Synthesis of 2-aminothiazole derivatives from easily available thiourea and alkyl/aryl ketones using aqueous NaICl2

Article abstract of DOI:10.1016/j.tetlet.2014.11.140

A simple methodology was developed to synthesize substituted aminothiazoles from the corresponding thiourea and substituted ketones using aqueous NaICl₂ at reflux temperature in THF. The products were obtained in good to excellent yields.

Full text of DOI:10.1016/j.tetlet.2014.11.140

Accepted Manuscript
Synthesis of 2-aminothiazole derivatives from easily available thiourea and al-
kyl/aryl ketones using aqueous NaICl
2
Shrikant M. Ghodse, Vikas N. Telvekar
PII:
S0040-4039(14)02054-1
DOI:
http://dx.doi.org/10.1016/j.tetlet.2014.11.140
TETL 45524
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
24 September 2014
28 November 2014
30 November 2014
Please cite this article as: Ghodse, S.M., Telvekar, V.N., Synthesis of 2-aminothiazole derivatives from easily
available thiourea and alkyl/aryl ketones using aqueous NaICl , Tetrahedron Letters (2014), doi: http://dx.doi.org/
2
1
0.1016/j.tetlet.2014.11.140
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Graphical Abstract
Synthesis of 2-aminothiazole derivatives
from easily available thiourea and alkyl/aryl
ketones using aqueous NaICl2
Shrikant M. Ghodse, Vikas N. Telvekar*

1
Tetrahedron Letters
journal homepage: www.elsevier.com
Synthesis of 2-aminothiazole derivatives from easily available thiourea and alkyl/aryl
ketones using aqueous NaICl2
Shrikant M. Ghodse, Vikas N. Telvekar*
Department of Pharmaceutical Sciences & Technology, Institute of Chemical Technology, Matunga,
Mumbai-400 019, India
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A simple methodology was developed to synthesize substituted aminothiazoles from
corresponding thiourea and substituted ketones using aqueous NaICl at reflux temperature
2
in THF. The products were obtained in good to excellent yields.
Available online
Keywords:
Aminothiazole
Thiourea
Ketones
2
Aqueous Sodium iodine dichloride (NaICl )
1
3
14
Aminothiazole have been recently identified as desired structural
element that is screened as part of many drug design processes in
medicinal chemistry due to their thiourea like properties and tendency to
various catalysts such as iodine,
silica chloride,
1,3-di-n-
1
5
butylimidazolium tetrafluoroborate, ammonium 12-molybdophosphate
1
6-17
and cyclodextrin.
1
modulate biological targets. Aminothiazole and its derivatives have
2
broad spectrum of medicinal applications such as antitubercular, anti-
Herein, we report the synthesis of aminothiazoles from thiourea and
alkyl/aryl ketones in the presence of aq. NaICl
3
4
5
6
inflammatory, antiplatelet, antiviral, anticancer and human lymphatic
2
.
7
filarial parasite. Aminothiazole analogs have also been reported as
ligands at adenosine receptors, estrogen receptor and inhibitors of
human platelet aggregation factor. This heterocyclic core is also
reported in many natural products and pharmaceuticals. (Fig. 1)
8
9
10
Scheme1. Synthesis of 2-amino 4-(phenyl)-1,3-thiazole using aq..NaICl
2
For our initial study, we took thiourea and acetophenone as the model
substrates (Scheme 1). The desirable 2-amino-4-(phenyl)-1,3-thiazole
was formed when 1 equivalents of thiourea and acetophenone were
treated with 1 equivalent of aq. NaICl
of THF at reflux temperature. Further, it was observed that in the absence
of aq. NaICl no product was formed. Thus, to optimize the reaction
2
(30% W/W in water) in presence
2
conditions, thiourea and acetophenone were treated with different
equimolar ratios and finally, optimum yield of desired aminothiazoles
was obtained when 2 equivalents of thiourea reacted with 1 equivalent of
2
acetophenone. It was observed that 0.5 equivalent of aq.NaICl was
sufficient to carry out the reaction. Further, the effect of temperature on
the model reaction was studied and it was showed that the reflux
temperature produced best results. The above reaction is also carried out
in different solvents, at reflux temperature, such as methanol, ethanol,
MDC and toluene instead of THF. No reactions were observed in MDC
and toluene, while in methanol and ethanol yields were 30% and 40%
respectively. Thus, THF was found to be the most suitable solvent for this
reaction.
Figure1. Some drugs containing aminothiazole moiety.
Various methodologies such as Hantzsch, Cook Heilborn, and Tchernic
for the synthesis of aminothiazole and their derivatives have been
reported. Among these, Hantzsch thiazole synthesis is the most widely
used, which involves reaction of α-halo carbonyl compounds with
1
1
thiourea or thioamides. There are very few reports available in which
α-halo carbonyl compounds were generated in-situ using ketones and
reacted with thiourea to form varieties of aminothiazoles.
12
These optimized reaction conditions were applied to varieties of aliphatic
and aromatic ketones in presence of thiourea and aq.NaICl
2
to convert
into corresponding aminothiazoles and the results are summarized in
Table 1.
Recently, aminothiazole derivatives were also synthesized by using
Corresponding author. Tel.: + 91 22 3361 2213; fax: +91 22 3361 1020;
E-mail: vikastelvekar@rediffmail.com
1
8


