Regioselective Syntheses of 3-Benzyl-Substituted 7H-Thiazolo[3,2-a]pyrimidine-7-ones through Palladium-Catalyzed Heteroannulation of Acetylenic Compounds

The Sonogashira reaction is one of the most widely used C– C bond formation ones [1, 2]. It provides an efficient route to aryl alkynes, which are interesting intermediates for the preparation of a variety of target compounds with applications ranging from natural products [3–7] and pharmaceuticals [8] to molecular organic materials [9]. Due to the utility of the products, development of new catalyst systems has received considerable attention. Palladium-catalyzed reactions have been immensely practical for both carboannulation [10, 11] and heteroannulation [12–16] processes. Thiazole and pyrimidine nuclei are the active core of various bioactive molecules. In general, heterocycles encompassing a pyrimidine unit have found applications in a wide spectrum of biological and therapeutic areas [17, 18]. Thus, the heterocyclic system resulting from annulation of a pyrimidine ring on the biologically versatile thiazole nucleus is an attractive scaffold to be utilized for exploiting chemical diversity. Continuing our efforts directed towards the straightforward preparation of biologically active target molecules through Sonogashira coupling reactions [19– 22], we performed the synthesis of new derivatives of thiazolo[3, 2-a]pyrimidones via Pdand Cu-catalyzed Sonogashira coupling reaction. 2. Results and Discussion


Introduction
The Sonogashira reaction is one of the most widely used C-C bond formation ones [1,2]. It provides an efficient route to aryl alkynes, which are interesting intermediates for the preparation of a variety of target compounds with applications ranging from natural products [3][4][5][6][7] and pharmaceuticals [8] to molecular organic materials [9]. Due to the utility of the products, development of new catalyst systems has received considerable attention. Palladium-catalyzed reactions have been immensely practical for both carboannulation [10,11] and heteroannulation [12][13][14][15][16] processes.
Thiazole and pyrimidine nuclei are the active core of various bioactive molecules. In general, heterocycles encompassing a pyrimidine unit have found applications in a wide spectrum of biological and therapeutic areas [17,18]. Thus, the heterocyclic system resulting from annulation of a pyrimidine ring on the biologically versatile thiazole nucleus is an attractive scaffold to be utilized for exploiting chemical diversity.

Results and Discussion
In this communication, we wish to report that treatment of 2-thiouracil 1 with propargyl bromide in MeONa/MeOH affords 2-propargylmercaptouracil 2 in a good yield. The 1 H NMR spectrum of 2 showed a CH proton at 2.17 ppm, CH 2 protons at 3.92 ppm, and a single resonance for the NH group at 13.05 ppm that disappeared on deuteration (as shown in Scheme 1).
Reaction of compound 2 with various aryl iodides, 3a-f, in acetonitrile at room temperature led only to the formation of 3-benzyl-substituted 7H-thiazolo[3, 2-a]pyrimidine-7-ones 4. The reactions were carried out under an argon atmosphere, and solvent was degassed prior to use. Presence of electron withdrawing groups such as NO 2 , Cl, and COMe on the aryl iodide seems to be essential. When iodobenzene was used as the aryl iodide, Sonogashira coupling could not be achieved. The results were tabulated in Table 1.
The following steps can be postulated for the mechanism of formation of either thiazolo [  attack of the nitrogen on the triple-bond intermediates (V) catalyzed by CuI led to product 4 or 5.
Structures 4 and 5 were characterized by comparing their spectra with those for the well-established compounds 6a [24], 6b [25], and 7 [25] (Scheme 3). The IR spectra for 4 or 5 were quite similar to that for 6. Therefore, we can conclude that the one-pot condensation, cyclization, and isomerization of acetylenic compounds regioselectively afford 4.
The 1 H NMR spectrum of 4a exhibited an aromatic proton at 6.70 ppm, which was characteristic of a fused thiazole ring. The other four aromatic protons appeared at 8.10-8.40 ppm. In the aliphatic region, the singlet at 4.30 ppm was due to the benzylic protons.
Organic Chemistry International  In conclusion, we have described a palladium-catalyzed, one-pot reaction for the regioselective syntheses of 3aryl-substituted 7H-thiazolo[3, 2-a]pyrimidine-7-ones from readily available starting materials in moderate-to-good yields.

Experimental
Melting points were uncorrected. The 1 H NMR spectra were recorded at 400 MHz, and the 13 C NMR spectra were recorded at 100 MHz in DMSO-d 6 . The J-coupling constants are reported in Hz.