A facile synthesis of new 4-amino-2-iminothiazoles from unsymmetrical thioureas

Article abstract of DOI:10.1246/cl.2012.535

An efficient methodology for the synthesis of 4-amino-2-iminothiazole derivatives has been developed. The synthesis involves the cyclization of unsymmetrical 1-aroyl-3-arylthioureas with a variety of 2-bromo-2- phenylacetonitriles bearing α-H in the presence of triethylamine and acetonitrile.

Full text of DOI:10.1246/cl.2012.535

doi:10.1246/cl.2012.535
Published on the web April 28, 2012
535
A Facile Synthesis of New 4-Amino-2-iminothiazoles from Unsymmetrical Thioureas
Yellajyosula Lakshmi Narasimha Murthy,* Rama Mohana Rao Saviri,
Parimi Atchuta Ramaiah, and Saranapu Nareesh
Department of Organic Chemistry, Andhra University,
Visakhapatnam, Andhra Pradesh-530 003, India
(Received January 26, 2012; CL-120066)
An efficient methodology for the synthesis of 4-amino-2-
iminothiazole derivatives has been developed. The synthesis
involves the cyclization of unsymmetrical 1-aroyl-3-arylthio-
ureas with a variety of 2-bromo-2-phenylacetonitriles bearing
¡-H in the presence of triethylamine and acetonitrile.
sulfur, carbodiimides, and acid chlorides.11 Although several
procedures have been reported12 for the synthesis of different
substituted 2-iminothiazoline derivatives, none of those proce-
dures utilized the 2-bromo-2-phenylacetonitrile as coupling
partner with thiourea derivative. Hence, herein we wish to
report the synthesis of 4-amino-2-imino-3-arylthiazoline deriv-
atives by the reaction of benzoylthiourea derivatives with
corresponding 2-bromo-2-phenylacetonitrile derivatives in the
presence of triethylamine, represented in Scheme 2. In fact,
these kinds of compounds were synthesized from the reaction of
¡-cyanobenzyl benzenesulfonates and thiourea derivatives.13
Initially, we synthesized various thiourea derivatives14
and 2-bromo-2-phenylacetonitriles by using known procedures
reported elsewhere. We then attempted the reaction by taking
N-benzoyl-N¤-phenylthiourea and 2-bromo-2-phenylacetonitrile
as starting materials in the presence of triethylamine. When the
reaction was carried out by taking both the reagents in equimolar
ratio (1:1) in one lot addition it resulted in the formation of the
desired product in poor yield. In order to improve the yield of
the desired product, we have screened several reaction con-
ditions. First, we screened various solvents like acetonitrile,
chloroform, dichloromethane (DCM), and ethanol for this reac-
tion; we found the reaction more efficient in acetonitrile than the
other solvents tested as described in Table 1. As it was known
from the literature that triethylamine works as the best base for
this kind of transformation,8d we also used the same base in our
method. To estimate the ratio of the reagents, we carried out the
reaction by taking different proportions of reagents. We obtained
the best results when benzoylthiourea, 2-bromo-2-phenylaceto-
nitrile, and triethylamine were taken in the ratio of 1:1.1:1.5
equivalents respectively and the reaction should be performed at
room temperature, dropwise addition of 2-bromo-2-phenylaceto-
nitrile to the mixture of thiourea derivative and triethylamine.
