b Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences, AR 72205, USA
Thiazole is a core structural motif present in a variety of natural products, such as vitamin B1 (thiamine) and penicillin. Thiazole derivatives also exhibit a broad spectrum of medicinal and biological properties, such as antibacterial, antifungal [1], antiinflammatory [2], antiviral [3], antimalarial [4] and anti-HIV activities [5]. Thiazole analogs have also been reported as ligands at estrogen receptors [6], neuropeptide Y5 [7], adenosine receptors [8], and act as inhibitors of human platelet aggregation factor [9], urokinase [10] and poly (ADP-Ribose) polymerase-1 [11]. Selenazoles have been reported to possess antibacterial [12], and superoxide anion scavenging activity [13], and exhibit cytotoxicity and DNA fragmentation effects in human HT-1080 fibrosarcoma cells [14]. The structures of sulfathiazole, meloxicam, and selenazofurin and their pharmacological activities are given in Fig. 1.
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Fig. 1.Biologically active thiazole and selenazole derivatives. |
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Scheme 1.Synthesis of 1,3-thiazoles and 1,3-selenazoles. |
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Scheme 2.Proposed mechanism. |
Melting points were recorded on Stuart SMP30 apparatus and are uncorrected. Analytical thin layer chromatography was performed on F254 silica-gel precoated sheets using hexane/ethyl acetate (8:2) as eluent, and visualized with UV light and iodine vapor. Products were characterized by comparison with authentic samples, and by spectral data (IR, 1H NMR and mass spectrometry). IR spectra were recorded on a Perkin-Elmer 100S spectrophotometer using a KBr disk. 1H NMR spectra were recorded on a Bruker 400 MHz spectrometer using DMSO-d6 as solvent and TMS as internal standard. Elemental analyses were performed on a Carlo Erba modal EA1108 unit, and the values obtained are within ±0.4% of the theoretical values. Mass spectra were recorded on a Jeol JMSD- 300 spectrometer.
The appropriate phenacylbromide or 3-(2-bromoacetyl)-2Hchromen- 2-one (1 mmol) and either thiourea, phenylthiourea or selenourea (1 mmol) were dissolved in 2 mL of methanol, water (2 mL) containing 0.02 g of NaF added and the mixture stirred at room temperature for the appropriate time. After completion of the reaction, 10 mL of water was added and the solid that separated out was filtered off and washed with water, affording analytically pure substituted 1,3-thiazoles or 1,3-selenazole derivatives in excellent yields.
Associated characterization data can be found in Supporting information.
In continuation of our studies toward the synthesis of biologically active molecules [22], we now report the synthesis of substituted 1,3-thiazoles and 1,3-selenazoles from the reaction of ω-bromoacetophenones and 3-(ω-bromoacetyl)coumarin with thiourea, phenylthiourea and selenourea utilizing NaF as catalyst in 1:1 (v/v) methanol/water at ambient temperature. Under these conditions excellent yields and rapid reaction times were obtained (Scheme 1).
In order to determine optimal conditions, initially, a model reaction between 4-chlorophenacyl bromide and thiourea was carried out in methanol by varying the amount of NaF catalyst. A maximum yield of 92% was obtained with 0.02 g of NaF within 5 min. Increasing amount of NaF led to no change in product yield or reaction time. Several similar synthetic methodologies have been reported utilizing water as solvent [21]; hence we carried out the reaction in 1:1 (v/v) water/methanol utilizing 0.02 g of NaF. To our surprise, under these conditions the reaction was completed within 1 min and afforded analytically pure 4-(4-chlorophenyl) thiazol-2-amine (4a) in 99% yield. We also carried out the reaction in pure water, but these conditions required a longer reaction time (25 min) for complete conversion. For authenticity, the structure of 4a was confirmed on the basis of IR, 1H NMR and mass spectral data and comparison with a literature report [19].
To investigate the unique catalytic activity of NaF, the above reaction was also carried out utilizing different inorganic and organometallic catalysts. These results clearly showed that, NaF is a unique and efficient catalyst for the synthesis of thiazoles at ambient temperature (Table 1).
After optimizing the reaction conditions, we examined the scope and generality of the method utilizing other substrates, i.e., a variety of phenacyl bromides, 3-(2-bromoacetyl)-2H-chromen-2- one, and thiourea, phenylthiourea and selenourea. All the products from these reactions were obtained within 1-3 min in excellent yields. The results are presented in Table 2.
The proposed reaction pathway for the NaF-catalyzed formation of 2,4-disubstituted-1,3-thiazoles and selenazoles is shown in Scheme 2. In the presence of NaF, the electrophilicity of the carbonyl carbon of substituted 2-bromo ethanones is enhanced due to coordination of the carbonyl oxygen with NaF. Amination followed by cyclization and dehydration affords the desired thiazole or selenazole.
In conclusion, we have developed a facile method for the synthesis of substituted 1,3-thiazoles and 1,3-selenazoles by the reaction of ω-bromoacetophenones and 3-(ω-bromoacetyl)-coumarin with thiourea, phenylthiourea, and selenourea in the presence of NaF as a catalyst at ambient temperature. This methodology offers several advantages over other procedures, including higher yields, shorter reaction times, easy work-up procedure, and analytically pure products. We believe that, this methodology is superior over other reported methods, and may have industrial utility in the synthesis of substituted 1,3-thiazoles and 1,3-selenazoles at ambient temperature.
We would like to thank the Director, National Institute of Technology, Warangal for providing facilities under this RSM project. The author (BJ) thanks the Ministry of Human Resource Development for their support, and acknowledges a UGC research fellowship to KVs.
Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.cclet.2013.10.001.
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