (s, 1H, NH, D2O exchangeable);
13C NMR δ:20.87, 27.09, 118.21, 119.16, 120.05 (q, J= 31.85 Hz), 128.78 (q, J=
233.69 Hz), 131.32 (q, J= 3.70 Hz), 131.54, 133.26, 160.06, 197.01;
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MS, m/z(%):300 (M+, 395) ; Anal. Calcd. For C13H11F3N2OS, C: 52.00; H, 3.69;
N, 9.33; S, 10.68. Found: C: 51.23; H, 3.65; N, 9.20; S, 10.61 %.
1-(4-methyl-2-(p-tolylamino)thiazol-5-yl)ethan-1-one (4b):
1
m.p. 194-196oC; Yield 99%; IR (KBr) v/cm−1:1652 (C=O), 1592 (C=N). H
NMR (400 MHz, DMSO), δ: 2.17 (s, 3H, CH3), 2.43 (s, 3H, CH3), 2.56 (s, 3H,
CH3), 7.68(d, J= 8.6 Hz, 2H, Ar-H), 7.82 (d, J= 8.5 Hz, 2H, Ar-H), 11.06 (s, 1H,
NH, D2O exchangeable); 13C NMR δ: 14.87, 18.87, 30.46, 117.68, 120.68, 128.95,
130.07, 143.79, 156.63, 164.66, 191.03; MS, m/z(%):246 (M+, 90) ; Anal. Calcd.
For C13H14N2OS: C, 63.39; H, 5.73; N, 11.37; S, 13.02. Found: C: 63.63; H, 5.31;
N, 11.25; S, 12.94 %.
1-(4-methyl-2-((3-(trifluoromethyl)phenyl)amino)thiazol-5-yl)ethan-1-one
(4c):
m.p. 179-181oC; Yield 99%; IR (KBr) v/cm−1:1642 (C=O), 1599 (C=N). 1H NMR
(400 MHz, DMSO), δ: 2.50 (s, 3H, CH3), 2.54 (s, 3H, CH3), 7.24 (dd, J= 3.8, 4.92
Hz, 1H, Ar-H), 7.93 (dd, J= 1.08, 3.8 Hz, 1H, Ar-H), 7.99 (dd, J = 1.08, 4.96 Hz,
13
1H, Ar-H), 8.17 (s, 1H, Ar-H), 11.08 (s, 1H, NH, D2O exchangeable); C
NMR δ:18.46, 27.16, 117.57, 123.8 (q, J= 273.3 Hz), 124.6 (q, J= 3.6 Hz),
128.79(q, J= 3.7 Hz), 129.26 (q, J= 33.11 Hz), 132.55,134.35, 144.59, 145.57,
156.23, 191.23. MS, m/z(%): 300 (M+, 91) ; Anal. Calcd. For C13H11F3N2OS: C,
52.00; H, 3.69; N, 9.33; S, 10.68. Found: C: 52.17; H, 3.67; N, 9.25; S, 10.62 %.
1-(2-((4-chlorophenyl)amino)-4-methylthiazol-5-yl)ethan-1-one (4d) :
m.p. 197-199oC; Yield 99%; IR (KBr) v/cm−1:1656 (C=O), 1592 (C=N). 1H NMR
(400 MHz, DMSO), δ: 2.37(s, 3H, CH3), 2.54 (s, 3H, CH3), 7.33 (d, J= 7.96 Hz,
2H, Ar-H), 7.86 (d, J= 8.2 Hz, 2H, Ar-H), 11.05 (s, 1H, NH, D2O exchangeable);
13C NMR δ: 21.31, 27.04, 125.86, 128.73, 129.66, 134.21, 143.95, 154.87,
159.13, 197.89; MS, m/z(%):266 (M+, 93) ; Anal. Calcd. For C12H11ClN2OS: C,
54.03; H, 4.16; N, 10.50; S, 12.02. Found: C: 54.27; H, 4.12; N, 10.37; S, 11.95
%.
