Green, one-pot, multicomponent synthesis of fused-ring 2-aminothiazoles

Article abstract of DOI:10.1080/00397911.2014.904880

A facile, green, and efficient Fe(III) chloride, one-pot, multicomponent reaction (MCR) for synthesis of 2-aminothiazole-based compounds is reported. Considering the medicinal importance of fused ring 2-aminothiazoles, this process provides an easy route

Full text of DOI:10.1080/00397911.2014.904880

This article was downloaded by: [Dalhousie University]
On: 23 June 2014, At: 07:23
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered office: Mortimer House,
37-41 Mortimer Street, London W1T 3JH, UK
Synthetic Communications: An International Journal
for Rapid Communication of Synthetic Organic
Chemistry
Publication details, including instructions for authors and subscription information:
http://www.tandfonline.com/loi/lsyc20
Green One-Pot Multicomponent Synthesis of Fused-Ring
2-Aminothiazoles
Siddique Anwar a , Satya B. Paul a , K. C. Mazumdar b & Sudip Choudhury a
a Department of Chemistry , Assam University , Silchar , India
b Department of Chemistry , Kalyani University , Kalyani , India
Accepted author version posted online: 10 Jun 2014.
To cite this article: Siddique Anwar , Satya B. Paul , K. C. Mazumdar & Sudip Choudhury (2014): Green One-Pot
Multicomponent Synthesis of Fused-Ring 2-Aminothiazoles, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, DOI: 10.1080/00397911.2014.904880
To link to this article: http://dx.doi.org/10.1080/00397911.2014.904880
Disclaimer: This is a version of an unedited manuscript that has been accepted for publication. As a service
to authors and researchers we are providing this version of the accepted manuscript (AM). Copyediting,
typesetting, and review of the resulting proof will be undertaken on this manuscript before final publication of
the Version of Record (VoR). During production and pre-press, errors may be discovered which could affect the
content, and all legal disclaimers that apply to the journal relate to this version also.
PLEASE SCROLL DOWN FOR ARTICLE
Taylor & Francis makes every effort to ensure the accuracy of all the information (the “Content”) contained
in the publications on our platform. However, Taylor & Francis, our agents, and our licensors make no
representations or warranties whatsoever as to the accuracy, completeness, or suitability for any purpose of the
Content. Any opinions and views expressed in this publication are the opinions and views of the authors, and
are not the views of or endorsed by Taylor & Francis. The accuracy of the Content should not be relied upon and
should be independently verified with primary sources of information. Taylor and Francis shall not be liable for
any losses, actions, claims, proceedings, demands, costs, expenses, damages, and other liabilities whatsoever
or howsoever caused arising directly or indirectly in connection with, in relation to or arising out of the use of
the Content.
This article may be used for research, teaching, and private study purposes. Any substantial or systematic
reproduction, redistribution, reselling, loan, sub-licensing, systematic supply, or distribution in any
form to anyone is expressly forbidden. Terms & Conditions of access and use can be found at http://
www.tandfonline.com/page/terms-and-conditions

ACCEPTED MANUSCRIPT
GREEN ONE-POT MULTICOMPONENT SYNTHESIS OF FUSED-RING 2-
AMINOTHIAZOLES
Siddique Anwar1, Satya B. Paul1, K. C. Mazumdar2, Sudip Choudhury1
1Department of Chemistry, Assam University, Silchar, India, 2Department of Chemistry,
Kalyani University, Kalyani, India
Corresponding to Satya B. Paul: E-mail: dr.sbpaul@gmail.com
Abstract
A facile, green and efficient Fe (III) chloride one-pot multicomponent reaction (MCR)
for synthesis of 2-aminothiazole based compounds. Considering the medicinal
importance of fused ring 2-aminothiazoles, the process reported here would provide an
easier route to the synthesis of this class of compound. Detailed mechanism of the
reaction has been discussed.
KEYWORDS: 2-aminothiazole, iron(III) catalysed, MCR
INTRODUCTION
ACCEPTED MANUSCRIPT
1

