Efficient synthesis of 2-aminothiazoles and fanetizole in liquid PEG-400 at ambient conditions

Article abstract of DOI:10.1002/jccs.200900068

A simple and practical procedure for the synthesis of 2-aminothiazoles from α-tosyloxyketones and thioureas is described using PEG-400[poly(ethylene glycol-400)] at ambient conditions. The developed protocol is successfully applied for the preparation of an anti-inflammatory drug, Fanetizole.

Full text of DOI:10.1002/jccs.200900068

Journal of the Chinese Chemical Society, 2009, 56, 455-458
455
Communication
Efficient Synthesis of 2-Aminothiazoles and Fanetizole in Liquid PEG-400
at Ambient Conditions
Pei-Ying Lina (
), Rei-Sheu Houb* (
), Huey-Min Wangb (
),
Iou-Jiun Kangc (
) and Ling-Ching Chena* (
)
aGraduate Institute of Pharmaceutical Sciences, College of Pharmacy, Kaohsiung Medical University,
Kaohsiung 807, Taiwan, R.O.C.
bChung Hwa University of Medical Technology, Tainan 717, Taiwan, R.O.C.
cDivision of Biotechnology and Pharmaceutical Research, National Health Research Institutes,
Miaoli County 350, Taiwan, R.O.C.
A simple and practical procedure for the synthesis of 2-aminothiazoles from a-tosyloxyketones and
thioureas is described using PEG-400[poly(ethylene glycol-400)] at ambient conditions. The developed
protocol is successfully applied for the preparation of an anti-inflammatory drug, Fanetizole.
Keywords: 2-Aminothiazoles; Poly(ethylene glycol); Ambient temperature.
INTRODUCTION
The thiazole ring system is a useful structural motif
solvent medium support for various transformations.16 In
recent times ionic liquids have been in the forefront of re-
search, and several publications and reviews have already
appeared.17 Even though ionic liquids offer some advan-
tages, the tedious preparation of ionic liquids (and raw ma-
terials for ionic liquids) and their environmental safety is
still debated. Compared with PEG, however, toxicity and
environmental burden data of ionic liquids are for the most
part unknown. Furthermore, the cost of ionic liquids is of-
ten more expensive than that of PEG.18 To date some of the
more important reactions have been carried out and investi-
gated in PEG, for example, Heck reaction,19 catalytic hy-
drogenations,20 asymmetric dihydroxylation reaction,21
Baylis-Hillman reaction,22 Biginelli reaction,23 Suzuki-
Miyaura reaction, Stille cross-coupling reaction,24 Wacker
reaction,25 and asymmetric aldol reaction,26 etc.
found in numerous biologically active molecules. This
structure has found applications in drug development for
the treatment of allergies,1 hypertension,2 inflammation,3
schizophrenia,4 bacterial,5 and HIV6 infections. Amino-
thiazoles are known to be ligands of estrogen receptors7 as
well as a novel class of adenosine receptor antagonists8
whereas other analogues are used as fungicides, inhibiting
in vivo growth of Xanthomonas and as an ingredient of her-
bicides 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 thio-
ureas or thioamides provides a useful method for the syn-
thesis of thiazoles.10 Solid supported synthesis have been
used to generate small organic libraries11 and solution
phase preparation of combinatorial libraries have been pre-
pared in DMF12 as well as in dioxane.13 Recently, amino-
thiazoles were synthesized by using b-cyclodextrin in wa-
ter.14 However, in spite of their potential utility, many of
these reported methods suffer from drawbacks such as
harsh reaction conditions, unsatisfactory yields, cumber-
some product isolation procedures, and polar/volatile/haz-
ardous organic solvents.
RESULTS AND DISCUSSION
As shown in Scheme I, the scope of the cycloconden-
sation of various a-tosyloxyketones (1) with thioureas (2)
in PEG-400 was investigated. We found that the cyclocon-
densation of a-tosyloxyketones (1) with thioureas (2) oc-
curred easily in PEG-400 at room temperature in the pres-
ence of sodium carbonate to form the corresponding 2-ami-
nothiazoles (3). The results are summarized in the Table 1.
