Eco-friendly synthesis of 2-aminothiazoles using Nafion-H as a recyclable catalyst in PEG-water solvent system

Article abstract of DOI:10.1080/17415993.2010.533773

A simple, efficient, single step and environmentally benign synthesis of 2-aminothiazoles is described in this paper. This green protocol was catalyzed by recyclable solid supported Nafion-H using polyethylene glycol-water solvent system with improved efficiency and reduced waste production.

Full text of DOI:10.1080/17415993.2010.533773

Journal of Sulfur Chemistry
Vol. 32, No. 1, February 2011, 37–44
Eco-friendly synthesis of 2-aminothiazoles using Nafion-H as a
recyclable catalyst in PEG–water solvent system
Mazaahir Kidwai*, Ritika Chauhan and Divya Bhatnagar
Green Research Laboratory, Department of Chemistry, University of Delhi, Delhi-110007, India
(Received 15 September 2010; final version received 16 October 2010)
A simple, efficient, single step and environmentally benign synthesis of 2-aminothiazoles is described in
this paper. This green protocol was catalyzed by recyclable solid supported Nafion-H using polyethylene
glycol–water solvent system with improved efficiency and reduced waste production.
Keywords: 2-aminothiazoles; Nafion-H; polyethylene glycol; green; recyclable
1. Introduction
In the recent decades, one of the most challenging tasks for researchers is to achieve the most
efficient methodology for the organic synthesis which can be realized by employing innovative
research which comprehensively meets the requirement of atom economy, economy of steps and
avoidance of any hazardous chemicals. One of the best methods will be that which will address
the goals of green chemistry.
Thiazoles are known to be associated with diverse physiological activities. The thiazole
framework, particularly 2-aminothiazole is an important medicinal scaffold. Several compounds
possessing this framework are important ingredients in many pharmaceutical preparations used in
the treatment of allergies (1), hypertension (2), inflammation (3), schizophrenia (4), bacterial (5)
and HIV infections (6). Recently, it has been utilized for the treatment of pain (7), as fibrinogen
receptor antagonists with antithrombotic activity (8), as inhibitors of bacterial DNA gyrase (9),
and in the development of cyclin-dependent kinase inhibitors (10). So, the development of library
*Corresponding author. Email: kidwai.chemistry@gmail.com
ISSN 1741-5993 print/ISSN 1741-6000 online
© 2011 Taylor & Francis
DOI: 10.1080/17415993.2010.533773
http://www.informaworld.com

38 M. Kidwai et al.
of 2-aminothiazoles might furnish additional lead molecules for the drug discovery. In view of the
importance of 2-aminothiazoles and its derivatives, several methods have been reported for their
synthesis in the literature (11). Some of these procedures have some major shortcomings such
as low yield, high reaction temperatures, involvement of expensive, moisture and air-sensitive
catalysts, tedious purification process and hazardous solvents. These processes also generate
waste-containing solvent, catalysts, which have to be recovered, treated and disposed of. Despite
this wide range of methods available, still there is a need to search for more better catalysts with
regard to their toxicity, handling, availability, economic viability and operational simplicity.
Nafion-H, a perflourinated sulfonic acid resin, is a useful solid acid catalyst for a variety of
acid-catalyzed organic transformations (12). It consists of a polymeric backbone with highly
acidic sulfonic acid groups and possess hydrophobic (−CF2CF2) as well as hydrophilic regions
(−SO3H). The high catalytic activity of Nafion-H, its selectivity, recyclability, inertness, thermal
stability and ease of separation from the reaction mixture render it a very attractive candidate
(13). It has a catalytic activity comparable with that of Bronsted acids having H0 < −12 (13a)
(H0 = Hammett acidity function). Owing to all these qualities, it has been found to be a suitable
replacement for various homogeneous acid catalysts. Water and aqueous-based solvent systems
may represent an increasingly significant choice for the replacement of traditional solvents in
synthetic chemistry. A recent American Chemical Society Symposium volume highlighted some
aspects of the use of water and aqueous solutions in green chemistry (14); however, relatively
few articles have focused on the use of aqueous polyethylene glycol (PEG) solutions in organic
reactions.
In this article, we describe the use of simple and widely available polymer PEG as a benign
medium due to its low volatility, non-flammability, ease of work-up, ability to act as a phase-
transfer catalyst and a good reaction medium, inexpensive price and eco-friendly nature (15).
As a part of our ongoing research program to devise greener chemical transformations (16), we
reveal herein for the first time a simple, convenient and an efficient method for the prepara-
tion of 2-aminothiazoles using Nafion-H as a catalyst coupled with aqueous PEG-400 system
(Scheme 1).
Scheme 1. Synthesis of 2-aminothiazoles from α-bromoketones and thioureas.
2. Results and discussion
In an initial endeavor, a blank reaction was carried out using 1 equiv. each of phenacyl bromide
and thiourea. These were stirred at ambient temperature in ethanol. After 3 h, only 65% of the
expected product was obtained. The same reaction was then carried out using Nafion-H as a
catalyst under similar conditions. Surprisingly, a significant improvement was observed and the
yield was dramatically increased to 80% after stirring the mixture for only 20 min. To further
improve the yield and to optimize the reaction conditions, the same reaction was carried out
employing PEG as a solvent system. A remarkable improvement was observed and the yield