ACCEPTED MANUSCRIPT
2-aminothiazole analogues and their fused ring counterparts are enjoying importance in
medicinal research. Aminothiazoles exhibit a diverse pharmacology and possess
significant bioavailability[1].
Ghaemmaghami and co-workers showed 2-aminothiazoles (Compounds 1-5) to be
potent leads for treatment of Prion disease, a class of neurodegenerative disease caused
by the accumulation of the misfolded, infectious isoform of the prion protein (PrP SC) [1].
In light of this work, Gallardo-Godoy and co-workers [2] studied the structure-activity
relationship of 2-aminothizole derivatives for achieving and sustaining high drug
concentrations in the brain (compound 6). In an effort to structure based drug design,
Huang and group reported substituted 2-aminothiazole-4-carboxamide as a new class of
CHK1 inhibitors [3]. Through bioinformatics studies, Das and co-workers [4] discovered
Dasatinib, a 2-aminothiazole analogue, to be as pan-Src inhibitors with nanomolar to
subnanomolar potencies in biochemical and cellular assays. Dasatinib is recently being
used for the treatment of chronic myelogenous leukemia (Sprycel®) [5].
ACCEPTED MANUSCRIPT
2

ACCEPTED MANUSCRIPT
Considering the therapeutic potential and importance as structural motif, a number of
synthetic strategies have been designed and reported for substituted 2-aminothiazoles,
including catalyst free (fanetizole)[6], PEG-400 mediated[7], solvent-free condition[8], etc.
Very recently, synthesis of discrete-ring thiazole-coumarin based compounds via
multicomponent approach has also been reported[9].
Coumarin- and quinolone-annulated 2-aminothiazole compounds (compound 7, 8) have
been reported to exhibit effective anti-inflammatory properties [10]
.
To the best of our knowledge, most of the reports to synthesise such fused ring, annulated
2-aminothiazole, employ harmful bromine for cyclisation [11,12], expensive catalytic
systems and/or complex precursors [13]. Keeping such synthetic issues about this
important class of compounds in concern, Majumder and co-worker reported Copper (II)
Triflate promoted synthesis of some annulated 2-Aminothiazoles [12]. In our continued
endeavour in this arena, we report here more facile FeCl3 catalysed one-pot synthesis of
Coumarin- and Quinolone-Annulated 2-Aminothiazoles. We have also explored the
mechanism of the reaction. In this method, Aromatic (with or without substitution),
ACCEPTED MANUSCRIPT
3

ACCEPTED MANUSCRIPT
Aliphatic (cyclic/acyclic) secondary amine can be employed to annulate either of the
rings of these system.
DISCUSSION
Keeping the earlier reports of copper(II) chloride catalyzed domino synthesis of 2-
aminobenzothiazoles[14] and copper(II) triflate catalysed synthesis of annulated 2-
aminothiazoles[12], we wanted to study the reactions in presence of cheaper and easily
available catalyst, iron(III)chloride. The reaction was run by putting all the reagents and
catalyst together and refluxing for 6-8 hours. On completion the reaction provided with
69-80% yield of the product.
Solvent plays an important role to play in the reaction. The reaction produced poor yield
in presence of ethanol, methanol and dichloroethane (DCE). There was no increase in
yield with increase in reaction time either. After several trials, dimethylsulphoxide
(DMSO) was found to be the best solvent (Table 1)
With the success of the process, we investigated the mechanism of the reaction. We broke
the reaction in batches and identified the intermediates. The process is schematically
presented in Figure 1.
In a representative reaction, cyclohexamine was stirred with CS2 and K2CO3 in DMSO,
which resulted the formation of corresponding dithiocarbamic acids. In presence of
potassium carbonate the dithiocarbamic acids converted to potassium salt of
ACCEPTED MANUSCRIPT
4

