Efficient synthesis of 2,4-disubstituted thiazoles using ionic liquid?under ambient conditions: a practical approach towards?the?synthesis of Fanetizole

Article abstract of DOI:10.1016/j.tet.2007.08.036

A highly efficient and rapid synthesis of 2-amino-4-arylthiazoles and 2-methyl-4-arylthiazole from α-bromoketone and thiourea/thioamide is described using room temperature ionic liquid at ambient conditions. The method is simple, rapid and practical, generating thiazole derivatives in excellent isolated yields. This protocol is utilized for a commercially feasible synthesis of an anti-inflammatory agent, Fanetizole.

Full text of DOI:10.1016/j.tet.2007.08.036

Tetrahedron 63 (2007) 11066–11069
Efficient synthesis of 2,4-disubstituted thiazoles using ionic
liquid under ambient conditions: a practical approach
towards the synthesis of Fanetizole
*
Taterao M. Potewar, Sachin A. Ingale and Kumar V. Srinivasan
Division of Organic Chemistry: Technology, National Chemical Laboratory, Dr. Homi Bhabha Road, Pune – 411 008,
Maharashtra, India
Received 14 May 2007; revised 26 July 2007; accepted 10 August 2007
Available online 15 August 2007
Abstract—A highly efficient and rapid synthesis of 2-amino-4-arylthiazoles and 2-methyl-4-arylthiazole from a-bromoketone and thiourea/
thioamide is described using room temperature ionic liquid at ambient conditions. The method is simple, rapid and practical, generating
thiazole derivatives in excellent isolated yields. This protocol is utilized for a commercially feasible synthesis of an anti-inflammatory agent,
Fanetizole.
Ó 2007 Published by Elsevier Ltd.
1. Introduction
In view of the importance of thiazoles and their derivatives,
several methods for the synthesis of thiazole derivatives
were developed by Hantzsch, Tchernic, Cook-Heilborn,
Gabriel and other groups. The most wildly used method is
Hantzsch synthesis,9,10 who originated it in 1887, involving
the reaction of a-halo carbonyl compounds with thioureas
or thioamides. Recently, thiazole derivatives were synthe-
sized by using catalyst such as ammonium 12-molybdophos-
phate,11 cyclodextrin,13 iodine14a and silica chloride14b in
organic solvents at elevated temperature and solvents such
as 1-methyl-2-pyrrolidinone,12 and with the use of micro-
wave.15 However, in spite of their potential utility, many of
these reported methods suffer from drawbacks such as harsh
reaction conditions, unsatisfactory yields, prolonged reaction
time, cumbersome product isolation procedures, polar, vola-
tile and hazardous organic solvents and often expensive cata-
lysts. These processes also generatewaste-containing solvent
and catalysts, which have to be recovered, treated and dis-
posed of. The development of efficient and environmentally
friendly chemical processes for the preparation of biologi-
cally active molecules constitutes a major challenge for
chemists in organic synthesis. In this context, in recent times,
room temperature ionic liquids (RTIL), especially those
based on the 1,3-di-alkylimidazolium salts, have shown great
promise as an attractive alternative to conventional solvents.
They possess the unique advantages of high thermal stability,
negligible vapour pressure, immiscibility with a number of
organic solvents and recyclability.16 In many cases, the prod-
ucts are weakly soluble in the ionic phase so that the products
can be easily separated by simple extraction. We have re-
cently shown that they can promote and catalyze organic
transformations particularly heterocyclization. The various
Thiazole and its derivatives are very useful compounds in
various fields of chemistry including medicine and agricul-
ture. For example, the thiazolium ring present in vitamin
B1 serves as an electron sink, and its coenzyme form is
important for the decarboxylation of a-keto acids.1 This
heterocyclic system has found broad application in drug
development for the treatment of inflammation,2 hyperten-
sion,3 bacterial4 and HIV infections.5 Aminothiazoles are
known to be ligands of estrogen receptors6 as well as a novel
class of adenosine receptor antagonists.7 Other analogues are
used as fungicides, inhibiting in vivo growth of Xanthomo-
nas, as an ingredient of herbicides or as schistosomicidal
and anthelmintic drugs.8 Fanetizole, a derivative of 2-amino-
thiazole is an anti-inflammatory agent. In addition, thiazoles
are also synthetic intermediates and common substructures
in numerous biologically active compounds. Thus the thi-
azole nucleus has been much studied in the field of organic
and medicinal chemistry.