Journal of Sulfur Chemistry 39
increased up to 92% after stirring the mixture for only 15 min. With these optimistic results in
hand, we further investigated the best reaction conditions by using different ratios of PEG–water
solvent system. A decrease in the quantity of PEG from 100% to 60% increased the product yield
slightly from 92% to 96%. But a further decrease in the ratio of PEG decreased the product yield,
which is attributed to the loss of solubility of the reactants.
The effect of different solvents on the reaction rate as well as yields of products was also
examined (Table 1). Only acetonitrile afforded products in good yields with similar reaction
times. The reason for the low yield in some solvents is due to the inability of solvent to swell
Nafion-H which results in its low catalytic activities. Nafion-H being non-porous relies on the
solvation of the ionic groups by an appropriate solvent to form solvents channels and clus-
ters. The low yields are observed due to the failure of the substrate to be able to access the
catalyst (17).
For practical applications of the catalyst Nafion-H, the lifetime of the catalyst and its reusability
are important factors. The catalyst showed excellent recyclability in this reaction. The catalyst was
physically removed by forceps after the completion of the reaction. The catalyst was washed with
acetone, dried and reused as such for subsequent reactions (four runs) with fresh substrates under
same conditions. The reaction times and yield remained the same, without the loss of catalytic
activity (18). The catalyst still remained active after fourth run with 94% yield (Table 2).
Using the optimized conditions, the efficiency of this protocol was studied for the synthe-
sis of various 2-aminothiazoles.Variety of thioureas (electron-donating, electron-withdrawing)
exemplify the versatility of this protocol (Table 3).
A plausible mechanism for the synthesis of 2-aminothiazoles is shown in Scheme 2.
Table 1. Effect of solvent on the synthesis of 2-aminothiazole 3a.a
Solvents
Time (min)
Yield (%)b
Ethanol
Acetonitrile
THF
Toluene
Ethylene glycol
PEG-400
20
15
25
35
25
15
80
82
76
72
82
92
PEG:H2O
90:10
80:20
70:30
60:40
50:50
40:60
10
10
10
10
15
25
96
96
96
96
88
83
Notes: aReactionconditions:phenacylbromide(1 mmol), thiourea(1 mmol);catalyst:Nafion-H;
temp.: 50 ◦C. bIsolated yields.
Table 2. Recycling yields.a
Number of cyclesa
Fresh
Run 1
Run 2
Run 3
Run 4
Yield (%)b
Time (min)
96
10
96
10
96
10
96
10
94
10
Notes: aReaction conditions: phenacyl bromide (1 mmol), thiourea (1 mmol); catalyst: Nafion-H;
solvent: PEG:water (60:40) system; temp: 50 ◦C. bIsolated yields.

40 M. Kidwai et al.
Table 3. Nafion-H-promoted synthesis of 2-aminothiazoles.a
Entry
1
R1
R2
Product
Time (min)
10
M.P. (◦ C)
Yield (%)b
96
−
H
H
3a
114–118 (19)
−
2
3
3b
3c
15
20
126–128 (19)
134–136 (19)
96
96
Me
Me
4
5
3d
3e
10
20
164–166 (19)
162–166 (20)
97
94
6
7
8
9
3f
3g
3h
3i
8
10
15
10
174–176
134–138 (21)
160–164 (22)
136–140
96
96
96
93
Br
Br
MeO
MeO
Me
Me
10
11
12
3j
3k
3l
10
20
25
110–116 (23)
204–208 (24)
206–210
96
97
97
HO
O2N
Notes: aReaction conditions: substituted phenacyl bromide (1 mmol), N-substituted thiourea (1 mmol); catalyst: Nafion-H; solvent:
PEG:water (60:40) system; temp: 50 ◦C. bIsolated yields.
3. Conclusion
In summary, we have developed a new and highly efficient methodology for the synthesis of 2-
aminothiazoles in the presence of catalytic amounts of Nafion-H employing PEG: water solvent
system under very mild conditions. The simplicity/reuse of the catalyst due to its heterogeneous
nature, excellent yields of the products and ease of work-up make this protocol an attractive,
environmentally acceptable synthetic tool for the preparation of these substrates.
4. Experimental
4.1. Materials and methods
All chemicals were purchased from Sigma-Aldrich and were used as such. All reactions and
purity of 2-aminothiazoles were monitored by thin-layer chromatography (TLC) using aluminum
plates coated with silica gel F254 plates (Merck) using 20% ethyl acetate and 80% petroleum

