Catalyst-free efficient synthesis of 2-aminothiazoles in water at ambient temperature

Article abstract of DOI:10.1016/j.tet.2008.03.082

A highly efficient and facile method has been described for the synthesis of substituted 2-aminothiazoles in water without any added catalyst or co-organic solvent. The reaction was carried out at ambient temperature and the products were obtained in excellent isolated yields. The developed protocol is successfully applied for the preparation of an anti-inflammatory drug, fanetizole.

Full text of DOI:10.1016/j.tet.2008.03.082

Tetrahedron 64 (2008) 5019–5022
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journal homepage: www.elsevier.com/locate/tet
Catalyst-free efficient synthesis of 2-aminothiazoles in water
at ambient temperature
*
Taterao M. Potewar, Sachin A. Ingale, Kumar V. Srinivasan
Division of Organic Chemistry, National Chemical Laboratory, Dr. Homi Bhabha Road, Pune 411 008, Maharashtra, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A highly efficient and facile method has been described for the synthesis of substituted 2-aminothiazoles
in water without any added catalyst or co-organic solvent. The reaction was carried out at ambient
temperature and the products were obtained in excellent isolated yields. The developed protocol is
successfully applied for the preparation of an anti-inflammatory drug, fanetizole.
Ó 2008 Elsevier Ltd. All rights reserved.
Received 21 January 2008
Received in revised form 20 March 2008
Accepted 23 March 2008
Available online 28 March 2008
Keywords:
2-Aminothiazoles
Environment-friendly synthesis
Water
Ambient temperature
1. Introduction
water,15 iodine,16 and by the use of microwave in ethanol.17
However, in spite of their potential utility, many of these reported
The thiazole ring system is a useful structural motif found in
numerous biologically active molecules. Thiazole ring is a structural
component of natural compounds such as vitamin B1 (thiamine),
penicillin, and carboxylase. The 2-aminothiazole ring system is
a useful structural element in medicinal chemistry having appli-
cation in drug development for the treatment of allergies,1 hyper-
tension,2 inflammation,3 schizophrenia,4 bacterial,5 and HIV6
infections. Aminothiazoles are known to be ligands of estrogen
receptors7 as well as a novel class of adenosine receptor antago-
nists8 whereas other analogues are used as fungicides, inhibiting in
vivo growth of Xanthomonas, and as an ingredient of herbicides or
as schistosomicidal and anthelmintic drugs.9
In view of the importance of 2-aminothiazole and its
derivatives, several methods were reported in the literature.
Hantzsch reaction of a-halocarbonyl compounds with thioureas or
thioamides provides a useful method for the synthesis of thi-
azoles.10 Solid supported synthesis have been used to generate
small organic libraries11 and solution phase preparation of com-
binatorial libraries have been prepared in DMF12 as well as in
dioxane.13 Recently, many improved methods have been reported
for the synthesis of thiazoles using catalyst such as ammonium-
12-molybdophosphate (AMP) in methanol,14 b-cyclodextrin in
methods suffer from drawbacks such as harsh reaction conditions,
unsatisfactory yields, cumbersome product isolation procedures,
polar/volatile/hazardous organic solvents, and often expensive
catalysts. These processes also generate waste-containing sol-
vent and catalysts, which have to be recovered, treated, and
disposed of.
The organic reactions in aqueous media have attracted much
attention in synthetic organic chemistry, not only because water is
one of the most abundant, cheapest, and environmentally friendly
solvent but also because water exhibits unique reactivity and se-
lectivity, which is different from those obtained in conventional
organic solvents. Thus, elements of novel reactivity as well as
selectivity that cannot be attained in conventional organic solvents
is one of the challenging goals of aqueous chemistry.18 The signifi-
cant enhancement in the rate of reaction has been attributed to
hydrophobic packing, solvent polarity, hydration, and hydrogen
bonding.19 Thus, the use of water instead of organic solvents has
gained importance as an essential component of the development
of sustainable chemistry.20 Our recent results obtained during the
synthesis of benzodiazepines promoted by water21 prompted us to
investigate the heterocyclization reaction for the synthesis of
biologically active heterocycles using water as a solvent. In con-
tinuation to our research devoted to development of green organic
processes for the synthesis of biologically active heterocycles,
herein we report an efficient and facile method for the synthesis of
2-aminothiazoles in water.