H
NH2
N
N
N
R1
S
S
R2
2-Aminothiazole
Fanetizole
Keywords: Ionic liquids; a-Bromo ketone; Thiourea/thioamide; Thiazoles.
* Corresponding author. Tel.: +91 20 2590 2098; fax: +91 20 2590 2629;
e-mail: kv.srinivasan@ncl.res.in
0040–4020/$ - see front matter Ó 2007 Published by Elsevier Ltd.
doi:10.1016/j.tet.2007.08.036

T. M. Potewar et al. / Tetrahedron 63 (2007) 11066–11069
11067
heterocyclization reactions investigated by us include regio-
selective synthesis of 1,5 benzodiazepines,17 substituted
quinoline and fused polycyclic quinolines using the Fried-
lander heteroannulation18 and 2-aryl-4(3H)-quinazolinone.19
the yield of 2-amino-4-phenylthiazole (3a) was compared
against the pKa values of the corresponding acid of the anion
(Table 1). Among these ionic liquids, ([bbim])BF4 was
found to be superior in terms of yields and reaction rates.
The reaction goes to completion in just 15 min, giving rise
to an excellent yield of 2-amino-4-phenylthiazole (96%).
Consequently, all further studies were conducted using this
IL as the reaction medium.
2. Result and discussion
As a continuation of our research devoted to the develop-
ment of green organic processes through performing reac-
tions in green solvents such as ionic liquids, herein we
report a versatile, environmentally friendly synthesis of
2-amino-4-arylthiazole and 2-methyl-4-arylthiazole in ionic
liquid (IL). The treatment of phenacyl bromides and thiourea
or thioamides in the IL 1,3-di-n-butylimidazolium tetrafluoro-
borate ([bbim]BF4) at ambient temperature afforded the
corresponding 2-amino-4-arylthiazole and 2-methyl-4-
arylthiazole derivative 3 in excellent yields (Scheme 1).
Similarly, several phenacyl bromides reacted smoothly with
thiourea and thioacetamide to give substituted 2-amino-4-
arylthiazole and 2-methyl-4-arylthiazole, respectively, in
87–96% yield in short reaction times. The results are summa-
rized in Table 2. It can be observed that the process tolerates
bothelectron-donatingandelectron-withdrawingsubstituents
in the phenacyl bromide. In all cases, the reactions proceeded
efficientlyatambienttemperatureundermildconditionstoaf-
ford the corresponding thiazoles in excellent yields. All the
1
products were characterized by H and 13C NMR spectros-
N
copy, IR, melting point and elemental analyses.
[bbim]BF4
rt
Ar
Br
O
+
H2N
R
Ar
R
S
S
In all the case, some common features were obtained for 1H
and 13C NMR chemical shift and IR frequencies, which are
as follows. The 1H NMR spectra of 2-amino-4-arylthiazoles
show a peak as a broad singlet at d 5.29–6.31 ppm, which
corresponds to the amino–NH group. Furthermore the
characteristic peak appearing at d 5.99–6.70 ppm corre-
sponds to C5–H of the thiazole ring. However, in the case
of 2-methy-4-aryllthiazole, C5–H of the thiazole ring ap-
pears at d 7.13–7.31 ppm. In the 13C NMR spectrum, the
peak appearing in the range of d 165–170 ppm corresponds
to C2 of the thiazole ring. The IR spectra of 2-amino-4-
arylthiazole shows peak at 3450–3200 cmꢀ1 corresponding
to the amino group while in the case of 2-methyl-4-arylthia-
zole, the peak corresponding to the methyl group appeared at
2970–2850 cmꢀ1. For the known compounds, the values
were in agreement with those reported in the literature.
1
2
3
Scheme 1.
Ionic liquids (ILs) based on 1,3-di-n-butylimidazolium salts
[bbim]X with varying basicity of anions such as BF4, Cl, Br
and ClO4 were studied in the typical reaction of phenacyl
bromide and thiourea to afford 2-amino-4-phenylthiazole
3a. The efficacy of the ILs to promote these heterocycli-
zation reactions was correlated to the basicity of the anions.