2-Aminothiazole and its isomeric derivatives 2-iminothia-
zoles are important structural scaffolds that are providing a broad
spectrum of biological activities.1 In particular, 2-iminothiazole
derivatives exhibit muscarinomimetic, antimicotic, antidiabetic,
anti-inflammatory, antianalgesic, and antibacterial activities.2
It has been reported that the manipulation of substitution on
2-iminothiazole core unit leads to a different bioactivity. For
instance, pifithrin (Pft-¡) (i) is a cyclohexane-fused 2-imino-
thiazole derivative which inactivates p53 human tumor cell
lines.3 While compound (ii) and compound (iv) have the same
core unit with different activity, compound (iii) has a different
core with different activity, represented in Scheme 1.4 Hence the
synthesis of various functionalized 2-imino or 2-aminothiazoline
derivatives is an interesting topic in recent times.5
In general, 2-iminothiazoline derivatives were synthesized
by the Hantzsch reaction from the corresponding thiourea and
¡-halocarbonyl compounds. This method leads to a mixture
of regioisomers depending upon the reaction conditions.6
Other than the Hantzsch reaction, several protocols have been
documented in literature for the synthesis of 2-iminothiazoline
derivatives; i.e., the reaction of ¡-haloimines with potassium
thiocyanate,7 the reaction of N,N¤-dialkylthiourea with ¡-
halocarbonyl compounds in the presence of base,8 the reaction
of 1,2-diaza-1,3-dienes with thiocyanic acid9 and other meth-
ods.10 Recently, Zhang and co-workers reported a four compo-
nent tandem sequence for the synthesis of 2-iminothiazoline
derivatives from readily available terminal alkynes, elemental
R1
H2N
R2
H
O
N
O
Br
TEA
N
S
O
H
N
R2
NH
N
N
CN
+
F
MeCN, 30 °C
O
N
1
R
R
N
S
S
O
R
S
NH
(i)
(ii)
F
Scheme 2. Our synthetic approach.
Table 1. Thiazole derivatives under different solvent systems
p53 inactivator
Skin whitening agent
OH
OH
NH2
N
R
O
S
N
S
HO
Entry
Solvent
Time
Yield/%a
O
OH
N
1
2
3
4
CH3CN
CHCl3
DCM
30 min
3 h
3.5 h
4 h
96
40
50
45
NH2
(iii)
(iv)
Antitumor
Ph
Respiratory stimulant
EtOH
Scheme 1. Compounds comprising 2-imino or 2-aminothiazo-
line moiety having different activities.
aIsolated yields.
Chem. Lett. 2012, 41, 535-537
© 2012 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/

536
Table 2. Reactions of various aroylthiourea derivatives with 2-
bromo-2-phenylacetonitrile in the presence of Et3N
Table 3. Reactions of various aroylthiourea derivatives with
different 2-bromo-2-phenylacetonitriles in the presence of Et3N
R
R1
H2
N
H2N
TEA
TEA
R2
H
N
H
N
R2
N
S
N
S
Br
H
H
N
Br
R2
R2
N
N
N
MeCN, 30 °C
R'
MeCN, 30 °C
Ph
CN
R1
R1
+
R'
CN
Ph
S
O
O
S
O
O
+
R
R
R= Cl , R' = H
R=R'=Methylene dioxy
Entry
Substrate
Product
Time/min Yield/%a,b
Entry
1
Substrate
Product
Cl
Time/min Yield/%a,b
H
N
H
H2N
Ph
N
S
N
1
2
2a16
20
30
80
82
N
S
S
O
O
H
N
H
N
H2N
N
N
2i
20
80
Cl
S
S
O
H
N
H
N
Cl
2b
O
H2N
Ph
Cl
Cl
N
S
Cl
N
Cl
O
O
O
OCH3
H2N
2
3
2j
20
20
80
80
N
N
S
H
H
N
N
H
N
H
N
H2N
Ph
3
2c
27
89
N
N
S
O
S
S
O
O
Cl
S
Cl
Cl
H3CO
O
Cl
Cl
H2N
H2N
2k
N
S
H
N
H
N
N
O
H
N
H
N
H2N
Ph
O
N
S
Cl
O
4
5
6
2d
2e
2f
30
30
26
80
86
90
N
Cl
Cl
S
S
O
O
O
N
S
H
H
N
4
5
2l
40
35
78
86
N
N
NO2
NO2
H
N
H
N
O
H2N
Ph
S
O
N
S
F
N
O
2m
H2N
H2N
N
N
N
H
H
O
S
N
N
O
H
N
H
N
H2N
Ph
N
S
S
O
O
N
O
S
O
F
N
S
6
7
2n
2o
30
20
88
85
Br
H
H
O
O
N
N
O
S
O
NO2
H
N
H
N
H2N
Ph
7
8
2g
2h
25
25
88
87
N
S
N
O
S
S
O
O
Cl
Br
Cl
Cl
H2N
N
N
H
H
O
O
S
N
N
NO2
NO2
O
H
N
H
N
H2N
Ph
N
S
Cl
S
O
N
O
O2N
Cl
H2N
N
S
8
2p
40
76
aReactions performed in 10 mmol scale. Details of reaction
conditions are shown in ref. 15. Isolated yields.