ACCEPTED MANUSCRIPT
dithiocarbamate. A little of the reaction mixture was isolated, washed with hexane and
dried. The absence of characteristic 20 N-H stretching band and appearance of C-S
stretching bands in the IR spectrum of the isolated compound supported the formation of
sodium salt of dithiocarbamate. Subsequently, FeCl3 was added to the original reaction
mixture and continued stirring. The system turned dark in colour with formation of very
fine crystalline precipitate. A small portion of the reaction mixture was again isolated,
filtered, washed with ethanol and dried in vacuuo. In spite of several attempts, we were
unable to prepare suitable crystal for single crystal XRD, although we were successful to
identify the compound through IR.
Then the precursor 1a was added to the original reaction system and was refluxed with
stirring at 1100C for 10 hrs to give the target compound 2a. This observation clearly
indicates that, the dithiocarbamate salt at first forms coordination complex with iron(III).
The complex subsequently reacts with the bromo amine to give the target product.
To visualize the mechanism of the reaction, the following observations were considered:
1)
Cyclic amines on treatment with CS2 in presence of base produced corresponding
salts of the dithiocarbamate. These dithiocarbamates immediately formed dark coloured
complex with FeCl3 (Figure 1). Such observation was also supported in previous
reports[15]. Dithiocarbamate salts are known to form chelated complex through both the S
atoms with iron and other transition metal ions [16]
.
ACCEPTED MANUSCRIPT
5

ACCEPTED MANUSCRIPT
2)
The reaction was run without the presence of FeCl3 (Entry 1). Negligible amount
of the product was formed (could not be recovered), indicating that, the haloaniline
analogue reacts with the Fe-complex of the dithiocarbamates and not with the free
dithiocarbamate or its salt.
Keeping those in view, the proposed mechanism for the reaction is presented in Figure 2.
The anilide moiety coming from the bromoaniline derivative binds with the complex 1.
This is followed by a reverse Friedel-Craft type step to form the compound 3, which
seems to be the key step in this process. This drives the bonding of the suitably oriented
S-atom with the aromatic ring, followed by cyclization and rearrangements to give the
final product.
CONCLUSION
We have developed and reported here a green, economic one pot synthesis of fused ring
2-aminothiazole based compounds with good yield. The reaction has been standardised
and mechanism proposed. Keeping the therapeutic potential of this type of compounds,
we feel that the reported procedure will be beneficial for the synthesis of these
compounds and their derivatives.
GENERAL EXPERIMENTAL SECTION
Materials
All chemicals were purchased from either Sigma Aldrich Chemicals Pvt. Ltd. or
Spectrochem, India. Melting points were determined in open capillaries and are
ACCEPTED MANUSCRIPT
6

ACCEPTED MANUSCRIPT
uncorrected. IR spectra were recorded on a Perkin-Elmer L 120-000A spectrophotometer
1
on KBr disks. H and 13C NMR spectra were recorded on a Bruker DPX-400
spectrometer in CDCl3 with TMS as internal standard.
Synthesis Of Coumarin And Quinolone Annulated 2-Aminothiazole Analogues With
Fusion At Carbocyclic Part (Entry 1 As Representative Reaction):
The general reaction is presented in Scheme 1. A mixture of CS2 (1.2mmol), 1.5mmol of
the secondary amine (piperidine in Entry 1), K2CO3 (3mmol) was stirred in 5ml DMSO
at room temperature for 10 minutes. To this solution, FeCl3 (1.5mmol) was added and
continued to steer at room temperature for another 10 minutes. Then 1mmol of ortho-
bromo amine (for Entry 1-10) was added to the solution. The mixture was then heated
with stirring at 1100C for 6-8 hrs under nitrogen atmosphere. After completion of the
reaction, the solution was allowed to cool to room temperature; 50ml water was added,
extracted with ethyl acetate. The organic layer was collected and washed with water,
brine and dried over Na2SO4. The solvent was removed to give the crude product and
then purified by column chromatography over silica gel (Table 1 and Table 2).
compound 2a
Colour: Greenish yellow, M.P: 141-1430C
IR (KBr, cm-1) 1540, 1617, 1722, 2862
1HNMR (CDCl3, at 400 MHz in ∂ ppm with TMS as internal standard)1.73(s, 6H),
3.63(s, 4H), 6.48(d, J=9.2 Hz, 1H), 7.27(d, J=8.4 Hz, 1H), 7.65(d, J=8.8Hz, 1H), 7.70(d,
J=10.8 Hz, 1H)
ACCEPTED MANUSCRIPT
7

