Synthesis of thiazoles and aminothiazoles from β-keto tosylates under supramolecular catalysis in the presence of β-cyclodextrin in water

Article abstract of DOI:10.1080/00397910701575913

This is the first report on the supramolecular synthesis of thiazoles/aminothiazoles from β-keto tosylates and thioamide/thiourea in water in the presence of β-cyclodextrin in impressive yields. Formation of inclusion complexes was explained from 1H NMR studies. Copyright Taylor & Francis Group, LLC.

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Synthesis of Thiazoles and Aminothiazoles
from β‐Keto Tosylates under Supramolecular
Catalysis in the Presence of β‐Cyclodextrin in
Water
V. Pavan Kumar a , M. Narender a , R. Sridhar a , Y. V. D. Nageswar a & K.
Rama Rao a
a Organic Chemistry Division I , Indian Institute of Chemical Technology ,
Hyderabad, India
Published online: 14 Dec 2007.
To cite this article: V. Pavan Kumar , M. Narender , R. Sridhar , Y. V. D. Nageswar & K. Rama Rao (2007)
Synthesis of Thiazoles and Aminothiazoles from β‐Keto Tosylates under Supramolecular Catalysis in the
Presence of β‐Cyclodextrin in Water , Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 37:24, 4331-4336, DOI: 10.1080/00397910701575913
To link to this article: http://dx.doi.org/10.1080/00397910701575913
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Synthetic Communicationsw, 37: 4331–4336, 2007
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910701575913
Synthesis of Thiazoles and Aminothiazoles
from b-Keto Tosylates under
Supramolecular Catalysis in the Presence of
b-Cyclodextrin in Water
V. Pavan Kumar, M. Narender, R. Sridhar,
Y. V. D. Nageswar, and K. Rama Rao
Organic Chemistry Division I, Indian Institute of Chemical Technology,
Hyderabad, India
Abstract: This is the first report on the supramolecular synthesis of thiazoles/amino-
thiazoles from b-keto tosylates and thioamide/thiourea in water in the presence of
b-cyclodextrin in impressive yields. Formation of inclusion complexes was
explained from 1H NMR studies.
Keywords: aminothiazoles, b-cyclodextrin, b-keto tosylate, supramolecular catalysis,
thiazoles, thioamide, thiourea, water
INTRODUCTION
Thiazoles are an important class of compounds of profound interest to
medicinal and industrial chemists because compounds bearing the thiazolyl
moiety exhibit diverse biological properties such as antiglutamate and anti-
Parkinson,[1] antimicrobial,[2] antihypertension,[3] anti-inflammatory,[4] and
antioxidant[5] properties and inhibition of enzymes such as aldose
reductase,[6] lipoxygenase,[7] acetylcholine esterase,[8] ATPase,[9] and HCV
helicase.[10] Heterocycle-bearing substrates are particularly desirable
Received in the USA May 9, 2007
IICT Communication Number 070503.
Address correspondence to K. Rama Rao, Organic Chemistry Division I, Indian
Institute of Chemical Technology, Hyderabad 500 007, India. E-mail: drkrrao@
yahoo.com
4331

4332
V. P. Kumar et al.
structures for screening and are prevalent in drugs that have reached the
marketplace.[11] Thus, it seems highly desirable to develop various practical
synthetic routes to aminothiazoles and thiazoles.
The supramolecular catalysis of the cyclodextrins and our earlier
expertise in biomimetic modeling of chemical reactions[12] prompted us to
investigate a variety of cyclization reactions using the substrate b-keto
tosylate–b-CD complexes with thioamide or thiourea in water to get
thiazole or aminothiazole, respectively, in high yields.
RESULTS AND DISCUSSION
The reaction was carried out by the in situ formation of the b-CD complex of
b-keto tosylate in water followed by the addition of thioamide/thiourea and
stirring for 1–3 h at room temperature to give the corresponding thiazole/
aminothiazole in impressive yields (Scheme 1). Several examples illustrating
this simple and practical methodology are summarized in Table 1. The
reaction proceeds smoothly without the formation of any rearranged
products. The catalyst b-CD can be easily recovered and reused. All the
products were characterized by 1H NMR, IR, mass spectroscopy, and
elemental analysis. These reactions do take place with a-cyclodextrin
(a-CD); however, b-CD was chosen as the catalyst because it is inexpensive
and easily accessible. Longer reaction times (.16 h) were seen in the absence
of b-CD, and the yields were also very low (10%). Some of the compounds
were insoluble in water. These experiments indicate the substantial role of
cyclodextrin.
The supramolecular catalysis of the reaction was studied by means of 1H
NMR spectroscopy with b-CD, phenacyl tosylate, and thiourea as representa-
tive examples. NMR spectroscopy is one of the most important techniques
used for the characterization of inclusion complexes.[13] The formation of
the inclusion complex results in chemical shift changes of cyclodextrin. In
general, the inclusion of an aromatic guest into the cyclodextrin cavity
causes major upfield shifts of the H-3 and H-5 of cyclodextrin situated
inside the cavity, which is attributed to the ring-current effect of the
1
aromatic ring.[14] The H NMR (dimethyl sulfoxide (DMSO)) of the b-CD,
b-CD–phenacyl tosylate complex, and freeze-dried reaction mixtures of
b-CD–phenacyl tosylate–thiourea at 30 min were studied. An upfield shift
Scheme 1.

