Journal of the Korean Chemical Society 2016, Vol. 60, No. 4 Printed in the Republic of Korea http://dx.doi.org/10.5012/jkcs.2016.60.4.245 -245- An Improved Protocol on the Synthesis of Thiazolo[3,2-a]pyrimidine Using Ultrasonic Probe Irradiation Sian Hui Tan † , Tse Seng Chuah ‡ , and Poh Wai Chia §, * † School of Marine Science and Environment, Universiti Malaysia Terengganu, 21030 Kuala Terengganu, Terengganu, Malaysia ‡ School of Food Science and Technology, Universiti Malaysia Terengganu, 21030 Kuala Terengganu, Terengganu, Malaysia § Institute of Marine Biotechnology, Universiti Malaysia Terengganu, 21030, Kuala Terengganu, Terengganu, Malaysia. * E-mail: pohwai@umt.edu.my (Received March 7, 2016; Accepted May 11, 2016) ABSTRACT. An improved protocol on the synthesis of thiazolo[3,2-a]pyrimidine-6-carboxylate derivatives are reported. Pre- viously, the thiazolo[3,2-a]pyrimidine-6-carboxylate derivatives were prepared in a two-step procedure. Under the improved procedure, the thiazolo[3,2-a]pyrimidine-6-carboxylate derivatives was readily prepared in a one-step reaction. This proce- dure was found to be more efficient than the previous protocol and also compared to the ultrasound bath and conventional heating methods in terms of yield and reaction time. Key words: One-pot three component synthesis, Thiazolo[3,2-a]pyrimidine, Ultrasound, Solvent- and catalyst-free reaction INTRODUCTION The thiazolopyrimidine derivatives had received con- siderable attention among scientists due to their attractive biological activities, such as calcium channel antagonism property, 1 anti-inflammatory activity, 2 anti-fungal activity, 3 CDC25 phosphatase antagonist activity, 4 anti-acetylcho- linesterase activity, 5 inhibition to mGluRs property, 6 anti- oxidant property, 7 anti-viral property, 8 anti-tumor property 8 and insecticide property. 9 The synthesis of thiazolopyrimidine derivatives could be easily achieved by employing the multicomponent reaction (MCR) method. The MCR has long been used for drugs and herbicide innovation programs. 10 Factors such as the sim- plicity of this method to generate natural products and drug- like molecules, 11 produce minimal waste as a result of the incorporation of all starting materials into a single product 12 and the shorter reaction time in microwave-assisted MCR reaction 13 have all contributed to the feasibility of this method. For decades, the ultrasound technology is known for facile access to synthesize molecular complex scaffolds in organic synthesis. 14 The application of ultrasound in organic synthesis has gained overwhelming attention as it offers chemists relatively simple and inexpensive method for chemical activation. 15 In addition, this method is also known to accelerate the rate of a chemical reaction, and at the same time enhance the reaction yield. 16 Recently, there are growing interests in this non-conventional method as it promotes shorter reaction time, eliminate the use of harm- ful reagents, catalysts- and solvent-free organic transfor- mations, such as in the case exhibited by the synthesis of the 1,4-diazabutadienes 17 and the 1,4-dihydropyridines. 18 Moreover, the inexpensive, fewer synthetic routes and high selectivity of this method has gained interest among the synthetic chemists in the preparation of biologically active scaffold molecules. 19 The traditional method of preparing thiazolo pyrimi- dine encompasses the use of acidic conditions or inorganic substances, such as boric acid, 20 microwave irradiation in the presence of acetic acid, 21 potassium fluoride/alumina catalyst 22 and strontium chloride hexahydrate 23 which requires the aid of acids or catalysts in the reaction. In a previous study, an ultrasound synthesis of thiazolo[3,2-a] pyrimidine-6-carboxylate derivatives was published involv- ing a two-step reaction, where the use of montmorillonite catalyst was employed to prepare the pyrimidinone derivative and subsequently treated with acetylenedicarboxylate in methanol under ultrasound irradiation to obtain the desired product (Scheme 1, Eq. (1)). 24 Apart from that, various substituted diesters of thiazo- lopyrimidine were also prepared by the treatment of 3,4- dihydropyrimidine-2-thione with α-haloester under reflux condition in ethanol. 25 Another similar approach was found involved the mixture of ethyl acetoacetate, substituted benzaldehyde, 2-aminothiazole and sulphamic acid in ethanol and refluxed for 1.5 h to afford the thiazolopyrimidine carboxylates. 26 Moreover, under the nanoparticle-catalyzed organic synthesis enhancement (NOSE) and solvent free