It was assumed that the nature of the anion would govern the
electrophilicity of the imidazolium cation, which in turn has
a bearing on the acidity of the ILs. It was observed that with
increasing basicity of the anion (increasing pKa of the corre-
sponding acid), there is a progressive increase in yield. Thus
Table 1. Synthesis of 2-amino-4-phenylthiazole (3a) in different ILs
a
The experimental procedure is very simple. A mixture of
phenacyl bromide, thiourea (or thioacetamide) and ionic
liquid, [bbim]BF4 was stirred at room temperature until com-
pletion of the reaction. The progress of the reaction was mon-
itored by thin-layer Chromatography. On completion, the
reaction mixture was extracted with a mixture of petroleum
ether and ethyl acetate (4:6). The product was pure enough
(single spot on TLC) for all practical purposes, however,
for characterization purposes it was further purified by
Sr. No.
Ils
pKa
Yieldc (%)
1
2
3
4
[bbim]ClO4
[bbim]Br
[bbim]Cl
ꢀ11
ꢀ9
48b
57b
71b
96d
ꢀ7
[bbim]BF4
0.5
The pKa values of the parent acid of the anions.25
The reaction was strirred upto 2 h.
Isolated yield after column chromatography.
The reaction was completed in 15 min.
a
b
c
d
Table 2. Synthesis of 2-amino-4-arylthiazole and 2-methyl-4-arylthiazole
Entry
Ar
R
Thiazole
Time (min)
Yielda (%)
Mp (ꢁC)
Lit. mp (ꢁC)
1
2
3
4
5
6
7
8
C6H5
C6H5
C6H5
NH2
Me
NHCH2Ph
NH2
Me
NHCH2Ph
NH2
Me
NHCH2Ph
NH2
Me
3a
3b
3c
3d
3e
3f
3g
3h
3i
15
10
20
15
20
10
15
15
15
10
10
15
15
96
94
92
93
89
93
88
96
95
94
87
90
93
150–151
67–68
100–101
125–126
60–61
111–112
202–203
66–67
15023
6722
101–10221
124–12524
58–5921
—
p-Me-C6H4
p-Me-C6H4
p-Me-C6H4
p-OMe-C6H4
p-OMe-C6H4
p-OMe-C6H4
p-Cl-C6H4
p-Cl-C6H4
p-Cl-C6H4
C6H5
200–20321
67–6821
—
9
83–84
10
11
12
13
3j
3k
3l
163–164
111–112
114–115
116–117
163–16424
11121
—
NHCH2Ph
NHCH2CH2Ph
3m
—
a
Isolated yield after column chromatography.

11068
T. M. Potewar et al. / Tetrahedron 63 (2007) 11066–11069
column chromatography. The advantage of the use of ionic
liquids as novel reaction media for this transformation is
that these ionic liquids can be easily recovered and recycled
in subsequent reactions. All reactions are general, clean and
very fast, almost completed in just 10–20 min. Since the
products were weakly soluble in the ionic phase, they were
easily separated by simple extraction with a mixture of petro-
leum ether and ethyl acetate (4:6). The rest of the viscous
ionic liquid was thoroughly washed with ether and reused
in subsequent reactions without further purification. The
recovered IL was used three times without loss in yield.
4. Experimental
4.1. General
1H NMR spectra were recorded at 200 MHz on a Bruker
AV-200 spectrometer and chemical shifts (d) are recorded
in parts per million relative to internal standard TMS
(d¼0.00). 13C NMR spectra were recorded at 50 MHz and
chemical shift (d) are recorded in parts per million relative
to CDCl3 (d¼77.0). Infrared spectra were recorded with
ATI MATT-SON RS-1 FTIR spectrometer using KBr pel-
lets. Elemental analyses were obtained using a flash
EA 1112 thermofinnigan instrument. Melting points were re-
corded in open capillary on Buchi melting Point B-540 appa-
ratus. All solvents and chemicals were of research grade and
were used as obtained from Merck and Lancaster. The ILs
were prepared as per the procedure reported by us earlier.18
The role of the IL may be postulated in terms of some Lewis/
Brønsted acidity of the imidazolium cation leading to its
interaction with the carbonyl oxygen of ketone I and III
resulting in its increased polarization leading to increased
electrophilicity of the carbocation, thus promoting condensa-
tion step A and cyclization step B to give five membered ring
IV, which on dehydration afforded thiazole V (Scheme 2).
Furthermore, high polarity of ionic liquid helps to solubilize
the starting materials, thus obviating the necessity of using
any additional solvents.