* Corresponding author. Tel.: þ91 20 2590 2098; fax: þ91 20 2590 2629.
E-mail address: kv.srinivasan@ncl.res.in (K.V. Srinivasan).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.03.082

5020
T.M. Potewar et al. / Tetrahedron 64 (2008) 5019–5022
2. Result and discussion
thiourea/substituted thiourea equally well to afford the corre-
sponding 2-aminothiazoles in excellent isolated yields. Further-
more, a-bromo-2-acetonaphthone smoothly reacted with thiourea
and substituted thiourea affording the corresponding products
3r–v in excellent yields (Table 1, entries 18–22).
When phenacyl bromide was treated with thiourea in water at
room temperature, to our surprise, the reaction occurred affording
4-phenylthiazol-2-amine 3a in 97% yield in just 1.5 h (Scheme 1).
The experimental procedure is very simple and easy to carry out.
A mixture of phenacyl bromide and thiourea was vigorously stirred
in water at room temperature until completion of the reaction.
Progress of reaction was monitored by thin layer chromatography
using ethyl acetate/petroleum ether in appropriate proportions as
eluent. Extraction in ethyl acetate followed by evaporation of
solvent gave crude products, which were purified by column
chromatography to yield pure products in excellent yields. All the
products were characterized by IR, melting point, 1H and 13C NMR
spectral analyses, and elemental analyses. The structure of all the
known compounds were further confirmed by comparing their
melting points with those reported in the literature. Complete
characterization data for all the new compounds are given in
Section 4.
N-Phenethyl-4-phenylthiazol-2-amine, commonly known as
fanetizole is an anti-inflammatory agent that was reported to have
reached phase II clinical trails for the treatment of rheumatoid
arthritis.23 Generally, fanetizole has been synthesized by using
stringent reaction conditions such as microreactors and heating in
solvents such as DMF and NMP. We applied our protocol for the
synthesis of the anti-inflammatory drug fanetizole 3d. For this, we
treated phenacyl bromide with 2-phenylethyl thiourea in water as
reaction medium under similar conditions to afford fanetizole in
92% yield in 1.5 h at ambient temperature (Table 1, entry 4).
Despite the various methods reported for the synthesis of the
2-aminothiazoles by using various organic solvents such as ethanol,
methanol, DMF, acetone, etc. with or without catalyst, there has
been considerable interest in the development of alternative
approaches avoiding the use of volatile polar organic solvents and
expensive catalyst. An alternative to this is the use of water as
reaction medium since water has emerging as one of the ‘Green
solvents’ in organic synthesis. To the best of our knowledge, this is
the first approach for the synthesis of 2-aminothiazoles carried out
in water at ambient temperature. It can be observed that almost all
S
O
N
Water
rt
1-2 h
Ar
NHR
+
Br
H2N
NHR
Ar
S
1
2
3
89-97%
R=H, Me, C6H5, C6H5CH2,
C6H5CH2CH2
Scheme 1. Synthesis of 2-aminothiazoles in water.
To investigate the advantageous role of water as a solvent for
this method, comparative reactions were carried out in other sol-
vents. The reaction of phenacyl bromide and thiourea was carried
out in CH2Cl2 and toluene under similar reaction conditions where
it furnished the desired 4-phenylthiazol-2-amine (3a) in yields of
only 48 and 12%, respectively. When the same reaction was carried
out in more polar solvents such as THF, MeCN, and MeOH under
identical conditions, 3a was obtained in yield of 68, 73, and 72%,
respectively. It is remarkable that the reaction carried out in water
afforded 4-phenylthiazol-2-amine (3a) in excellent yield (97%),
which is significantly higher than those obtained for the volatile/
toxic/polar organic solvents. The structure of 3a was assigned on
the basis of 1H and 13C NMR spectral data and by comparison with
authentic samples prepared by literature procedure as well as by
our methods.22 The 1H NMR spectra of 3a shows a characteristic
peak at d 6.48 ppm corresponding to the hydrogen of thiazole ring,
whereas in the 13C NMR spectrum, the peak appearing of d 101.4
and 167.8 ppm corresponds to C-5 and C-2, respectively, of the
thiazole ring.