When the reaction was conducted in the classical molecular
solvent, such as acetonitrile, the preparation of 4-phenyl-
thiazol-2-amine (3a) needs refluxing for 5 h. But, the same
Poly(ethylene golycol) (PEG),15 a biologically ac-
ceptable polymer used extensively in drug delivery and in
bioconjugates as tools for diagnostics has been used as a

456 J. Chin. Chem. Soc., Vol. 56, No. 3, 2009
Lin et al.
Scheme I
S
2
O
N
Ar
PEG-400, r.t.
NHR
Na2CO3
OTs
Ar
H2N
NHR
S
1
3
a, R = H
b, R =C6H5
c, R =C6H5CH2
d, R =C6H5CH2CH2
Table 1. Synthesis of 2-aminothiazoles 3a-m in PEG-400
Table 2. Effect of solvent on the cyclocondensation of a-
toxyloxyacetophenone (1) with thiourea (2a) to form 4-
phenylthiazol-2-amine (3a)
Entry
Product
Ar
C6H5
4-MeOC6H4
4-FC6H4
C6H5
4-MeOC6H4
4-FC6H4
C6H5
4-MeOC6H4
4-FC6H4
C6H5
R
Yield (%)
1
2
3
4
5
6
7
8
3a
3b
3c
3d
3e
3f
H
H
H
C6H5
C6H5
94
90
87
92
85
89
91
86
88
92
86
85
93
Reaction
temperature (°C) time (h)
Reaction
Entry
Solvent
Yield (%)
1
2
MeCN
PEG-400
80
25
5
1
80
94
C6H5
3g
3h
3i
C6H5CH2
C6H5CH2
C6H5CH2
C6H5CH2CH2
condition, high yields and green aspects such as avoiding
hazardous organic solvents, toxic catalysts and waste, ease
of recovery and reuse of this novel reaction medium. The
successful application of this protocol for the preparation
of the anti-inflammatory drug fanetizole is a significant
contribution for the development of a green commercial
process for the same.
9
10
11
12
13
3j
3k
3l
4-MeOC6H4 C6H5CH2CH2
4-FC6H4
2-Furyl
C6H5CH2CH2
C6H5CH2CH2
3m
reaction was successful in PEG-400 at room temperature in
only 1 h, and gave a higher yield (Table 2).
EXPERIMENTAL SECTION
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 treat-
ment of rheumatoid arthritis.27 Generally, fanetizole has
been synthesized by using stringent reaction conditions
such as microreactors and heating in solvents such as
DMF28 and NMP.29 We applied our protocol for the synthe-
sis of the anti-inflammatory drug fanetizole. For this, we
treated a-tosyloxyketone with 2-phenylethyl thiourea (2d)
in PEG-400 as reaction medium under similar conditions to
afford fanetizole 3j in 92% yield in 1 h at ambient tempera-
ture (Table 1).
All melting points are uncorrected. The IR spectra
were recorded on a Shimadzu IR-27 G spectrophotometer.
1H NMR and 13C NMR spectra were recorded on a Varian
Unity Plus 400 MHz. Chemical shifts (d) were measured in
ppm with respect to TMS. MS were obtained on a JEOL
JMS D-300 instrument.
Typical one-pot procedure for the synthesis of 4-
phenylthiazol-2-amine (3a)
a-Toxyloxyacetophenone (1) (290 mg, 1.0 mmol),
thiourea (2a) (76 mg, 1.0 mmol) and sodium carbonate
(106 mg, 1.0 mmol) were added to PEG-400 (2 g). The re-
sulting mixture was stirred at room temperature for 1 h.
