Synthesis of pyrimido[2,1-b ][1,3]benzothiazoles and [1,3]benzothiazolo [3,2-a ]quinazolines via one-pot three-component reactions from 2-aminobenzothiazole, arylglyoxals and 1,3-dicarbonyl compounds

A simple and efficient synthesis of pyrimido[2,1-b ][1,3]benzothiazoles and [1,3]benzothiazolo[3,2-a ]quinazolines has been developed by using a one-pot, three-component reaction between arylglyoxals, 2-aminobenzothiazole, and various 1,3-dicarbonyl compounds in acetic acid. All the products were obtained in good yields and their structures were established from their spectroscopic data.

To find the optimized conditions, we studied the synthesis of 2-(4-methylbenzoyl)-4H-benzo [4,5]thiazolo-[3,2-a]pyrimidin-4-one 4a via the three-component reaction of 4-methylphenylglyoxal 1a, 2-aminobenzothiazole 2, and Meldrum's acid 3 under a variety of conditions (Table 1).The optimization of the reaction conditions, including the reaction solvent, the reaction temperature, and the equivalents of starting materials, was investigated.First, various solvents were examined (Table 1, entries 1-5), and acetic acid was proven to be the preeminent solvent for this reaction.Then, we examined the influence of different temperatures on this reaction.To our satisfaction, when the reaction was carried out at room temperature in 3 hr, the product was formed in only 12% yield, but under reflux conditions in the same time, the product was formed in 45% yield (Table 1, entries 5 and 10).Finally, we observed that the amount of starting materials also have an important influence on the reaction (Table 1, entries 10-13).A larger amount of 4-methylphenylglyoxal 1a, and Meldrum's acid 3 (for example, 1.0 mmol) in acetic acid at reflux conditions resulted in a higher yield, 58% (Table 1, entry 13).It was found that a longer time of the reaction in acetic acid at reflux conditions did not improve the yield (Table 1, entry 14).A series of experiments revealed that the optimal results were obtained when the reaction of 4-methylphenylglyoxal 1a (1.0 mmol) was conducted with 2-aminobenzothiazole 2 (0.9 mmol), and Meldrum's acid 3 (1.0 mmol) in acetic acid at reflux conditions.Under these optimized conditions, the yield of 4a reached 58%.Under the optimized reaction conditions, were then used to synthesize and explore the scope of this novel transformation with various 1,3-dicarbonyl compounds such as Meldrum's acid 3, dimedone 5 or barbituric acid 7 to give a series of pyrimido[2,1-b][1,3]benzothiazole derivatives (4a-e), (8a-i), and [1,3]benzothiazolo[ [3,2-a]quinazoline derivatives (6a-f) (Table 2).As can be seen from Table 2, the kind of products 4, 6 or 8 are dependent on the nature of the 1,3-dicarbonyl compounds.When the arylglyoxal especially with electron-withdrawing groups and the 1,3-dicarbonyl compounds such as barbituric acid were employed, a shorter reaction time was required, and also a higher yield was obtained.
All the synthesized compounds were previously unknown to the best of our knowledge and were characterized by 1 H and 13 C NMR, IR, CHN analysis and melting points.For instance, the 1 H NMR spectrum of the compound 4a consisted of one singlet at δ = 2.46 ppm for the three hydrogens of the methyl group, and one signal at δ = 6.87 ppm for the alkenic hydrogen.The aromatic protons resonated in the region δ = 7.32-9.16ppm.The 13 C NMR spectrum of compound 4a exhibited 16 distinct signals in agreement with the proposed structure.In the IR spectrum, the carbonyl absorption was observed at 1676 cm −1 .Partial assignments of these resonances for the other products are given in the experimental section.

Conclusions
In summary, we have successfully developed an efficient and one pot, three-component reaction for synthesis of pyrimido[2,1-b] [1,3]benzothiazole and [1,3]benzothiazolo[[3,2-a]quinazoline derivatives by treatment of 1,3-dicarbonyl compounds such as Meldrum's acid, dimedone or barbituric acid with arylglyoxals and 2aminobenzothiazole.Moreover, the method has advantages in terms of higher yields, low cost of the starting materials, shorter reaction time, easy work-up, and mild reaction conditions.

Experimental Section
General.All chemicals were purchased from Aldrich and Merck with high-grade quality, and used without any purification.All melting points were obtained by Barnstead Electrothermal 9200 apparatus and are uncorrected.The reactions were monitored by TLC and all yields refer to isolated products.NMR spectra were obtained on a Varian 500 MHz spectrometer ( 1 H NMR at 500 MHz, 13 C NMR at 125 MHz) in DMSO using TMS as an internal standard.Infrared spectra were recorded on a Bruker FT-IR Equinax-55 spectrophotometer in KBr with absorption in cm -1 .Elemental analyses were performed using a Carlo Erba EA 1108 instrument.All products were characterized by their spectral and physical data.
General procedure for the synthesis of compounds 4a-e.A mixture of arylglyoxal 1 (1.0 mmol), 2aminobenzothiazole 2 (0.9 mmol), and Meldrum's acid 3 (1.0 mmol) was stirred in 5.0 mL of acetic acid under reflux conditions for 130-180 min.After completion of the reaction, determined by TLC, the solvent was removed under reduced pressure, and the viscous residue was purified by plate chromatography (2020 cm) using n-hexane/EtOAc (2:1) as eluent to give the pure compounds 4a-e (55-68%).General procedure for the synthesis of compounds 6a-f.A mixture of arylglyoxal 1 (1.0 mmol), 2aminobenzothiazole 2 (0.9 mmol), and dimedone 5 (1.0 mmol) was stirred in 5.0 mL of acetic acid under reflux conditions for 50-80 min.After completion of the reaction, determined by TLC, the solvent was removed under reduced pressure, and the resulting crude product was recrystallized from ethanol to give the pure compounds 6a-f (70-85%).General procedure for the synthesis of compounds 8a-i.A mixture of arylglyoxal 1 (1.0 mmol), 2aminobenzothiazole 2 (0.9 mmol), and barbituric acid 7 (1.0 mmol) was stirred in 5.0 mL of acetic acid under reflux conditions for 15-40 min.After completion of the reaction, determined by TLC, the solvent was removed under reduced pressure, and the resulting crude product was recrystallized from ethanol to give the pure compounds 8a-i (80-95%).

Supplementary Material
The experimental procedures and 1 H NMR and 13 C NMR spectra associated with this article are available as supplementary data.

Table 1 .
Optimization of the reaction conditions in the synthesis of 4a b Isolated yields.c Reaction time was 12 h.