After optimizing the conditions, we next examined the scope
and generality of this method to other substrates using different
substituted phenacyl bromides and substituted thioureas. The
results are summarized in Table 1. The phenacyl bromide with
electron-rich functionality (entries 5–8) as well as electron-poor
functionality (entries 14–17) undergoes condensation reaction with
Table 1
Synthesis of 2-aminothiazoles in water
N
Ar
NHR
S
Entry
Ar
R
Product 3
Time (h)
Yielda (%)
Mp (ꢀC)
Lit. mp (ꢀC)
1
2
3
4
5
6
7
8
C6H5
C6H5
C6H5
C6H5
H
CH3
C6H5
C6H5CH2CH2
H
CH3
C6H5
C6H5CH2CH2
H
CH3
3a
3b
3c
3d
3e
3f
3g
3h
3i
1.5
2
1
1.5
1
1
1
1.5
2
2
1
1
1
2
2
1.5
2
1
2
2
97
94
96
92
89
93
96
97
93
93
96
96
95
97
92
90
91
94
89
90
93
92
150–151
136–137
135–136
116–117
206–207
138–139
138–139
121–122
102–103
136–137
110–111
109–110
108–109
189–190
156–157
122–124
102–103
153–154
123–124
149–150
131–132
125–126
150–15124
135–13624
136–13724
116–11722
204–20526
138–13924
139–14024
d
p-CH3–O–C6H4
p-CH3–O–C6H4
p-CH3–O–C6H4
p-CH3–O–C6H4
p-F–C6H4
p-F–C6H4
p-F–C6H4
p-F–C6H4
p-F–C6H4
m-O2N–C6H4
m-O2N–C6H4
m-O2N–C6H4
m-O2N–C6H4
b-C10H7
9
d
10
11
12
13
14
15
16
17
18
19
20
21
22
3j
3k
3l
137–13825
111–11225
d
C6H5
C6H5CH2
C6H5CH2CH2
H
CH3
C6H5
C6H5CH2
H
CH3
C6H5
C6H5CH2
C6H5CH2CH2
3m
3n
3o
3p
3q
3r
3s
3t
d
188–19026
d
d
d
152–15324
121–12224
147–14824
d
b-C10H7
b-C10H7
b-C10H7
b-C10H7
3u
3v
2
2
d
a
Isolated yield after column chromatography.

T.M. Potewar et al. / Tetrahedron 64 (2008) 5019–5022
5021
reactions were complete in 1–2 h in water without the need of any
added catalyst or co-organic solvents at ambient temperature.
Water itself promotes the reactions. The use of water as a clean,
inexpensive, and universal solvent combines features of both eco-
nomic and environmental advantages. The amount of water used in
the reaction did not have any significant influence on the overall
rate of the reaction and yields of products. This was confirmed by
scaling up the concentration from the present 2% solids (w/v) to
20% solids (w/v) in the case of 4-phenyl-2-aminothiazole and
fanetizole, respectively. The reactions went to completion in iden-
tical times and with the same isolated yields as for the diluted
reaction mixture. This observation assumes great significance for
optimizing reactor volumes during scale-up operations. A highly
efficient stirring is required for the success of these reactions. The
role of water as the reaction medium and its mechanism are still
not clear. Water, probably due to its unique abilities such as hy-
drogen bonding, high dielectric constant, and polarity appears to be
more efficient medium for this reaction. The good results obtained
following our simple procedure are a pleasant surprise in view of
the numerous catalysts employed in organic solvents to synthesize
this class of compounds.