ACCEPTED MANUSCRIPT
13C NMR (CDCl3, at 100 MHz in ∂ ppm with TMS as internal standard):24.1, 25.3, 49.8,
112.6, 114.9, 121.9, 127.9, 140.9, 149.2, 149.9, 160.8, 168.2
Synthesis Of Coumarin Annulated 2-Aminothiazole Analogues With Fusion At
Heterocyclic Part (Entry 11 As Representative Reaction):
The reaction is presented in Scheme 2. The procedure is similar to the earlier one. In this
case, 1mmol of 3-amino-4-bromo coumarin was used (Entry 11-12; Table 3).
compound 4a
Colour: Brown, M.P: 244-2460C
IR (KBr, cm-1) 1558, 1602, 1723, 2855
1H NMR (CDCl3, at 400 MHz in ∂ ppm with TMS as internal standard) 2.11(s, 4H),
3.61(s, 4H), 7.28(s, 1H), 7.37(s, 3H).
13C NMR (CDCl3, at 100 MHz in ∂ ppm with TMS as internal standard) 25.8, 50.2,
116.8, 117.1, 123.5, 124.6, 128.5, 135.0, 137.9, 150.2, 156.0, 165.6
1H, 13C NMR spectra and other Spectral data, of all the target compounds synthesized are
present in Supplementary Information. The spectral data and melting points of all these
compounds were of excellent match with earlier reports [12] thus confirming the
standardization of the present protocol for synthesis of diverse array of complicated
fused-ring 2-aminothiazoles.
ACKNOWLEDGEMENTS
ACCEPTED MANUSCRIPT
8

ACCEPTED MANUSCRIPT
Authors are grateful to SAIF, Kochin, SAIF, NEHU and CIL, Assam University for
spectral studies. SA is thankful to DST, Govt of India for MANF Fellowship.
REFERENCES
(1)
Ghaemmaghami, S.; May, B. C. H.; Renslo, A. R.; Prusiner, S. B. J. Virol. 2010,
84, 3408–3412.
(2)
Gallardo-Godoy, A.; Gever, J.; Fife, K. L.; Silber, B. M.; Prusiner, S. B.; Renslo,
A. R. J. Med. Chem. 2011, 54, 1010–1021.
(3)
Huang, X.; Cheng, C. C.; Fischmann, T. O.; Duca, J. S.; Richards, M.; Tadikonda,
P. K.; Reddy, P. A.; Zhao, L.; Siddiqui, M. A.; Parry, D.; Davis, N.; Seghezzi, W.;
Wiswell, D.; Shipps, G. W. Bioorg. Med. Chem. Lett. 2013, 23, 2590–2594.
(4)
Das, J.; Chen, P.; Norris, D.; Padmanabha, R.; Lin, J.; Moquin, R. V; Shen, Z.;
Cook, L. S.; Doweyko, A. M.; Pitt, S.; Pang, S.; Shen, D. R.; Fang, Q.; de Fex, H. F.;
McIntyre, K. W.; Shuster, D. J.; Gillooly, K. M.; Behnia, K.; Schieven, G. L.; Wityak, J.;
Barrish, J. C. J. Med. Chem. 2006, 49, 6819–6832.
(5)
http://www.nlm.nih.gov/medlineplus/druginfo/meds/a607063.html, last accessed
on February 2, 2014.
(6)
Potewar, T. M.; Ingale, S. A.; Srinivasan, K. V. Tetrahedron 2008, 64, 5019–
5022.
(7)
Lin, P.-Y.; Hou, R.-S.; Wang, H.-M.; Kang, I.-J.; Chen, L.-C. J. Chinese Chem.
Soc. 2009, 56, 455–458.
(8)
(9)
Shockravi, A.; Sadeghpour, M.; Olyaei, A. Synth. Commun. 2010, 40, 2531–2538.
Pavurala, S.; Vedula, R. R. Synth. Commun. 2014, 44, 583–588.
ACCEPTED MANUSCRIPT
9

