Ultrasound-promoted One-Pot, Three Component Synthesis Of Novel 5-Amino-2-(4-Chlorophenyl)- 7- Substituted Phenyl-8,8a-Dihydro-7H- [1,3,4]Thiadiazolo[3,2-a]Pyrimidine-6-Carbonitrile Derivatives

Here is the report of an environment friendly, rapid, and conveni ent one-pot ultrasound-promoted synthesis of 5-amino-2-(4-chlorophenyl)-7substituted phen yl-8,8a-dihydro-7H-[1,3,4]thiadiazolo[3,2a]pyrimidine-6-carbonitrile derivatives. Multi-component reactions are useful for the creation of chemical libraries of drug-like compounds with levels of molec ular complexity and diversity. 1,3,4Thiadiazolo[3,2-a]pyrimidine skeleton belongs to a well-known and important class of fused heterocycles prevalent in a number of natural products of biologi cal activities including antitumor, fungicidal, antibacterial, and herbicidal, hence, prompted us to s ynthesis 1,3,4-Thiadiazolo[3,2a]pyrimidines. The final ten derivatives were obtained in exc ellent yield through a one-pot, three component condensation reaction of aldehyde, 4-chlorophenyl-2-ami nothiadiazole, and malononitrile in 10-12 ml of ethanol as solvent and sodium hydroxide as a catalyst. (VCX 500-220, Ultrasound Solid probe, irradiation at 800C and 20% amplitude). We have carried out the same reaction by conventional method, whi c requires 9-10 hrs of refluxing and yield is lesser. Because of the advantage of faster reaction rates an d better yields, use of Ultrasound solid probe, was found to be more suitable for this reaction. Str ucture of the synthesized derivatives was confirmed by IR, NMR and Mass spectral study.


Graphical abstract Introduction Introduction
Heterocyclic compounds have drawn special attention in organic chemistry because of their abundance in natural products and their diverse biological properties [1]. During recent years there have been intense investigations on fused thiadiazole and pyrimidine systems. Literature survey revealed that [1,3,4] thiadiazolo [3,2-a]pyrimidine nucleus is associated with diverse pharmacodynamic and chemotherapeutic activities [2,3], including antimicrobial [4,5,6] and antitumor activities [4,6], herbicidal, antifungal, neuramidase inhibitors. 1,3,4-thiadiazolo[3,2-a]pyrimidines have been used as key building blocks for the preparation of a variety of novel bioactive agents. [7] The conventional multistep methods for the preparation of complex molecules involve large synthetic operations, including extraction and purification processes for each individual step, that lead to synthetic inefficiency and the generation of large amounts of waste. individual step, that lead to synthetic inefficiency and the generation of large amounts of waste. So designing multicomponent reactions (MCRs) in one pot and creation of several bonds in a single operation are the major challenge for modern organic chemistry. Multicomponent reactions (MCRs) are chemical transformations in which three or more different starting materials combine together via a one-pot procedure to give a final complex product. MCRs advantages [8][9].
high atom economy, low cost, reduction in overall reaction time operational simplicity Less or no generation of waste No individual step extraction and purification processes less amount of solvents required Green chemistry has become a major inspiration for organic chemists to develop environmentally benign routes for synthesis of organic compounds of biological values. For instance, performing reactions under ultrasonic irradiation due to the formation of high energy intermediates to enhance the reaction efficiency from both economical and ecological points has significant synthetic value and received great attention.
In recent years, ultrasound has been extensively applied as a fantastic tool for different types of chemical reactions [8] Ultrasound-promoted synthesis has various advantages over conventional synthesis techniques

Mechanism of ulrasound irradiation in synthesis:
The waves of ultrasound can be transmitted through any substance containing elastic property. The motion of these sounds is transferred to the particles of the environment, which vibrate in the route of the ultrasound wave. As the molecules oscillate, the molecular distance decreases in the compaction cycle and increases during rarefaction. When the molecular distance exceeds the critical amount necessary to hold the liquid perfect, the liquid collapse; bubbles and cavities are generated. This procedure (cavitation), refers to the generation and the energetic life of bubbles in liquids. The bubbles absorb energy from the generation and the energetic life of bubbles in liquids. The bubbles absorb energy from the waves of ultrasound and grow. Then bubble collapse consequences in pressure changes and high temperature. The solvent vapor suffers fragmentation to produce reactive particles, such as carbenes or free radicals. These high-energy particles are concentrated and lead to intermolecular reactions. In general, the yield of product increases, reactions occur faster, with lower temperatures and minor percentage of by-products achieved [10].

NEED of study NEED of study
The existing synthetic methodologies for [1,3,4] The existing synthetic methodologies for [1,3,4]  Most of these are multistep protocols, which suffer from generation of by Most of these are multistep protocols, which suffer from generation of by--products, low yields, and use products, low yields, and use of metal of metal--containing reagents. containing reagents.
Therefore, it is quite significant to develop the direct, efficient, and green alternative approaches to get Therefore, it is quite significant to develop the direct, efficient, and green alternative approaches to get the functionalized the functionalized thiadiazolo thiadiazolo[3,2 [3,2--a] a]pyrimidine pyrimidine derivatives from the viewpoint of green chemistry. derivatives from the viewpoint of green chemistry.

To conduct physicochemical characterization of intermediates and synthesized compounds
To conduct physicochemical characterization of intermediates and synthesized compounds. .

3.
To confirm the structures of synthesized compounds by analytical and spectral techniques such as TLC, FT To confirm the structures of synthesized compounds by analytical and spectral techniques such as TLC, FT--IR, MS, IR, MS, 1 1 H NMR and H NMR and 13 13 C NMR C NMR . .

General
All the reactions were performed in oven-dried glassware's. All reagents and solvents were used as obtained from the supplier or recrystallized /redistilled unless otherwise noted. The ultrasound sonicator (Sonics Vibra-cell, Modelno. The 1 H NMR and 13 C NMR spectra of synthesized compounds were recorded on Bruker Avance II 400 NMR Spectrometer at 400 MHz Frequency in deuterated DMSO and CDCl 3 and using TMS as internal standard (chemical shift δ in ppm). Mass spectra of some compounds were scanned on FTMS+p ESI full mass (100.00-1500.00).
After completion of the reaction (i.e formation of Schiff base) as indicated by TLC, malononitrile (0.01mol) was added to the reaction mixture and again was kept inside an Ultrasonicator acoustic chamber at 80 0 C at 20% amplitude for 1-1.30 hrs. After completion of the reaction (monitored by TLC), the mixture was poured into ice cold water. The product obtained, was filtered and dried. The corresponding product was obtained in high purity after recrystallization of the crude product from ethanol.

Results and discussion
Chemistry: Herein we report the one-pot synthesis of novel 5-Amino-2-  Table 1, the desired product was not formed when H2O was chosen as solvent and when acetonitrile, methanol and dimethylformaide was chosen as solvent , the desired product solvent and when acetonitrile, methanol and dimethylformaide was chosen as solvent , the desired product was formed in low yield under reflux and ultrasonic irradiation as shown in Table 1     5-amino-2-(4-chlorophenyl)-7-(3-hydroxy-4-methoxyphenyl)-7H- [1,3,4]