4.2.1. 4-(4-Methoxyphenyl)-N-phenethylthiazol-2-amine (3h)
White solid; mp 121–122 ꢀC; Rf (15% ethyl acetate/petroleum
ether) 0.31; IR (KBr): 3228, 3019, 2958, 1549, 1492, 1333, 758 cmꢂ1
;
1H NMR (CDCl3, 200 MHz): d¼2.93–3.0 (t, J¼6.9 Hz, 2H, CH2), 3.51–
3.60 (q, J¼6.9 Hz, 2H, CH2N), 3.82 (s, 3H, OMe), 5.32 (br s, 1H, NH),
6.56 (s, 1H, thiazole H), 6.87–6.92 (d, J¼8.9 Hz, 2H, ArH), 7.21–7.37
(m, 5H, ArH), 7.69–7.74 (d, J¼8.9 Hz, 2H, ArH); 13C NMR (CDCl3,
50 MHz): d¼35.3, 47.1, 55.2, 98.8, 113.8, 126.5, 127.2, 127.8, 128.6,
128.7, 138.4, 151.1, 159.1, 169.5. Anal. Calcd for C18H18N2OS: C, 69.65;
H, 5.84; N, 9.02%. Found: C, 69.42; H, 5.95; N, 9.11%.
4.2.2. 4-(4-Fluorophenyl)thiazol-2-amine (3i)
Yellow solid; mp 102–103 ꢀC; Rf (40% ethyl acetate/petroleum
ether) 0.52; IR (KBr): 3489, 3019, 1601, 1537, 1490, 1333, 758 cmꢂ1
;
1H NMR (CDCl3, 200 MHz): d¼5.04 (br s, 2H, NH2), 6.64 (s, 1H,
thiazole H), 7.01–7.09 (m, 2H, ArH), 7.70–7.77 (m, 2H, ArH); 13C
NMR (CDCl3, 50 MHz): d¼102.1, 115.3, 115.5, 127.6, 127.6, 130.9,
150.1, 161.3, 163.3, 167.6. Anal. Calcd for C9H7FN2S: C, 55.65; H, 3.63;
N, 14.42%. Found: C, 55.73; H, 3.56; N, 14.53%.
4.2.3. N-Benzyl-4-(4-fluorophenyl)thiazol-2-amine (3l)
White solid; mp 109–110 ꢀC; Rf (15% ethyl acetate/petroleum
ether) 0.42; IR (KBr): 3213, 3019, 2977, 1578, 1546, 1490, 1336,
757 cmꢂ1; 1H NMR (CDCl3, 200 MHz): d¼4.49–4.51 (d, J¼5.0 Hz, 2H,
CH2), 5.69 (br s, 1H, NH), 6.62 (s, 1H, thiazole H), 6.98–7.09 (m, 2H,
ArH), 7.29–7.40 (m, 5H, ArH), 7.71–7.81 (m, 2H, ArH); 13C NMR
(CDCl3, 50 MHz): d¼49.7, 100.4, 115.1, 115.5, 127.4, 127.5, 127.6, 127.7,
128.6, 131.08, 131.1, 137.5, 150.3, 159.8, 164.7, 169.7. Anal. Calcd for
3. Conclusion
In conclusion, we have described a simple, highly efficient, and
facile protocol for the synthesis of 2-aminothiazole derivatives in
water as reaction medium at ambient temperature. This process
avoids the use of highly polar and toxic volatile organic solvents
such as DMF, dioxane, and methanol, and catalyst, with the water
itself playing the dual role of a solvent and promoter. Furthermore,
the procedure offers several advantages including improved yields,
simple experimental procedure, cleaner reactions, and low cost,
which makes it a useful and attractive strategy in view of economic
and environmental advantages. The successful application of this
protocol for the preparation of the anti-inflammatory drug faneti-
zole is a significant contribution for the development of a green
commercial process for the same.
C16H13FN2S: C, 67.58; H, 4.61; N, 9.85%. Found: C, 67.72; H, 4.49; N,
9.72%.