2
Tetrahedron
a,
Table 1. Aliphatic and aromatic ketones are converted into aminothiazoles
b
entry
1
substrate
product
%Yield
7
8
8
7
9
0
5
4
4
1
2
3
4
5
8
8
6
9
6
7
8
9
83
7
9
2
0
1
0
a
2
Reaction conditions: thiourea (2 equiv), ketones (1 equiv) and aq. NaICl (0.5 equiv) in THF at reflux temperature.
Isolated yields after column chromatography, Structure were confirmed by comparison of IR, H NMR and M.P. with literature reports.
b
1
19-25

3
-
1
1
Both aliphatic and aromatic ketones are suitable for this conversion
Table 1 entries 1-10). In case of aliphatic substrates like acetone,
chloroacetone, methyl acetone and isopropyl acetone, the desired
aminothiazoles were obtained in moderate to good yields (Table 1,
entries 1- 4). Under these reaction conditions, ether linkages are stable
2926, 1616, 1519, 1367 cm ; H NMR (400 MHz, CDCl
3
): δ 7.77-
7
5
1
.76 (d, J = 7.7, 2H), 7.39-7.36 (d, J = 7.4, 2H), 7.30-7.35 (m, 2H),
.78 (bs, 2H); MS: m/z calcd for C
76.00.
(
9 8 2
H N S (M ): 176.26; found
20
2
-amino-4-(methyl)-1,3-thiazole (Table 1, entry 1): yellow oil,
1
H NMR (300 MHz, CDCl
3
): δ 6.13 (d, J= 0.9 Hz, 1H), 5.30 (bs,
(
Table 1, entry 7, 8). In most of the literature, it is reported that p-
26
2H), 2.18 (d, J= 0.9 Hz, 3H)
-amino-4-(p- methylphenyl)-1,3-thiazole (Table 1, entry 6):
Mp 129–131 C (Lit Mp 130-132 C); H NMR (300MHz, CDCl
.67(d, J = 6.8, 2H), 7.16 (d, J = 7.2, 2H), 7.10 (s, 1H), 6.90 (s, 2H);
10 2
MS: m/z calcd for C10H N S (M ): 190.26; found 190.00
Yadav, J. S.; Reddy, B. V. S.; Rao, Y. G.; Narsaiah, A. V.
Tetrahedron Lett.. 2008, 49, 2381.
Huang, G.; Sun, H.; Qiu, X.; Jin, C.; Lin, C.; Shen, Y.; Jiang, J.;
Wang, L. Org. Lett. 2011, 13, 5224.
Morales-Bonilla, P.; Perez-Cardena, A.; Quintero-Mármol, E.; Arias-
Téllez, J. L.; Mena-Rejón, G. J. Heter. Chem, 2006, 17, 254.
Veretennikov, E. A.; Pavlov, A. V. Russian. J. Org. Chem. 2013, 49,
aminoacetophenone does not react with thiourea , but in our case
aqueous NaICl is found to give the desired product (Table1, entry 9).
21
2
2
o
o
1
3
): δ
7
In conclusion, a novel, facile and highly efficient methodology has been
developed to synthesize substituted aminothiazoles using easily available
aliphatic and aromatic ketones in presence of aq. sodium iodine
dichloride under metal free conditions. The conditions are general and
applicable to variety of pharmaceutical intermediate. This methodology
is also useful for conversion of substrate like p-aminocetophenone to
corresponding aminothiazole.
+
1
2
9.
0.
21.
2.
23.
2
Acknowledgment
575.
SMG thanks University Grants Commission (UGC) and VNT thanks
Science and Engineering Research Board (SERB), New Delhi, India, for
providing financial support.
Donohoe, T. J.; Kabeshov, M. A.; Rathi, A.H.; Smith , E. D. Org.
Biomol. Chem. 2012, 10, 1093.
Bhargava, P. N.; Singh, P. R. J. Ind. Chem. Soc. 1960, 37, 241.
Pathan S. R.; Ali M. S.; Pathan, J. S.; Purohit, S. S.; Reddy V. V. K.;
Nataraj B. R. Indi. J. Chem. 2006, 45, 1929.
2
2
4.
5.
References
2
6.