4.2. General experimental procedure for thiazole
synthesis
A mixture of phenacyl bromide (1 mmol), thiourea or thio-
acetamide (1 mmol) in 1,3-di-n-butylimidazolium tetra-
fluoroborate [bbim]BF4 (2 mL) was stirred at ambient
temperature for the appropriate time (Table 2). After com-
pletion of the reaction, as indicated by TLC, the reaction
mixture was washed with a mixture of petroleum ether and
ethyl acetate (4:6) (3ꢂ10 mL). The combined solvent ex-
tracts were concentrated in vacuo and the resulting product
was directly charged on small silica gel column and eluted
with a mixture of ethyl acetate:petroleum ether to afford
pure thiazoles 3. The immiscible ionic liquid was separated,
further washed with ether and dried at 80 ꢁC under reduced
pressure, which was reused for subsequent reactions.
-
-
BF4
Bu
BF4
+
+
N
N
N
N
Bu
I
Bu
Bu
HO
Ar
O
Ar
Br
N
NH
B
A
-
O
NH
Ar
R
S
HS
R
R
IV
S
-H2O
C
II
III
Ar
N
R
S
V
Scheme 2.
4.2.1. 2-Benzylamino-4-(p-methylphenyl)thiazole (3f).
Yellow solid; mp 111–112 ꢁC; IR (KBr) 3226, 3018, 1546,
2-Phenylethylamino-4-phenylthiazole, commonly known as
Fanetizole is an anti-inflammatory agent that has been
reported to have reached phase II clinical trails for the treat-
ment of rheumatoid arthritis.12,20 Fanetizole has been
synthesized by using stringent reaction conditions such as
microreactors and heating in solvents such as DMF and
1-methyl-2-pyrrolidinone (NMP). The developed protocol is
successfully utilized for a practical synthesis of this anti-
inflammatory agent Fanetizole 3m from phenacyl bromide
and 2-phenylethylthiourea in 93% yield (Table 2, entry 13).
As compared to reported conditions, we have synthesized
this molecule under ambient conditions in excellent yield us-
ing the recyclable IL as a reaction medium and promoter.
1
1528, 1492, 1453, 1329, 756 cmꢀ1; H NMR (200 MHz,
CDCl3): d 2.35 (s, 3H, CH3), 4.50 (s, 2H, ArCH2), 6.08 (br
s, 1H, NH), 6.62 (s, 1H, thiazole H), 7.15–7.18 (d,
J¼8.1 Hz, 2H, ArH), 7.31–7.39 (m, 5H, ArH), 7.66–7.70
(d, J¼8.2 Hz, 2H, ArH); 13C NMR (50 MHz, CDCl3):
d 21.2, 49.7, 100.0, 125.8, 127.5, 128.6, 129.1, 132.0, 137.4,
137.6, 151.2, 169.5. Anal. Calcd for C17H16N2S: C, 72.82;
H, 5.75; N, 9.99%. Found: C, 72.53; H, 5.89; N, 10.11%.
4.2.2. 2-Benzylamino-4-(p-methoxyphenyl)thiazole (3i).
Yellow solid; mp 83–84 ꢁC; IR (KBr) 3214, 3017, 2838,
1
1610, 1577, 1546, 1492, 1464, 1301, 756 cmꢀ1; H NMR
(200 MHz, CDCl3): d 3.81 (s, 3H, OCH3), 4.49 (s, 2H,
ArCH2), 6.13 (br s, 1H, NH), 6.54 (s, 1H, thiazole H),
6.87–6.91 (d, J¼8.8 Hz, 2H, ArH), 7.31–7.39 (m, 5H,
ArH), 7.69–7.74 (d, J¼8.8 Hz, 2H, ArH); 13C NMR
(50 MHz, CDCl3): d 49.8, 55.1, 98.9, 113.7, 127.2, 127.4,
127.4, 127.6, 128.5, 137.6, 150.8, 159.1, 169.8. Anal. Calcd
for C17H16N2OS: C, 68.89; H, 5.44; N, 9.45%. Found: C,
68.79; H, 5.37; N, 9.56%.
3. Conclusion
In conclusion, we have described a novel and efficient
method for the synthesis of 2-amino-4-arylthiazole and
2-alkyl-4-arylthiazole using ionic liquid as reaction medium
as well as a promoter. The important features of this proce-
dure are enhanced reaction rate, mild reaction conditions,
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. This methodology
is successfully applied for a practical synthesis of an anti-
inflammatory agent, Fanetizole.