ACCEPTED MANUSCRIPT
(10) Kalkhambkar, R. G.; Kulkarni, G. M.; Shivkumar, H.; Rao, R. N. Eur. J. Med.
Chem. 2007, 42, 1272–1276.
(11) López-Calahorra, F.; Martı
Tetrahedron 2004, 60, 285–289.
́
(12) Majumdar, K. C.; De, N.; Ghosh, D.; Ponra, S.; Roy, B. Synthesis (Stuttg). 2011,
44, 87–92.
(13) (a) Wang, J.; Peng, F.; Jiang, J.; Lu, Z.; Wang, L.; Bai, J.; Pan, Y. Tetrahedron
Lett. 2008, 49, 467–470; (b) Shen, G.; Lv, X.; Bao, W. European J. Org. Chem. 2009,
2009, 5897–5901.
(14) Ma, D.; Lu, X.; Shi, L.; Zhang, H.; Jiang, Y.; Liu, X. Angew. Chem. Int. Ed. 2011,
50, 1118.
(15) Bernal, C.; Neves, E. A.; Cavalheiro, É. T. G. Thermochim. Acta 2001, 370, 49–
55.
(16) Hogarth, G.; Holman, K. T.; Pateman, A.; Sella, A.; Steed, J. W.; Richards, I.
Dalton Trans. 2005, 2688–2695.
ACCEPTED MANUSCRIPT
10

ACCEPTED MANUSCRIPT
Table 1: Effect of solvent with Entry 1 as the representative test case
Entry
Product
Solvent
Hexane
CH2Cl2
CH3OH
CH3CH2OH
DCE
Time (Hrs)
Yield (%)
1
24
20
15
15
20
8
negligible
3
10
10
5
DMSO
70
ACCEPTED MANUSCRIPT
11

ACCEPTED MANUSCRIPT
Table 2: Coumarin annulated 2-aminothiazole analogues (Fused ring on carbocyclic part)
Melting
Yield
Entry
‘Amine’*
Product
point
(0C)
(%)
2a
2b
2c
2d
1
141-143
70
2
255-257
144-146
199-201
74
63
78
3
4
ACCEPTED MANUSCRIPT
12

ACCEPTED MANUSCRIPT
2e
191-193
71
5
* The Secondary amine used
* The Secondary amine used
ACCEPTED MANUSCRIPT
13

ACCEPTED MANUSCRIPT
Table 3: Quinolone annulated 2-aminothiazole analogues (Fused ring on carbocyclic
part)
Entry ‘Amine’*
Product
Melting Yield
point
(0C)
(%)
6
3a 154-156
69
7
3b 142-144
74
8
9
3c 177-179
80
80
3d 177-179
ACCEPTED MANUSCRIPT
14

ACCEPTED MANUSCRIPT
10
3e 232-234
75
* The Secondary amine used
ACCEPTED MANUSCRIPT
15

ACCEPTED MANUSCRIPT
Table 4:Coumarin annulated 2-aminothiazole analogues (Fused ring on Heterocyclic
part)
Entry ‘Amine’*
Product
Melting Yield
point
(0C)
(%)
11
4a 244-246
76
12
4b 182-184
74
* The Secondary amine used
ACCEPTED MANUSCRIPT
16

ACCEPTED MANUSCRIPT
Scheme 1.
ACCEPTED MANUSCRIPT
17

ACCEPTED MANUSCRIPT
Scheme 2.
ACCEPTED MANUSCRIPT
18

ACCEPTED MANUSCRIPT
Figure 1: Schematic presentation of the process
ACCEPTED MANUSCRIPT
19

ACCEPTED MANUSCRIPT
Figure 2: Proposed mechanism for the reaction. Only aromatic bromo amine segment is
shown in the mechanism to simplify the presentation.
ACCEPTED MANUSCRIPT
20