Caceres-Castillo, D.; Carballo, R. M.; Tzec-Interián, J. A.; Mena-
Rejon, G. J. Tetrahedron Lett. 2012, 53, 3934.
1
2
.
.
Baell, J. B.; Holloway, G. A. J. Med. Chem. 2010, 53, 2719.
Meissner, A.; Boshoff, H.; Vasan, M.; Duckworth, B. P.; Barry, C.
E.; Aldrich, C. C. Bioorg. & Med. Chem. 2013, 21, 6385.
Helal, M. H. M.; Salem, M. A.; El-Gaby, M. S. A.; Aljahdali, M.
Eur. J. Med. Chem. 2013, 65, 517.
Pi, Z.; Sutton, J.; Lloyd, L.; Hua, J.; Price, L.; Wu,Q.; Chang, M.;
Zheng,J.; Rehfuss, R.; Huang, C. S.; Wexler, R. R.; Lam, P. Y. S.
Bioorg. Med. Chem. 2013, 23, 4206.
3
4
.
.
5
6
.
.
Liu, R.; Huang, Z.; Murray, M. G.; Guo, X.; Liu, G. J. Med. Chem.
2
011, 54, 5747.
Romagnoli, R.; Baraldi, P. G.; Salvador, M. K.; Camacho, M. E.;
Preti, D.; Tabrizi, M. A.; Bassetto, M.; Brancale, A.; Hamel, E.;
Bortolozzi, R.; Basso, G.; Viola, G. Bioorg. Med. Chem. 2012, 20,
7
083.
7
8
9
.
.
.
Sashidhara, K. V.; Rao, K. B.; Kushwaha, V.; Modukuri, R. K.;
Verma, R.; Murthy, P. K. Eur. J. Med. Chem. 2014 , 81, 473.
Van Tilburg, E. W.; Van der Klein, P. A. M.; De Groote, M. W.;
IJzerman, A. P. Bioorg. Med. Chem. Lett. 2001, 11, 2017.
Fink, B. E.; Mortensen, D. S.; Stauffer, S. R.; Aron, Z. D.;
Katzenellengbogen, J. A. Chem. Biol. 1999, 6, 205.
1
1
0.
1.
Umadevi, B. Eur. J. Med. Chem. 2007, 42, 1144.
Hantzsch, A.; Weber, J. H. Ber. Dtsch. Chem. Ges. 1887, 20,
3
118
1
2.
(a) Zhu, Y. P. ; Yuan, J. J.; Zhao, Q.; Lian, M. ; Gao , Q. H. ; Liu, M.
C.; Yang ,Y.; Wu, A.X. Tetrahedron, 2012, 68, 173. (b) Xue, W.J.;
Zheng, K. L.; Li, H. Z.; Geo, F. F.; Wu A. X. Tetrahedron Lett. 2014,
5
5, 4212.
Siddiqui, H. L.; Iqbal, A.; Ahmed, S.; Weaver, G. Molecules, 2006,
1, 206
1
1
3.
4.
1
Karade, H.; Sathe, M.; Kaushik, M. P. Catal. Commun. 2007, 8, 741.
1
5.
Potewar, T. P.; Ingale, S. A.; Srinivasan, K. V.; Tetrahedron,
2
007, 63, 11066.
Das, B.; Reddy, S. V.; Ramu, R. J. Mol. Catal. A: Chem.
006, 252, 235.
1
6.
2
1
1
7.
8.
Narender, M.; Somi Reddy, M.; Sridhar, R.; Nageswar, K.;
Nageswar, K.; Rama Rao, K.. Tetrahydron Lett. 2005, 46, 7779.
General procedure for the synthesis of 2-aminothiazole: To a
stirred solution of thiourea (2 equiv), and ketone (1equiv) in THF (10
mL) at room temperature was slowly added aqueous NaICl
2
(0.5
equiv, 30% W/W aqueous NaICl ). The resultant reaction mixture
2
was refluxed for 12 h. After completion of reaction (TLC), the
solvent was evaporated under the vacuum. The resulted residue was
diluted with water (10 mL) and extracted with ethyl acetate (3 × 10
mL). The organic layer was separated and washed successively with
1
0% sodium bisulfate solution (2 x 10 mL), 10% sodium bicarbonate
(2 × 10 mL) and water (2 × 15 mL). The organic layer finally dried
over anhydrous sodium sulphate and concentrated under the reduced
pressure to give crude product. Pure product was obtained after silica
gel column chromatography (30% EtOAc-Hexane).
1
9
2
-amino-4-(phenyl)-1,3-thiazole (Table 1, entry 5): colorless
o o
solid, Mp 148-150 C (Lit. Mp 149-151 C); IR (neat): 3325, 3192,