One-pot synthesis of 2-aminothiazoles in PEG-400

Article abstract of DOI:10.1016/j.cclet.2009.11.035

A facile one-pot synthesis of 2-aminothiazoles has been carried in PEG-400 as a greener medium at room temperature. This method avoids the use of lachrymatric α-bromoketones as well as the volatile, toxic organic solvents.

Full text of DOI:10.1016/j.cclet.2009.11.035

Available online at www.sciencedirect.com
Chinese Chemical Letters 21 (2010) 412–416
www.elsevier.com/locate/cclet
One-pot synthesis of 2-aminothiazoles in PEG-400
*
Dhanaji V. Jawale, Dinesh L. Lingampalle, Umesh R. Pratap, Ramrao A. Mane
Department of Chemistry, Dr. Babasaheb Ambedkar Marathwada University, Aurangabad (MS) 431 004, India
Received 19 August 2009
Abstract
A facile one-pot synthesis of 2-aminothiazoles has been carried in PEG-400 as a greener medium at room temperature. This
method avoids the use of lachrymatric a-bromoketones as well as the volatile, toxic organic solvents.
#
2009 Ramrao A. Mane. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
Keywords: One-pot synthesis; 2-Aminothiazoles; Polyethylene glycol-400; N-Bromosuccinimide
Thiazoles play an important role in nature and have broad spectrum of applications in the field of agriculture and
medicinal chemistry. Thiazole ring is a structural motif of natural compounds such as vitamin B (thiamine), penicillin
1
and carboxylase. Moreover 2-aminothiazoles have been employed in the preparation of different important drugs
required for the treatment of allergies [1], hypertension [2], inflammation [3], schizophrenia [4], bacterial [5], and HIV
infections [6]. Aminothiazoles are known to be ligands of estrogen receptors [7] as well as a novel class of adenosine
receptors antagonists [8]. Where as other analogues are used as fungicides, inhibiting in vivo growth of Xanthomonas
and as an ingredient of herbicides or as schistosomicidal and anthelmintic drugs [9]. Given this proven utility, it seems
reasonable that the development of library of 2-aminothiazoles might provide additional lead molecules for use in drug
discovery. Owing to important features of 2-aminothiazole and its derivatives, various research groups reported the
synthesis of 2-aminothiazoles.
Hantzsch reaction of a-halocarbonyl compounds with thioureas or thioamides provides useful method for the
synthesis of thiazoles [10]. Solid supported synthesis has been used to generate small organic libraries of
aminothiazoles [11] and solution phase preparation of combinatorial libraries have been prepared in DMF [12] as well
as in dioxane [13]. Recently, many improved methods have been reported for the synthesis of thiazoles using
ammonium-12-molybdophosphate in methanol [14], b-cyclodextrin in water [15], iodine [16], silica chloride [17],
microwave assisted reaction in ethanol [18], ionic liquid [19], and in water [20]. These reported methods are having
drawbacks like high reaction temperature, handling of volatile, hazardous, toxic organic solvents, cumbersome
product isolation procedures, often used expensive catalysts, expensive ionic liquids and handling of lachrymatric
a-halocarbonyl compounds. In view of the above drawbacks, chemists are putting more efforts to modify the Hantzsch
method employing green tools. Polyethylene glycol (PEG) is non-toxic, easily available, inexpensive, non-ionic liquid
medium of low volatility. PEG and its monoethyl ethers are inexpensive, thermally stable, reusable, and non-toxic
*
Corresponding author.
E-mail address: manera@indiatimes.com (R.A. Mane).
1001-8417/$ – see front matter # 2009 Ramrao A. Mane. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
doi:10.1016/j.cclet.2009.11.035