4.2.3. 2-Benzylamino-4-(p-chlorophenyl)thiazole (3l).
White solid; mp 114–115 ꢁC; IR (KBr) 3240, 3019, 1547,
1477, 1328, 758 cmꢀ1 1H NMR (200 MHz, CDCl3):
;
d 4.45 (s, 2H, ArCH2), 6.06 (br s, 1H, NH), 6.60 (s, 1H, thi-
azole H), 7.19–7.31 (m, 7H, ArH), 7.62–7.68 (m, 2H, ArH);

T. M. Potewar et al. / Tetrahedron 63 (2007) 11066–11069
11069
13C NMR (50 MHz, CDCl3): d 49.7, 101.2, 127.2, 127.5,
127.7, 128.6, 128.6, 133.1, 133.2, 137.4, 150.0, 169.6.
Anal. Calcd for C16H13ClN2S: C, 63.89; H, 4.36; N,
9.31%. Found: C, 63.72; H, 4.53; N, 9.47%.
Parrish, C. A.; Pranc, P.; Sahlberg, C.; Ternansky, R. J.;
Vasileff, R. T.; Vrang, L.; West, S. J.; Zhang, H.; Zhou, X.-X.
J. Med. Chem. 1995, 38, 4929.
6. Fink, B. A.; Mortensen, D. S.; Stauffer, S. R.; Aron, Z. D.;
Katzenellenbogen, J. A. Chem. Biol. 1999, 6, 205.
7. Van Muijlwijk-Koezen, J. E.; Timmerman, H.; Vollinga, R. C.;
Von Drabbe Kunzel, J. F.; De Groote, M.; Visser, S.; Ijzerman,
A. P. J. Med. Chem. 2001, 44, 749.
4.2.4. Fanetizole (3m). White crystal; mp 116–117 ꢁC; IR
(KBr) 3196, 3016, 2975, 1602, 1584, 1552, 1495, 1463,
1335, 754 cmꢀ1 1H NMR (200 MHz, CDCl3): d 2.94–
;
8. Metzger, J. V. Comprehensive Heterocyclic Chemistry I;
Pergamon: New York, NY, 1984; Vol. 6, p 328.
9. Hantzsch, A.; Weber, J. H. Ber. Dtsch. Chem. Ges. 1887, 20,
3118.
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1984; Vol. 6, pp 235–332.
3.01 (t, J¼7.0 Hz, 2H, CH2), 3.52–3.62 (q, J¼7.0 Hz, 2H,
N–CH2), 5.24 (br s, 1H, NH), 6.70 (s, 1H, thiazole H),
7.24–7.37 (m, 8H, ArH), 7.76–7.80 (m, 2H, ArH); 13C
NMR (50 MHz, CDCl3): d 35.4, 47.5, 100.7, 126.03,
126.59, 127.59, 128.51, 128.66, 134.96, 138.46, 151.5,
169.4. Anal. Calcd for C17H16N2S: C, 72.82; H, 5.75; N,
9.99%. Found: C, 72.68; H, 5.81; N, 10.04%.
11. Das, B.; Saidi Reddy, V.; Ramu, R. J. Mol. Catal. A: Chem.
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12. Garcia-Egido, E.; Wong, S. Y. F.; Warrington, B. H. Lab Chip
2002, 2, 31.
Acknowledgements
13. Narender, M.; Somi Reddy, M.; Sridhar, R.; Nageswar,
Y. V. D.; Rama Rao, K. Tetrahedron Lett. 2005, 46, 5953.
14. (a) Siddiqui, H. L.; Iqbal, A.; Ahmed, S.; Weaver, G. Molecules
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Commun. 2007, 8, 741.
T.M.P. thanks the CSIR, New Delhi, for the award of
Research Fellowship.
Supplementary data
15. George, W. K.; Arjun, R. M. Tetrahedron Lett. 2006, 47, 5171.
16. (a) Welton, T. Chem. Rev. 1999, 99, 2071; (b) Wasserscheid, P.;
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S. M. S. Tetrahedron 2005, 61, 1015.
1H and 13C NMR spectra of compounds 3a–m are given as
supplementary data. Supplementary data associated with
this article can be found in the online version, at
doi:10.1016/j.tet.2007.08.036.
17. Jarikote, D. V.; Siddiqui, S. A.; Rajagopal, R.; Daniel, T.;
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