Subsequently, the reaction mixture was extracted with Et2O
(3 ´ 5 mL). The remaining PEG suspension was filtered
and reused for further runs. The combined ethereal solution
was evaporated under reduced pressure. The resulting resi-
due was chromatographed on silica gel using ethyl acetate
as eluent to give 3a, mp 148-149 °C (Lit.,30 150-151 °C). IR
The PEG-400 can be typically recovered by extract-
ing out the product first and the recovered solvent can be
reused without loss activity.
In conclusion, we have described a novel and effi-
cient method for the synthesis of 2-aminothiazole using
PEG-400 as reaction medium. The important features of
this procedure are enhanced reaction rate, mild reaction

Synthesis of 2-Aminothiazoles and Fanetizole
J. Chin. Chem. Soc., Vol. 56, No. 3, 2009 457
(KBr) n: 3432, 3112, 1596, 1480, 1333, 712 cm-1; 1H NMR
(CDCl3) d: 5.29 (s, 2H), 6.71 (s, 1H), 7.25-7.31 (m, 1H),
7.35-7.40 (m, 2H), 7.75-7.78 (m, 2H).
(CDCl3) d: 2.81 (t, J = 7.4 Hz, 2H), 3.42 (dd, J = 6.8, 10.8
Hz, 2H), 6.32 (s, 1H), 6.64 (s, 1H), 7.08 (d, J = 6.8 Hz, 2H),
7.15-7.28 (m, 4H), 7.34-7.37 (m, 2H), 7.77-7.80 (m, 2H).
4-(4-Methoxyphenyl)-N-phenethylthiazol-2-amine (3k)
mp 118-119 °C (Lit.,30 121-122 °C). IR (KBr) n:
3214, 2947, 1580, 1489, 1456, 1327, 688 cm-1; 1H NMR
(CDCl3) d: 2.90 (t, J = 7.2 Hz, 2H), 3.50 (dd, J = 6.6, 10.8
Hz, 2H), 3.80 (s, 3H), 5.70 (s, 1H), 6.54 (s, 1H), 6.90 (dd, J
= 2.8, 12.0 Hz, 2H), 7.16-7.31 (m, 5H), 7.72 (dd, J = 3.0,
11.6 Hz, 2H).
4-(4-Methoxyphenyl)thiazol-2-amine (3b)
mp 203-204 °C (Lit.,30 206-207 °C). IR (KBr) n:
3437, 3115, 1625, 1490, 1326, 696 cm-1; 1H NMR (CDCl3)
d: 3.83 (s, 3H), 5.06 (s, 2H), 6.59 (s, 1H), 6.91 (td, J = 2.4,
9.2 Hz, 2H), 7.71 (td, J = 2.4, 8.8 Hz, 8H).
4-(4-Fluorophenyl)thiazol-2-amine (3c)
mp 101-102 °C (Lit.,30 102-103 °C). IR (KBr) n:
3441, 3115, 1627, 1485, 1335, 685 cm-1; 1H NMR (CDCl3)
d: 5.48 (s, 2H), 6.61 (s, 1H), 7.02-7.08 (m, 2H), 7.69-7.74
(m, 2H).
4-(4-Fluorophenyl)-N-phenethylthiazol-2-amine (3l)
mp 111-112 °C (Lit.,30 108-109 °C). IR (KBr) n:
3195, 2959, 1580, 1491, 1327, 687 cm-1; 1H NMR (CDCl3)
d: 2.87 (t, J = 7.0 Hz, 2H), 3.48 (dd, J = 6.4, 10.4 Hz, 2H),
5.91 (s, 1H), 6.58 (s, 1H), 7.04 (t, J = 8.8 Hz, 2H), 7.15-
7.29 (m, 5H), 7.75 (dd, J = 5.2, 8.4 Hz, 2H).
N-Phenyl-4-phenylthiazol-2-amine (3d)
mp 132-133 °C (Lit.,30 135-136 °C). IR (KBr) n:
3226, 2952, 1601, 1498, 1313, 697 cm-1; 1H NMR (CDCl3)
d: 6.78 (s, 1H), 6.99-7.03 (m, 1H), 7.24-7.29 (m, 5H),
7.33-7.37 (m, 2H), 7.84 (d, J = 7.6 Hz, 2H), 8.28 (s, 1H).