N
H
H
N
O
O
N
b
O
S
O
Cl
aReactions performed in 10 mmol scale. Details of reaction
conditions are shown in ref. 15. Isolated yields.
Under these conditions, we obtained the desired product in 80%
yield along with a trace of unidentified product which was
washed out with hexane. The product was fully characterized by
using spectroscopic techniques (IR, 1H NMR, 13C NMR, and
MS). In the IR spectrum, the characteristic peak for NH2 was
b
It should be noted that the substitution on the aroylthiourea
derivatives has considerable effect on reaction. Under the
present reaction conditions sensitive aryl ring such as furfuryl
ring survived and gave good yield of its corresponding product.
Encouraged by the successful application of the reaction
conditions to various thiourea derivatives with 2-bromo-2-
phenylacetonitrile, we further focused our attention to make
use of other substituted 2-bromo-2-phenylacetonitriles. In this
context, we took two more 2-bromo-2-phenylacetonitriles,
namely 2-bromo-2-(4-chlorophenyl)acetonitrile and 2-(benzo-
[d][1,3]dioxol-5-yl)-2-bromoacetonitrile to study the generality
of this with respect to substituted 2-bromo-2-phenylacetonitrile.
¹1
observed at 3340-3222 cm and C=N was observed at 1590-
1550 cm¹1. In 1H NMR, NH2 appeared as a broad singlet at
3.5 ppm.
After optimizing the reactions, we focused our attention on
exploring the scope and generality of the method with respect to
various aroylthiourea derivatives and 2-bromo-2-phenylacetoni-
trile. The results are summarized in Table 2. As can be seen
from Table 2, the reactions of various aroylthiourea derivatives
occurred smoothly to produce their corresponding of 4-amino-2-
iminothiazoline derivatives in good to excellent yields.
Chem. Lett. 2012, 41, 535-537
© 2012 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/

537
Table 4. Reaction of ethyl 2-bromo-2-cyanoacetate with N-
(phenylcarbamothioyl)benzamide in the presence of Et3N
4
5
D.-S. Kim, Y.-M. Jeong, I.-K. Park, H.-G. Hahn, H.-K. Lee,
S.-B. Kwon, J. H. Jeong, S. J. Yang, U. D. Sohn, K.-C. Park,
Biol. Pharm. Bull. 2007, 30, 180.
O
O
Br
Et3
N
H
H
S
O
N
+
O
a) Q. Zhao, C. Shen, H. Zheng, J. Zhang, P. Zhang,
Carbohydr. Res. 2010, 345, 437. b) M. Han, K. D. Nam,
D. Shin, N. Jeong, H.-G. Hahn, J. Comb. Chem. 2010, 12,
518. c) I. Ohno, M. Tomizawa, K. A. Durkin, Y. Naruse, J. E.
Casida, S. Kagabu, Chem. Res. Toxicol. 2009, 22, 476. d) H.
Ohta, T. Ishizaka, M. Tatsuzuki, M. Yoshinaga, I. Iida, Y.
Tomishima, Y. Toda, S. Saito, Bioorg. Med. Chem. Lett.
2007, 17, 6299.
