A simple and efficient synthesis of novel pyranothiadiazolopyrimidine derivatives by three component reactions in solvent-free conditions

A simple and efficient protocol for the synthesis of novel pyranothiadiazolopyrimidine derivatives via the reaction of aromatic aldehydes, malononitrile and 7-hydroxy-2-phenyl-5 H -[1,3,4]thiadiazolo[3,2-a]pyrimidine-5-one in solvent-free conditions and in the presence of 1,4-diazabicyclo[2.2.2]octane (DABCO) as organ catalyst, is reported. The procedure involves initial Knoevenagel reaction, followed by Michael addition and subsequent internal heterocyclization. The short reaction time, environmentally friendly conditions and good to high yields are the main advantages of the protocol.


Introduction
3][4][5] In this context, thiadiazolo [3,2-a]pyrimidines are important heterocycles that are also present in a number of natural products.Such structure has been proven to act as an antifungal, antibacterial (Figure 1, 1-2), 6,7 antitumor, 8 antimicrobial, 9 anti-allergy 10 and herbicidal agent. 11Moreover, thiadiazolo[3,2-a]pyrimidin-7ones are important heterocyclic cores, since they exhibit interesting biological activities.3][14] Furthermore, it is well known that pyrans are important scaffolds and play a crucial role in organic synthesis and medicinal chemistry.6][17] In addition, pyran derivatives have been effective agents against Alzheimer's disease and schizophrenia disorders. 18,19urthermore, they have been applied in laser dyes, cosmetics and pigments. 20 It is also well known that the development of environmentally benign and clean synthetic techniques is of particular interest Solvent-free procedures are usually recommended as a better substitute for classical protocols due to their pollution prevention and significant rate acceleration as well as less energy consumption. 22he use of organ catalysts which have unique characteristics, is associated with a low toxicity, easy availability, low cost and stability against air and water. 23As a solid green organ catalyst, 1,4-diazabicyclo[2.2.2]octane (DABCO) has attracted considerable attention as an inexpensive, eco-friendly, highly reactive, easy-to-handle and non-toxic base catalyst for various organic transformations and leads to excellent yields of products with a high selectivity. 24Based on the above information this study aimed to combine thiadiazolopyrimidine and pyran moieties and lead to the synthesis of novel pyranothiadiazolopyrimidine frameworks as biologically-active agents via three-component reactions and specifically of 7-hydroxy-2-phenyl-5H- [1,3,4]thiadiazolo [3,2-a]pyrimidine-5-one, aromatic aldehydes and malononitrile in the presence of DABCO in solvent-free conditions.Three-component reactions of aldehydes, malononitrile and heterocyclic 1,3-diones have already been investigated in other studies  however, According to our knowledge , there are not any literature reports on the use of 7-hydroxy-2-phenyl-5H- [1,3,4]thiadiazolo [3,2-a]pyrimidine-5-one as a heterocyclic dione. Thus,a new, simple and eco-friendly onepot synthetic strategy for the preparation of the desired new densely-functionalized pyranothiadiazolopyrimidine derivatives 4 (Scheme 1) is presented in this study.

Results and Discussion
Initially, the reaction of 7-hydroxy-2-phenyl-5H- [1,3,4]thiadiazolo[3,2-a]pyrimidine-5-one (3) (1 mmol), benzaldehyde (1 mmol) and malononitrile (1 mmol) was taken as the model reaction, and the effect of various parameters, such as reaction catalyst, temperature, time and medium, was evaluated on the outcome of the desired product.The results about the optimization of conditions are summarized in Tables 1 and 2. The model reaction was investigated in the absence of catalysts in solvent-free conditions and the trace amount of the desired product was isolated after 12 h (Table 1, entry 1).The addition of p-TSA as a Brönsted acid catalyst did not enhance the product yield even after 12 h (Table 1, entry 2).In order to obtain higher yields, a variety of base catalysts, i.e. 1,8-diazabicyclo[5.4.0]undec-7-ene, diisopropylethylamine, piperidine, 4dimethylaminopyridine, K2CO3 and 1,4-diazabicyclo[2.2.2]octane (DABCO), were investigated.Among these, DABCO led to the best results in terms of yield and reaction time (Table 1, entries 3-8).
The effect of various solvents, such as H2O, EtOH, CH3CN, Toluene, THF, PEG, DMF and glycerin, was investigated on the model reaction, leading to 32%, 55%, 71%, 25%, 30%, 70, 10% and trace amounts of the product respectively, in 12 h.According to the results presented in Table 2, a solvent-free medium can be used as a green and efficient condition for this reaction (Table 2, entries 1-9).
The amount of catalyst was then also optimized by performing the model reaction in the presence of different amounts of DABCO.Higher yields of the desired product in a short reaction time were obtained by applying 10 mol% of the catalyst.Using 5 mol% of the catalyst reduced the yield, and increasing the amount of catalyst was not significantly effective on the yield and the rate of reaction (Table 2, entries 13, 14).The best results were thus obtained in the presence of DABCO (10 mol%) in solvent-free conditions at 100 °C.
With the optimized conditions established, the versatility of the noted protocol was examined for the onepot synthetic procedure, which proceeded smoothly under mild conditions with structurally-diverse aldehydes.The reactions were successfully performed with aromatic aldehydes and both electronwithdrawing and electron-donating groups on the aromatic ring, and good to excellent yields of the corresponding products, i.e. 4a-k, were obtained in a short reaction time.The procedure was also adopted for 4-Pyridinecarboxaldehyde and 4l was produced with an 85% yield.
The structures of all the synthesized products were confirmed with their IR, 1 HNMR and 13 CNMR spectra and by mass spectrometry (Ref.the supplementary data).The characteristic absorptions at 3444, 3336, 2191, 1700 and 1655 cm -1 in IR spectrum of 4a imply the stretching vibration of NH2, C≡N, C=O and C=N groups.The mass spectra of the compound 4a displayed a molecular ion peak at m/z = 399.According to the 1 HNMR spectrum of 4a, one singlet was exhibited at δ 4.59 for Ar-CH proton, one multiplet at δ 7. 25   Based on the reported catalytic activity of DABCO in the literature, 48 a relevant mechanism is proposed in Scheme 2. As a bicyclic amine base, DABCO facilitates Knoevenagel condensation of aldehyde and malononitrile.The synthetic pathway proceeds via the Michael-type addition of 7-hydroxy-2-phenyl-5H- [1,3,4]thiadiazolo [3,2-a]pyrimidine-5-one to the Knoevenagel adduct (I) that accelerates with the catalytic activity of the solid base catalyst used.In the next step, the intramolecular cyclization of the intermediate (II) led to intermediate (III), which finally underwent tautomeric proton shift to generate the desired product, i.e. 4.

Conclusions
A rapid and environmentally-benign one-pot protocol has been developed for preparing novel pyranothiadiazolopyrimidine derivatives as important hybrid frameworks containing both thiadiazolopyrimidine and pyran with biologically-valuable moieties.The advantages of this new synthetic protocol include the application of DABCO as an organocatalyst along with a solvent-free medium, a nonchromatographic purification process and good to high yields of products.
ring protons and NH2 protons and another multiplet at δ 7.61-7.70for the aromatic ring protons.Furthermore, two doublets appeared for the aromatic protons at δ 7.96 (J=1.8Hz) and 7.98 (J=1.8Hz), respectively.The 13 CNMR spectrum of the product 4a indicated 17 distinct resonances -as closely consistent with the proposed structure.Additionally, the structure of product 4a was further confirmed by single-crystal X-ray diffraction analysis and Figure2presents the ORTEP diagram for 4a (See supplementary data).