Journal of Sulfur Chemistry 41
2
2
1
1
2
2
1
1
1
2
2
2
2
2
2
1
2
Scheme 2. Plausible mechanism for the Nafion-H catalyzed 2-aminothiazole synthesis.
ether as an eluent. The spots were detected either under UV light or by placing in an iodine
chamber. Melting points were determined using a Thomas Hoover melting point apparatus and
are uncorrected. IR spectra were recorded on a Perkin-Elmer FTIR-1710 spectrophotometer using
KBr as pastilles. 1H NMR and 13C NMR were recorded on a JEOL JNM-ECX 400P FT NMR
system using TMS as an internal standard. ESI-MS were recorded on waters LCT Micromass.
Elemental analysis was performed on a Hereaus CHN rapid analyzer. The temperature of the
reaction mixture was measured through a non-contact infrared minigun thermometer (AZ minigun
type, model 8868).
4.2. General procedure for the synthesis of 2-aminothiazoles
A 50 ml round-bottomed flask was filled with phenacyl bromide (1 mmol), thiourea (1 mmol)
and Nafion-H (1 bead) followed by 5 ml of PEG:water (60:40) solvent system. The mixture
was then stirred at 50◦C until the reaction was complete (TLC). Then to the reaction mixture,
50 ml of ice-cold water was added. The solid 2-aminothiazole product that separated out was
filtered, then washed with water and dried. The crude product, thus obtained was subjected to
purification by column chromatography on silica gel (100–200 mesh size) using 25% ethyl acetate
in petroleum ether as an eluent to yield 2-aminothiazoles, 3a–l. The structures of all products were
unambiguously established on the basis of spectral analysis (IR, 1HNMR, 13C NMR, mass spectral
data, elemental analysis) and melting point determination (19–24).
4.3. Regeneration of catalyst
The catalyst was washed successively with acetone and deionized water and then dried overnight
at 105◦C. The obtained catalyst had the same catalytic activity as the fresh catalyst.