4.2.4. 4-(4-Fluorophenyl)-N-phenethylthiazol-2-amine (3m)
White solid; mp 108–109 ꢀC; Rf (15% ethyl acetate/petroleum
ether) 0.46; IR (KBr): 3209, 3019, 2959, 1578, 1551, 1491, 1327,
757 cmꢂ1
;
1H NMR (CDCl3, 200 MHz): d¼2.94–3.01 (t, J¼6.9 Hz,
2H), 3.52–3.62 (q, J¼6.9 Hz, 2H), 5.21 (br s, 1H, NH), 6.62 (s, 1H,
thiazole H), 6.99–7.10 (m, 2H, ArH), 7.21–7.37 (m, 5H, ArH), 7.70–
7.80 (m, 2H, ArH); 13C NMR (CDCl3, 50 MHz): d¼35.3, 47.0, 100.2,
115.1, 115.5, 126.6, 127.5, 127.7, 128.6, 128.7, 131.1, 131.2, 138.3, 150.5,
159.8, 164.7, 169.4. Anal. Calcd for C17H15FN2S: C, 68.43; H, 5.07; N,
9.39%. Found: C, 68.32; H, 5.18; N, 9.51%.
4. Experimental
4.1. General
1H NMR and 13C NMR spectra were recorded on a Bruker AV-200
spectrometer in CDCl3 and DMSO-d6 using TMS as internal stan-
dard. Infrared spectra were recorded with ATI MATT-SON RS-1 FTIR
spectrometer using KBr pellets. Elemental analyses were obtained
using a flash EA 1112 thermofinnigan instrument. Melting points
were recorded in open capillary on Buchi melting Point B-540
apparatus. All solvents and chemicals were of research grade and
were used as obtained from Merck and Lancaster. Column chro-
matography was performed using silica gel (60–120 mesh size). Tap
water (pH¼6.7) was used for the reaction.
4.2.5. N-Methyl-4-(3-nitrophenyl)thiazol-2-amine (3o)
Orange needles; mp 156–157 ꢀC; Rf (20% ethyl acetate/petro-
leum ether) 0.28; IR (KBr): 3431, 3019, 2923, 1591, 1565, 1534, 1517,
1353, 761 cmꢂ1
;
1H NMR (CDCl3, 200 MHz): d¼3.02–3.04 (d,
J¼5.12 Hz, 3H, Me), 5.39 (br s, 1H, NH), 6.86 (s, 1H, thiazole H), 7.48–
7.56 (t, J¼7.9 Hz, 1H, ArH), 8.09–8.13 (dd, J¼1.9 and 7.9 Hz, 2H, ArH),
8.63–8.65 (t, J¼1.9 Hz, 1H, ArH); 13C NMR (CDCl3, 50 MHz): d¼32.1,
103.0, 120.8, 122.1, 129.4, 131.7, 136.5, 148.5, 149.2, 170.8. Anal. Calcd
for C10H9N3O2S: C, 51.05; H, 3.86; N,17.86%. Found: C, 51.13; H, 3.77;
N, 17.92%.
4.2. General procedure for the synthesis of 2-aminothiazoles
4.2.6. 4-(3-Nitrophenyl)-N-phenylthiazol-2-amine (3p)
Yellow solid; mp 122–124 ꢀC; Rf (20% ethyl acetate/petroleum
A mixture of phenacyl bromide 1 (1 mmol) and thiourea 2
(1.1 mmol) was stirred in water (5 mL) at room temperature under
vigorous magnetic stirring for the specified time as mentioned in
Table 1. The progress of the reaction was monitored by TLC. After
completion of the reaction, the product was extracted using ethyl
acetate (2ꢁ15 mL). The organic layer was separated from aqueous
layer. The combined organic layer was dried over anhydrous mag-
nesium sulfate and evaporated under reduced pressure to obtain
the crude solid product. The crude product was further purified by
column chromatography using ethyl acetate/petroleum ether as
eluent to afford the pure product 3.