4-((5-acetyl-4-methylthiazol-2-yl)amino)benzenesulfonamide (4e):
m.p. 254-256oC; Yield 99%;
IR (KBr) v/cm−1:1644 (C=O), 1599 (C=N),
1311,1193 (SO2). 1H NMR (400 MHz, DMSO), δ: 2.45 (s, 3H, CH3), 2.58 (s, 3H,
CH3), 7.25 (s, 2H, NH2, D2O exchangeable), 7.46 (m, 4H, Ar-H), 11.07 (s, 1H,
13
NH, D2O exchangeable); C NMR δ:18.94, 30.27, 117.76, 123.921, 127.54,
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137.82, 143.18, 156.72, 164.72, 189.96; MS, m/z(%):311 (M+, 87) ; Anal. Calcd.
For C12H13N3O3S2: C, 46.29; H, 4.21; N, 13.50; S, 20.60. Found: C: 46.51; H,
4.18; N, 13.39; S, 20.52 %.
1-(4-((5-acetyl-4-methylthiazol-2-yl)amino)phenyl)ethan-1-one (4f):
m.p. 223-225oC; Yield 98%; IR (KBr) v/cm−1:1687, 1645 (2 C=O), 1599 (C=N).
1H NMR (400 MHz, DMSO), δ: 2.27 (s, 3H, CH3), 2.41(s, 3H, CH3), 2.54 (s, 3H,
CH3), 7.17 (d, J= 8.4 Hz, 2H, Ar-H), 7.46 (d, J= 8.32 Hz, 2H, Ar-H), 10.64 (s, 1H,
NH, D2O exchangeable); 13C NMR δ:18.92, 26.81, 30.26, 8..221, 125.25, 130.32,
133.26, 137.97, 157.24, 165.94, 189.43, 193.41; MS, m/z(%):274 (M+, 84) ; Anal.
Calcd. For C14H14N2O2S: C, 61.29; H, 5.14; N, 10.21; S, 11.69. Found: C: 61.84;
H, 5.09; N, 10.10; S, 11.61 %.
1-(4-methyl-2-(phenylamino)thiazol-5-yl)ethan-1-one (4g):
m.p. 154-156 oC; Yield 98%; IR (KBr) v/cm−1:1643 (C=O), 1601 (C=N). 1H NMR
(400 MHz, DMSO), δ: 2.50 (s, 3H, CH3), 2.55 (s, 3H, CH3), 7.05 (t, J= 7.36 Hz,
1H, Ar-H), 7.36 (t, J= 8.4 Hz, 2H, Ar-H), 7.60 (d, J= 8.4 Hz, 2H, Ar-H), 10.73 (s,
13
1H, NH, D2O exchangeable); C NMR δ: 18.93, 30.18, 118.58, 122.72, 123.22,
129.62, 140.43, 157.10, 165.62, 189.58; MS, m/z(%):232 (M+, 90) ; Anal. Calcd.
For C12H12N2OS, C, 62.04; H, 5.21; N, 12.06; S, 13.80. Found: C: 62.33; H, 5.15;
N, 11.91; S, 13.72 %.
1-(4-methyl-2-(o-tolylamino)thiazol-5-yl)ethan-1-one (4h):
1
m.p. 169-170oC; Yield 91%; IR (KBr) v/cm−1:1644 (C=O), 1599 (C=N). H
NMR (400 MHz, DMSO), δ: 2.21 (s, 3H, CH3), 2.43 (s, 3H, CH3), 2.56 (s, 3H,
CH3), 7.19 (d, J = 7.6 Hz, 1H, Ar-H), 7.31-7.46 (m, 3H, Ar-H), 10.13 (s, 1H, NH,
13
D2O exchangeable); C NMR δ: 14.81, 19.22, 26.84, 126.01, 126.14, 127.35,
129.38, 131.14, 133.51, 136.27, 154.32, 162.14, 191.08; MS, m/z(%):246 (M+, 81)
; Anal. Calcd. For C13H14N2OS: C, 63.39; H, 5.73; N, 11.37; S, 13.02. Found: C:
63.60; H, 5.65; N, 11.27; S, 12.99 %.
Acknowledgement
This project was funded by the Deanship of Scientific Research (DSR), University
of Jeddah, Jeddah, Saudi Arabia, under grant No. (UJ-02-017-DR). The authors,
therefore, acknowledge with thanks DSR technical and financial support.
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Supporting information
Copies of 1H and 13C NMR spectra of most synthesized compounds are provided.
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