N
N
N
MeCN
O
N
NH2
S
O
Entry
Substrate
Product
Time/min
34
Yield/%a,b
O
O
H
H
S
N
O
N
N
N
1
2q
84
NH2
S
O
6
7
8
A. Hantzsch, J. H. Weber, Ber. Dtsch. Chem. Ges. 1887, 20,
3118.
aReactions performed in 10 mmol scale. Details of reaction
conditions are shown in ref. 15. Isolated yields.
S. E. Bramley, V. Dupplin, D. G. C. Goberdhan, G. D.
Meakins, J. Chem. Soc., Perkin Trans. 1 1987, 639.
a) A. Saeed, U. Shaheen, A. Hameed, F. Kazmi, J. Fluorine
Chem. 2010, 131, 333. b) A. Saeed, U. Shaheen, Synth.
Commun. 2010, 40, 564. c) S. Murru, C. B. Singh, V. Kavala,
B. K. Patel, Tetrahedron 2008, 64, 1931. d) C. B. Singh, S.
Murru, V. Kavala, B. K. Patel, Org. Lett. 2006, 8, 5397. e) S.
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O. A. Attanasi, G. Favi, P. Filippone, F. R. Perrulli, S.
Santeusanio, Synlett. 2010, 1859.
b
The results are placed in Table 3. As shown in Table 3, the
reactions with both the substituted 2-bromo-2-phenylaceto-
nitriles reacted with various thiourea derivatives to form their
corresponding thiazoline derivatives in good yields. Finally, we
also used the present reaction conditions for the reaction of ethyl
2-bromo-2-cyanoacetate with N-(phenylcarbamothioyl)benz-
amide to obtain the desired 4-amino-2-iminothiazoline deriva-
tive in good yield. (Table 4).
In summary, we report an efficient methodology for the
synthesis of 4-amino-2-iminothiazoline derivatives by using
various 2-bromo-2-phenylacetonitriles and unsymmetrical thio-
urea derivatives as substrates. We have developed a simple,
convenient, and effective method for easy synthesis of imino-
thiazoline derivatives under room temperature conditions. Pres-
ent methodology has attractive features such as reduced reaction
times and high yields. The simple procedure combined with ease
of workup make this method economical, environmentaly
benign, and a waste-free chemical process for the synthesis of
iminothiazoline derivatives of biological importance.
9
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The authors are thankful to The Dept. of Organic Chemistry,
Andhra University, Visakhapatnam, India for providing neces-
sary laboratory facilities.
15 General synthesis of 4-amino-2-iminothiazoline deriva-
tives: To 10 mmol of thiourea derivative in acetonitrile, was
added triethylamine (10.50 equiv) and the mixture was stirred
at room temperature (25-30 °C) for ten minutes then solution
turned pale yellow. To that 10.10 mmol of 2-bromo-2-
phenylacetonitrile (which was dissolved in 10 mL of ace-
tonitrile) are added dropwise for ten minutes. After 15 min,
yellow precipitate was observed. Solvent was concentrated
under reduced pressure, solid material was filtered and
washed with hexane to get rid off the excess of triethylamine.
A yellow colored crystalline compound was observed. It was
purified and characterized by the advanced spectroscopy.17
16 N-(4-Amino-3,5-diphenyl-3H-thiazol-2-ylidine)benzamide
(2a): mp: 78-80 °C; IR (KBr): 3220, 1670, 1598, 1560,
1219 cm¹1; 1H NMR (CDCl3, 400 MHz): ¤ 6.0 (s, 2H, NH2),
6.9-8.0 (m, 15H, aromatic); 13C NMR (CDCl3, 100 MHz): ¤
95.3, 124.1, 126.7, 127.2, 129.8, 131.2, 133.7, 135.5, 136.8,
137.6, 167.0, 174.4, 178.5.; EIMS (m/z): 371.1.17
17 Supporting Information is available electronically on the
CSJ-Journal Web site, http://www.csj.jp/journals/chem-lett/
index.html. Synthetic details of all new compounds with
characterization.
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Chem. Lett. 2012, 41, 535-537
© 2012 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/