ether) 0.42; IR (KBr): 3019, 1602, 1543, 1519, 1498, 1352, 758 cmꢂ1
;
1H NMR (CDCl3, 200 MHz): d¼6.96 (s, 1H, thiazole H), 7.08–7.17 (m,
1H), 7.37–7.42 (m, 4H, ArH), 7.52–7.60 (t, J¼7.8 Hz,1H, ArH), 7.94 (br
s, 1H, NH), 8.12–8.20 (m, 2H), 8.66–8.88 (t, J¼1.8 Hz, 1H, ArH); 13C
NMR (CDCl3, 50 MHz): d¼103.7, 118.6, 120.8, 122.3, 123.5, 129.4,
129.5, 131.8, 135.7, 139.8, 148.0. Anal. Calcd for C15H11N3O2S: C,
60.59; H, 3.73; N, 14.13%. Found: C, 60.48; H, 3.81; N, 14.21%.
4.2.7. N-Benzyl-4-(3-nitrophenyl)thiazol-2-amine (3q)
Yellow solid; mp 102–103 ꢀC; Rf (20% ethyl acetate/petroleum
ether) 0.43; IR (KBr): 3227, 3020, 2977, 1548, 1518, 1495, 1351,

5022
T.M. Potewar et al. / Tetrahedron 64 (2008) 5019–5022
755 cmꢂ1
;
1H NMR (CDCl3, 200 MHz): d¼4.53–4.55 (d, J¼5.5 Hz,
References and notes
2H, CH2Ar), 5.67 (br s,1H, NH), 6.85 (s, 1H, thiazole H), 7.29–7.41 (m,
5H, ArH), 7.47–7.55 (t, J¼8.0 Hz, 1H, ArH), 8.08–8.13 (m, 2H, ArH),
8.63–8.64 (t, J¼1.9 Hz, 1H, ArH); 13C NMR (CDCl3, 50 MHz): d¼49.7,
103.2, 120.8, 122.0, 127.6, 127.7, 128.7, 129.3, 131.6, 136.4, 137.3,
148.5, 148.9, 169.5. Anal. Calcd for C16H13N3O2S: C, 61.72; H, 4.21; N,
13.50%. Found: C, 61.83; H, 4.13; N, 13.39%.
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ether) 0.46; IR (KBr): 3205, 3019, 2976, 1601, 1549, 1515, 1490, 1350,
757 cmꢂ1; 1H NMR (CDCl3, 200 MHz): d¼4.54–4.56 (d, J¼4.7 Hz, 2H,
CH2Ar), 5.73 (s, 1H, NH), 6.83 (s, 1H, thiazole H), 7.29–7.45 (m, 7H,
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C
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4.2.9. 4-(Naphthalen-2-yl)-N-phenethylthiazol-2-amine (3v)
Yellow solid; mp 125–126 ꢀC; Rf (15% ethyl acetate/petroleum
ether) 0.39; IR (KBr): 3201, 3019, 2965, 1583, 1556, 1496, 1357,
757 cmꢂ1; 1H NMR (CDCl3, 200 MHz): d¼2.96–3.03 (t, J¼6.9 Hz, 2H,
CH2), 3.56–3.66 (q, J¼6.9 Hz, 2H, CH2), 5.32 (br s, 1H, NH), 6.83 (s,
1H, thiazole H), 7.20–7.50 (m, 7H, ArH), 7.77–7.89 (m, 4H, ArH), 8.32
(s, 1H, ArH); 13C NMR (CDCl3, 50 MHz): d¼35.4, 47.2, 101.3, 124.0,
124.9, 125.8, 126.1, 126.6, 127.6, 128.0, 128.3, 128.6, 128.7, 132.1,
132.9, 133.6, 138.3, 151.4, 169.5. Anal. Calcd for C21H18N2S: C, 76.33;
H, 5.49; N, 8.48%. Found: C, 76.43; H, 5.35; N, 8.57%.
Acknowledgements
T.M.P. thanks CSIR, New Delhi, for the award of Research
Fellowship.
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Supplementary data
1H and 13C NMR spectra associated with this article are pro-
vided. Supplementary data associated with this article can be found
in the online version, at doi:10.1016/j.tet.2008.03.082.
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