42 M. Kidwai et al.
4.4. Spectral data for the synthesized 2-aminothiazole derivatives
4.4.1. 2-Amino-4-phenyl thiazole (3a)
White solid. IR (KBr) νmax cm−1: 3369, 3255, 1624, 1462, 1377, 769, 689. 1H NMR (DMSO-d6,
400 MHz): δ = 6.96 (s, 1H, −CH), 8.34 (br s, 2H, NH2), 7.35–7.58 (m, 5H, Ar-H).13C NMR
(DMSO-d6, 75 MHz): δ = 101.74, 125.43, 128.07, 128.66, 129.22, 138.75, 170.17. m/z (ESI-
MS, HRMS): 176.332 (M+). C9H8N2S: Calcd. C, 61.33; H, 4.57; N, 15.8; found C, 61.24; H,
4.61; N, 15.7.
4.4.2. 2-Amino-4-(4ꢀ-methylphenyl) thiazole (3b)
1
Creamy white solid. IR (KBr) νmax cm−1: 3383, 3264, 1627, 1570, 1377, 765, 653. H NMR
(DMSO-d6, 400 MHz): δ = 6.81 (s, 1H, −CH), 8.87 (br s, 2H, NH2), 2.31 (s, 3H, Me), 7.18–7.48
(m, 4H,Ar-H).13C NMR (DMSO-d6, 75 MHz): δ = 20.49, 99.09, 124.30, 124.79, 129.03, 138.24,
139.20, 169.82. m/z (ESI-MS, HRMS): 190.549 (M+). C10H10N2S: Calcd. C, 63.10; H, 5.3; N,
14.7; found C, 63.30; H, 5.12; N, 13.93.
4.4.3. 2-Phenylamino-4-phenyl thiazole (3c)
White solid. IR (KBr) νmax cm−1: 3256, 1602, 1542, 1444, 1246, 750, 706. H NMR (CDCl3,
1
400 MHz): δ = 6.76 (s, 1H, -CH), 8.18 (br s, 1H, NH), 6.99-7.82 (m, 10H, Ar-H).13C NMR
(CDCl3, 75 MHz): δ = 101.54, 118.29, 122.99, 126.09, 127.90, 128.60, 129.34, 134.26, 140.18,
150.89, 164.98. m/z(ESI-MS, HRMS): 252.598 (M+). C15H12N2S: Calcd. C, 71.3; H, 4.8; N,
11.1; found C, 71.1; H, 5.01; N, 10.95.
4.4.4. 2-Phenylamino-4(4ꢀ-methylphenyl) thiazole (3d)
1
Light yellow solid. IR (KBr) νmax cm−1: 3246, 1599, 1462, 1326, 751, 692. H NMR (CDCl3,
400 MHz): δ = 6.66 (s, 1H, −CH), 8.59 (br s, 1H, NH), 2.36 (s, 3H, Me), 7.38–7.70 (m, 9H,
Ar-H).13C NMR (CDCl3, 75 MHz): δ = 21.29, 99.12, 119.50, 125.10, 125.80, 129.75, 139.33,
160.03. m/z (ESI-MS, HRMS): 266.878 (M+). C16H14N2S: Calcd. C, 72.10; H, 5.3; N, 10.6;
found C, 72.28; H, 5.12; N, 10.24.
4.4.5. 2-(1ꢀ-Naphthyl)-amino-4-phenyl thiazole (3e)
White solid. IR (KBr) νmax cm−1: 3179, 1560, 1420, 1396, 771, 708. 1H NMR (CDCl3, 400 MHz):
δ = 6.77 (s, 1H, −CH), 1.88 (br s, 1H, NH), 7.29−7.90 (m, 12H, Ar-H).13C NMR (CDCl3,
75 MHz): δ = 101.97, 118.55, 121.24, 125.64, 125.83, 126.01, 126.52, 127.86, 128.61, 134.51,
136.09, 152.76, 167.92. m/z (ESI-MS, HRMS): 302.089 (M+). C19H14N2S: Calcd. C, 75.47; H,
4.67; N, 9.26; found C, 75.23; H, 4.78; N, 9.11.
4.4.6. 2-(1ꢀ-Naphthyl)-amino-4(4ꢀꢀ-bromophenyl) thiazole (3f)
1
White solid. IR (KBr) νmax cm−1: 3054, 1544, 1397, 1105, 767, 680. H NMR (DMSO-d6,
400 MHz,): δ = 7.02 (s, 1H, −CH), 10.14 (br s, 1H, −NH), 7.45−7.74 (m, 11H, Ar-H).13C NMR
(DMSO-d6, 75 MHz,): 102.84, 121.80, 123.87, 125.41, 125.56, 125.81, 127.25, 127.89, 131.13,
146.76, 166.50. m/z (ESI-MS, HRMS): 379.965 (M+). C9H13BrN2S: Calcd. C, 59.85; H, 3.44;
N, 7.35; found C, 59.67; H, 3.27; N, 7.22.