Thiazoles and Aminothiazoles
4333
Table 1. Synthesis of thiazoles/aminothiazoles with b-keto tosylates in the presence
of b-CD in water
Time Yieldb
Entry
Substrate
Producta
R
(h)
(%)
1
2
3
R ¼ CH3
R ¼ Ph
2.0
1.4
1.2
91
93
89
R ¼ NH2
4
5
6
R ¼ CH3
R ¼ Ph
2.2
2.1
1.5
93
90
84
R ¼ NH2
7
8
9
R ¼ CH3
R ¼ Ph
2.1
2.0
1.4
90
91
86
R ¼ NH2
10
11
12
R ¼ CH3
R ¼ Ph
2.4
2.1
1.5
89
84
82
R ¼ NH2
13
14
15
R ¼ CH3
R ¼ Ph
3.1
2.5
2.3
88
83
81
R ¼ NH2
1
aAll the products were charaterized by H NMR, IR, and mass spectroscopy.
bIsolated yields after purification.
was observed for the H-3 proton in the complex (Dd ¼ 0.021 ppm) and in the
reaction mass at 30 min (Dd ¼ 0.026 ppm) as well as for the H-5 proton in the
complex (Dd ¼ 0.028 ppm) and in the reaction mass at 30 min
(Dd ¼ 0.034 ppm), indicating the formation of the inclusion complex. Thus,
cyclodextrin binds the substrate and promotes the reaction in shorter
reaction times. Hydrogen bonding of the tosyl group with cyclodextrin
hydroxyl may be facilitating the attack by the substrate nucleophile for the
reaction to take place at room temperature.
CONCLUSIONS
These cyclodextrin reactions with water as solvent are not only economical
but environmentally friendly. b-CD, apart from being nontoxic, is also meta-
bolically safe.[15] Significant improvements offered by this procedure are (i)
simple operational and mild conditions (room temperature), (ii) excellent
yields, (iii) cost-efficiency, providing recyclability of the catalyst, and (iv)

4334
V. P. Kumar et al.
environmental friendliness, because hazardous organic solvents are avoided.
Further applications of the reaction are under study.
EXPERIMENTAL
Materials
All the reactions were carried out without any special precautions in an atmos-
phere of air. Chemicals were purchased from Aldrich and S.D. Fine Chemicals
1
and used as received. The H NMR spectra were recorded on Varian 200 or
Brucker 300-MHz spectrometers. IR spectra were recorded on a Nicolet
fourier transform-infrared spectroscopy (FT-IR) spectrometer. Mass spectra
were observed on V.G. auto spectrometer.
General Procedure
b-CD (1 mmol) was dissolved in water (15 ml) at 608C, and then b-keto
tosylate (1 mmol) dissolved in acetone (1 ml) was added slowly with
stirring and cooled to room temperature. It was followed by the addition of
thioamide/thiourea (1 mmol), and stirring continued for 1–3 h at room temp-
erature. After completion of the reaction, the organic material was extracted
with ethyl acetate; the organic phase was separated, filtered, and washed
with NaHCO3 followed by brine. The organic phase was then dried
(Na2SO4) and filtered, and the solvent was removed under vacuum. The
crude product thus obtained was purified by silica-gel column chromato-
graphy using ethyl acetate–n-hexane (2:8) as eluent. The aqueous layer was
cooled to 58C to recover the b-CD by filtration.
Data
4-Tert-butyl-2-methylthiazole (Table 1, Entry 13)
IR (KBr) 3227, 2944, 1582 cm21; 1H NMR (CDCl3, 300 MHz) d: 1.25 (s, 9H),
1.36 (s, 3H), 7.25 (s, 1H); mass (EI) 155 m/z. Anal. calcd. for C8H13NS
(155.26): C, 61.89; H, 8.44; N, 9.02. Found: C, 61.79; H, 8.52; N, 9.07.
4-Tert-butyl-2-phenylthiazole (Table 1, Entry 14)
IR (KBr) 3288, 2926, 1597 cm21; 1H NMR (CDCl3, 200 MHz) d: 1.42 (s, 9H),
6.85 (s, 1H), 7.34–7.47 (m, 3H), 7.93–8.01 (m, 2H); mass (EI) 217 m/z.
Anal. calcd. for C13H15NS (217.33): C, 71.84; H, 6.96; N, 6.44. Found: C,
71.91; H, 6.91; N, 6.87.

Thiazoles and Aminothiazoles
4335
4-Tert-butylthiazol-2-amine (Table 1, Entry 15)
IR (KBr) 3438, 3279, 3163, 2961, 1524 cm21; 1H NMR (CDCl3, 300 MHz) d:
1.24 (s, 9H), 5.09 (bs, 2H), 6.02 (s, 1H); mass (EI) 156 m/z. Anal. calcd. for
C7H12N2S (156.25): C, 53.81; H, 7.74; N, 17.93. Found: C, 53.89; H, 7.68; N,
17.97.
ACKNOWLEDGMENTS
V. P. K. and M. N. thank Council of Scientific and Industrial Research (CSIR),
New Delhi, India, for the award of research fellowships.
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