D.V. Jawale et al. / Chinese Chemical Letters 21 (2010) 412–416
413
Scheme 1. Synthesis of 2-aminothiazoles in PEG-400.
media and also are phase transfer catalysts [21]. PEG is a biologically acceptable polymer used extensively in drug
delivery and in bio-conjugates as tool for diagnostics. It has been not only widely used as a solvent medium but also as
a support for various organic transformations [22]. In recent times ionic liquids have been in the forefront of research,
and several reports have already appeared in literature [23]. Even though ionic liquids offer some advantages, the
tedious preparation of ionic liquids (and raw materials for ionic liquids) and their environmental safety is still debated
and is often more expensive than that of PEG [24]. Many organic reactions have been carried out in PEG [25] like
Heck, asymmetric dihydroxylation, Baylis–Hillman, Biginelli, Stille cross coupling, Wacker and asymmetric Aldol
reaction. In continuation of our work for developing convenient synthetic protocols for bioactive molecules [26] and
considering the need of developing environmentally accepted convenient protocols for aminothiazoles here it was
thought worthwhile to optimize the conditions of cyclocondensation of thioureas and in situ generated a-
bromoketones for getting the high yields of the thiazoles. Therefore, we have attempted for the first time the synthesis
of 2-aminothiazoles by allowing interactions of aromatic ketones, N-bromosuccinimide (NBS), thioureas and aryl
thioureas in PEG-400, a greener reaction medium at ambient temperature.
We have developed a versatile, environmentally friendly, one-pot method for the synthesis of 2-amino thiazoles in
non-ionic liquid medium, PEG-400. The reactions of acetophenones, N-bromosuccinimide and thiourea or aryl
thioureas were carried out in PEG-400 as greener reaction medium at room temperature (R.T.) and obtained the
corresponding 2-aminothiazole derivatives with excellent yields (Scheme 1, Table 1).
In order to generate a-bromoketones in situ we have carried out bromination of acetophenone in PEG-400 at R.T.
using various brominating agents, viz.: (i) KBr, KBrO and catalytical amount of acetic acid, (ii) bromine and (iii)
3
NBS. Among these brominating reagents, it was observed that when NBS reagent was used for carrying bromination
of the acetophenones at room temperature in PEG-400, the bromination was found to be completed within 6 h. It was
also noted that there was no need to add any radical initiator to carry this bromination.
As it is reported that N-halosuccinamides effectively halogenate acyl functionality generating mono haloketones in
presence of p-toluene sulphonic acid in polar solvent, acetonitrile than the aprotic solvents DCM/CCl [27]. In
4
continuation of our earlier interest [26] of replacing volatile organic media by non-volatile organic media while
carrying organic transformations here we attempted the bromination of substituted acetophenones using NBS in PEG-
4
00 at room temperature. The reaction when carried out at R.T., it was found to be completed within 6 h. This fact can
be attributed to the activation of NBS in protic media, PEG-400 by forming intermolecular H-bonding between
terminal OH group of PEG-400 and carbonyl oxygen of NBS. There is also possibility of rapid generation of donor
enolate of acetophenones in PEG-400 than those in CCl /DCM. This can be because of possibility of formation of
4
intermolecular H-bonding between hydroxyl group of acetophnone enols and ethereal oxygens of PEG-400. PEG-400
might be activating substrates acetophenones and even reagent NBS, for favourable interaction leading to a-
bromoketones even at R.T.
To thus generated solution of a-bromoketones in PEG-400, stiochiometric quantity of thiourea was added and the
reaction mass was stirred at R.T. The progress of the cyclocondensation was monitored by TLC. It was recorded that
the condensation has been accomplished within 1 h. This protocol has following advantageous: (i) it prevents the
handling of lachrymatric phenacyl bromides as these were generated in situ; (ii) it does not require high temperature;
(iii) it avoids use of toxic organic solvents; (iv) it does not need radical initiators [27] or UV light to convert aromatic
ketones to phenacyl bromides. The a-bromoketones generated in situ have been found to undergo heterocyclization
with thiourea or aryl thioureas to afford the corresponding thiazoles in PEG-400 with excellent yields (Table 1). The
1
1
product 3n was characterized by IR, H NMR and mass spectral analyses. The melting points of 3a–3m and HNMR
are in good agreement with those reported in the literature [20,28] and are recorded in Table 1.
Probably the formation of 2-aminothiazoles by employing PEG-400 as reaction medium may be due to the
H-bonding between the PEG etheral oxygen and hydrogen attached to sulphur of thiourea (enolic forms) which makes

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D.V. Jawale et al. / Chinese Chemical Letters 21 (2010) 412–416
415
S–H bond weaker enhancing the nucleophilicity of sulphur for nucleophilic addition to electron deficient a-carbon of
acetophenones. The electron deficiency of carbonyl carbon of acetophenones may be enhanced by forming H-bonding
with terminal –OH group of PEG-400.
Herein we have developed an efficient, convenient, ecosustainable and environmentally benign synthesis of 2-
aminothiazoles. In this method medium used is safer PEG-400 and avoids the use of volatile and toxic organic
solvents. The main advantages of this method are (i) bromination and successive cyclocondensation occur at R.T., (ii)
no need to isolate in situ generated lachrymatric a-bromoketones, (iii) yields of the 2-aminothiazoles are relatively
higher and (iv) isolation and other work up are not tedious.
1
. Experimental
1
Melting points were taken in open capillary and are uncorrected. H NMR spectra were recorded on a Brucker
00 MHz spectrometer and mass spectra on a V.G. auto spectrometer using ESI techniques. IR spectra were scanned
3
using KBr disc on the JASCO FT-IR 4100, Japan. Acetophenones, thiourea and NBS used in the work were of
synthetic grade, obtained from Merck, S.D. Fine Chemicals and Spectrochem, India.
A mixture of aromatic acetophenones (5 mmol), N-bromosuccinimide (5.5 mmol) in PEG-400 (15 mL) was stirred
for 6 h at R.T. The formation of a-bromoketones was monitored by thin layer chromatography (TLC). After
completion of the bromination, thiourea (5 mmol) or aryl thiourea (5 mmol) were added and the reaction mass further
stirred for 1 h and the progress of the reaction was monitored by thin layer chromatography (TLC). After the
completion of the reaction 25 mL of ethyl acetate was added. The precipitation occurred, was filtered. To the solid
2
obtained was filtered and crystallized from proper solvents: (3n) white solid. IR (KBr): 3458, 3283, 3127, 1633, 1338
0 mL of distilled water was added and its pH was maintained at 9–10 with drop wise addition of ammonia. The solid
Àl 1
and 663 cm . H NMR (300 MHz, CDCl ): d 5.00 (br s, 2H, NH , exchangeable with D O), 7.12 (s, 1H, thiazole H),
3
2
2
+
7.32 (d, 1H, J = 8.00 Hz, ArH), 7.45 (dd, 1H, J = 8.00 Hz, J = 3.00 Hz, ArH), and 7.85 (d, 1H, J = 3.00 Hz, ArH). ESI
+
mode: m/z 245 (M , 100%), 247 (M + 2, 66%) and 249 (M + 4, 14%).
+
+
Acknowledgments
Authors are thankful to Professor D.B. Ingle for his invaluable discussion and guidance and one of the authors, D.V.
Jawale is also thankful to U.G.C., New Delhi, India for the meritorious student research fellowship.
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