Journal of Sulfur Chemistry 43
4.4.7. 2-(4ꢀ-Bromophenyl)-amino-4-phenyl thiazole (3g)
Light brown solid. IR (KBr) νmax cm−1: 3379, 1560, 1326, 818, 770, 706, 672. 1H NMR (DMSO-
d6, 400 MHz,): δ = 7.09 (s, 1H, −CH), 8.06 (br s, 1H, −NH), 7.36−7.86 (m, 11H, Ar-H).13C
NMR (DMSO-d6,75 MHz,): 102.13, 115.06, 119.54, 126.07, 126.45, 128.03, 128.66, 132.29,
134.24, 139.24, 151.75, 163.70. m/z (ESI-MS, HRMS): 329.275 (M+). C15H11BrN2S: Calcd. C,
54.39; H, 3.55; N, 8.46; found C, 54.20; H, 3.27; N, 8.22.
4.4.8. 2-(4ꢀ-Methoxyphenyl)-amino-4-phenyl thiazole (3h)
1
White solid. IR (KBr) νmax cm−1: 3383, 1565, 1305, 1245, 827, 768, 705. H NMR (CDCl3,
400 MHz,): δ = 6.75 (s, 1H, −CH), 1.74 (s, 3H, OMe), 1.74 (br s, 1H, −NH), 6.91-7.83 (m, 9H,
Ar-H).13C NMR (DMSO-d6,75 MHz,): 55.49, 101.14, 114.61, 122.08, 126.05, 127.73, 128.52,
133.64, 134.59, 151.31, 156.28, 167.18. m/z (ESI-MS, HRMS): 282.564 (M+). C16H14N2OS:
Calcd. C, 68.06; H, 5.00; N, 9.92; found C, 67.88; H, 4.84; N, 9.67.
4.4.9. 2-(4ꢀ-Methoxyphenyl)-amino-4(4ꢀꢀ-methylphenyl) thiazole (3i)
Yellow solid. IR (KBr) νmax cm−1: 3383, 1592, 1482, 1388, 769, 671. 1H NMR (CDCl3, 400 MHz):
δ = 3.82 (s, 3H, OMe), 2.37 (s, 3H, Me), 6.69 (s, 1H, −CH), 1.73 (s, 1H, −NH), 6.90–7.72
(m, 8H, Ar-H). 13C NMR (CDCl3, 75 MHz): δ = 21.29, 55.53, 98.87, 114.96, 122.94, 125.79,
128.36, 129.67, 131.68, 139.10, 146.51, 157.57, 167.99. m/z (ESI-MS, HRMS): 296.102 (M+).
C17H16N2OS: calcd. C, 68.89; H, 5.44; N, 9.45; found C, 68.73; H, 5.31; N, 9.34.
4.4.10. 2-(4ꢀ-Methylphenyl)-amino-4-phenylthiazole (3j)
1
White solid. IR (KBr) νmax cm−1: 3245, 1610, 1545, 1509, 1465, 1247, 824, 752, 669. H
NMR (CDCl3, 400 MHz): δ = 2.33 (s, 3H, Me), 6.79 (s, 1H, −CH), 6.69 (br s, 1H, −NH),
7.30–7.84(m, 9H,Ar-H). 13CNMR(CDCl3, 75 MHz):δ = 20.78, 101.44, 118.91, 126.06, 127.80,
128.58, 129.94, 132.95, 134.55, 137.80, 151.19, 165.47.m/z (ESI-MS, HRMS): 266.444 (M+).
C16H14N2S: Calcd. C, 72.15; H, 5.30; N, 10.52; found C, 71.89; H, 5.09; N, 10.22.
4.4.11. 2-(4ꢀ-Hydroxyphenyl)-amino-4-phenylthiazole (3k)
White solid. IR (KBr) νmax cm−1: 3322, 2917, 1542, 1436, 1244, 820, 750, 663. 1H NMR (DMSO-
d6, 400 MHz): δ = 6.74 (s, 1H, −CH), 8.61 (br s, 1H, −NH), 6.83–7.86 (m, 9H, Ar-H). 13C
NMR (DMSO-d6, 75 MHz): δ = 101.95, 116.53, 121.76, 126.83, 128.45, 129.34, 134.68, 135.90,
151.80, 167.66. m/z (ESI-MS, HRMS): 266.444 (M+). C15H12N2OS: Calcd. C, 67.14; H, 4.51;
N, 10.44; found C, 6728; H, 4.32; N, 10.27.
4.4.12. 2-(4ꢀ-Nitrophenyl)-amino-4-phenylthiazole (3l)
1
Orange solid. IR (KBr) νmax cm−1: 3302, 2922, 1533, 1306, 1264, 1180. H NMR (DMSO-
d6, 400 MHz): δ = 6.99 (s, 1H, −CH), 10.47 (br s, 1H, −NH), 7.39-8.22 (m, 9H, Ar-H). 13C
NMR (DMSO-d6, 75 MHz): δ = 103.21, 115.84, 124.98, 125.57, 127.52, 128.25, 134.01, 140.29,
146.76, 151.01, 161.65. m/z (ESI-MS, HRMS): 297.062 (M+). C15H11N3O2S: Calcd. C, 60.59;
H, 3.73; N, 14.13; found C, 60.45; H, 3.62; N, 14.23.

44 M. Kidwai et al.
Acknowledgements
Ritika Chauhan and Divya Bhatnagar would like to express their thanks to the Director of University Science and
Instrumentation Centre, University of Delhi, Delhi, for providing the spectral analysis. They also thank the Department
of Chemistry, University of Delhi, for financial assistance.
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