A New and Efficient Method for the Synthesis of Pyrimido [ 2 , 1-b ] benzothiazole Derivatives

The one-pot three-component reaction of 2-aminobenzothiazole, benzaldehyde derivatives and β-ketoester, β-diketone or malonate derivatives in solvent-free conditions provides the corresponding pyrimido[2,1-b]benzothiazole derivatives at 60 ̊C in 60% 72% yields without using any catalyst in an optimistic time.


Introduction
Fused heterocyclic compounds are very important compounds partially because of their pharmacological properties which include wide applications in medicinal chemistry [1].Nowadays, much attention has been drawn to pyrimidines and condensed pyrimidine compounds for their worthwhile and interesting biological properties [2].
Although the above methods that have been described for the synthesis of pyrimido[2,1-b]benzothiazole derivatives have their own advantages, but many of these reported procedures lead to some disadvantages including low yields, prolonged reaction time, various use of reagents, catalysts, toxic organic solvents in the reaction media as well as high temperature during completion of the reaction.Recently, solvent free conditions has received considerable interest ascribed to increasing of Global concerns over harmful chemical reagents and replacement of noxious organic solvents is one of the most important goals in green chemistry.
We have introduced a one-pot three-component con- (2)  densation reaction (MCR) that is one of the most useful methods for the synthesis of organic compounds in an optimistic time and only in a single step.Moreover, the aforementioned reaction most often leads to product that can be easily separated and purified by simple filtering and washing out with a regular solvent.In fact, we have not established a mechanism for the formation of these two compounds although a proposed mechanism is indicated in Schemes 2 and 3.
It seems benzaldehyde as an electrophile and β-ketosters (2)/β-diketones (3), malonate (4) derivatives as active methylene compounds take part through an in-situ Knoevenagel reaction and an alkene is primarily formed.Afterwards, during the Michael addition reaction, 2aminbenzothiazole as a Michael donor attacks alkene during nucleophilic reaction, so an iminium ion is formed, subsequently with a proton transformation and an intramolecular cyclization, products 6a-g are produced.In the final step, during intramolecular cyclization, malonates with two proper leaving groups (two alkoxy groups), with considering the temperature, easily omit carbon dioxide from their structure and give rise to the formation of compounds 6f-h (2-oxo-pyrimido[2,1-b]benzotiazole de-rivatives).Schemes 1 and 2 show the proposed mechanisms for the formation of products.
The structures of compounds 6a-g were deduced from their 1 H NMR, 13 C NMR and IR spectral data and also by mass spectrometry.The 6a-e products exhibited a singlet in 1 H spectra at about δ = 5.54 -6.33 ppm for H-4 and also a distinguished peak at δ = 50.9-56.5 ppm for C-4 in 13 CNMR spectroscopy.The 6f-g products demonstrated a singlet in 1 H spectra at δ = 9.02 -10.2 ppm for H-3 and also a distinguished peak at δ = 110.9-116.2 ppm for C-3 in 13 CNMR spectroscopy.The mass spectra of these compounds displayed molecular ion peaks.The selected spectroscopic data are reported in the experimental section.

Conclusion
As a result, 4H-pyrimido[2,1-b]benzothiazole (6a-e) and 2-oxo-pyrimido[2,1-b]benzothiazole (6f-g) are formed smoothly with the reaction of β-ketosters, β-diketone, malonates and benzaldehyde derivatives in the solventfree conditions with no solvent as well as no catalyst and subsequent annulation's reactions proceeded in accept- able yields.These derivatives present a class of compounds that can be used as procedures for the synthesis of new derivatives with useful biological activities.In addition, our method has significant advantages, such as the high bond forming efficiency, solvent-free reaction conditions.

Instruments and Characterization
Melting points were recorded on an Electrothermal 9100 melting point apparatus and Infrared (IR) spectra were recorded on a ABB FTLA-2000 spectrophotometer using KBr disks. 1 H-NMR and 13 C-NMR spectra were recorded on Bruker DRX 500 (500 MHz) AVANCE spectrometer in DMSO using TMS as the internal standard.Mass spectra were recorded on HP 5379(Agilent Technology) (EI, 20eV, 70eV).

General Procedure for the Synthesis of 4-Aryl-2H-pyrimido-[2,1-b]benzothiazol-2-one: (6f-g)
A mixture of 2-aminobenzothiazole (1 mmol, 152 mg) and benzaldehyde derivatives (1 mmol) and diethylmalonate (1 mmol, 160 mg) or dimethylmalonate (1 mmol, 132 mg) was heated at 60˚C in the solvent-free conditions for 3 -3.5 hr.Completion of the reaction was confirmed by TLC (Petroleum ether: EtOAc 1:2).At the end of the reaction the mixture was washed 2 -3 times with water and diethylether.The desired products were obtained with high purity.The purity of prepared compounds was tested by the elemental analysis of C, H, and N elements using a Heraus CHN rapid analyzer.