N-Phenyl-4-(4-methoxyphenyl)thiazol-2-amine (3e)
mp 140-141 °C (Lit.,30 138-139 °C). IR (KBr) n:
3347, 2986, 1600, 1484, 1316, 689 cm-1; 1H NMR (CDCl3)
d: 3.85 (s, 3H), 6.67 (s, 1H), 6.89-6.93 (m, 2H), 7.02-7.05
(m, 1H), 7.29-7.35 (m, 4H), 7.76-7.78 (m, 2H), 7.94 (d, J =
9.2 Hz, 1H).
4-(2-Furyl)-N-phenethylthiazol-2-amine (3m)
mp 88-89 °C. IR (KBr) n: 3080, 1614, 1521, 1080
cm-1; 1H NMR (CDCl3) d: 2.87 (t, J = 7.0 Hz, 2H), 3.54 (dd,
J = 6.8, 12.8 Hz, 2H ), 5.36 (s, 1H), 6.43 (dd, J = 1.8, 3.6
Hz, 1H), 6.62 (d, J = 3.6 Hz, 1H), 6.67 (s, 1H), 7.21-7.26
(m, 3H), 7.30-7.34 (m, 2H), 7.38 (s, 1H); 13C NMR (CDCl3,
100 MHz) d: 35.3, 47.1, 100.3, 106.2, 111.2, 126.7, 128.7,
128.8, 138.2, 141.7, 143.0, 150.5, 169.6; EI-MS m/z (rela-
tive intensity) 270 (M+), 179, 166, 151. Anal. Calcd for
C15H16N2OS: C, 66.15; H, 5.92; N, 10.29. Found: C, 66.28;
H, 5.75; N, 10.38.
N-Phenyl-4-(4-fluorophenyl)thiazol-2-amine (3f)
mp 107-108 °C (Lit.,30 110-111 °C). IR (KBr) n:
3232, 2925, 1592, 1488, 1318, 688 cm-1; 1H NMR (CDCl3)
d: 6.71 (s, 1H), 7.01-7.06 (m, 3H), 7.28-7.30 (m, 4H),
7.77-7.82 (m, 2H), 8.17 (s, 1H).
ACKNOWLEDGEMENT
N-Benzyl-4-phenylthiazol-2-amine (3g)
We gratefully acknowledge the National Council Sci-
ence of Republic of China for financial support of this
work.
mp 95-96 °C (Lit.,31 100-101 °C). IR (KBr) n: 3215,
2969, 1570, 1482, 1443, 1332, 720 cm-1; 1H NMR (CDCl3)
d: 4.38 (s, 2H), 6.61 (s, 1H), 6.90 (s, 1H), 7.18-7.30 (m,
8H), 7.75-7.77 (m, 2H).
Received February 27, 2009.
N-Benzyl-4-(4-methoxyphenyl)thiazol-2-amine (3h)
mp 84-85 °C (Lit.,31 83-84 °C). IR (KBr) n: 3214,
2971, 1576, 1488, 1415, 1331, 687 cm-1; 1H NMR (CDCl3)
d: 3.80 (s, 3H), 4.40 (s, 2H), 6.50 (s, 1H), 6.73 (s, 1H),
6.79-6.83 (m, 2H), 7.25-7.34 (m, 5H), 7.68-7.71 (m, 2H).
N-Benzyl-4-(4-fluorophenyl)thiazol-2-amine (3i)
mp 112-113 °C (Lit.,30 109-110 °C). IR (KBr) n:
3223, 2971, 1586, 1487, 1324, 693 cm-1; 1H NMR (CDCl3)
d: 4.44 (s, 2H), 6.38 (s, 1H), 6.58 (s, 1H), 6.96-7.02 (m,
2H), 7.23-7.34 (m, 5H), 7.71-7.76 (m, 2H).
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