الفهرس 
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Abstract
Green chemistry (GC) is no longer a luxury but a necessity. It became imperative for industry and scientific research. Implementing green chemistry’s principles offers a multitude of benefits such as minimizing or eliminating hazardous substances, cost saving, improving occupational health and safety, and innovation for new technologies, materials, and processes.
Green chemistry’s principles and metrics can be applied in the synthesis of pharmaceuticals and biologically-relevant compounds by using no solvents or green solvents, alternative reaction media, one-pot synthesis, multicomponent reactions (MCRs), grinding techniques, visible light, and microwave and ultrasound irradiation.
Nitrogen-containing heterocycles are widespread in pharmaceutical and biologically active scaffolds. They make up more than 75% of medications approved by the U.S. Food and Drug Administration (FDA) and now they are on the market. The work presented in this thesis involves a novel one-pot synthesis of 4-aryl-6-alkylamino/piperidinyl-1,3,5-triazine-2-amines and melam under controlled microwave irradiation (Part 1) and synthesis of polyfunctionally substituted cinnolines via visible-light and solventless grinding as green techniques (Part 2) with respect of green chemistry’s principles.
Part (1): A Novel One-Pot Synthesis of 4-Aryl-6-alkylamino/piperidinyl-1,3,5-triazine-2-amines and Melam under Controlled Microwave Irradiation.
In this part, we developed an efficient protocol for the synthesis of 2-amino-4-aryl-6-alkylamino/piperidinyl-1,3,5-triazine derivatives (391a-e, 392a-c and 393a-d) via one step, multi-component reaction (MCR) of cyanamide (387) or [2-cyanoguanidine (381)], aromatic aldehydes 60 with secondary and primary amines [piperidine (388) (1.5 equiv), aqueous dimethylamine (389) (2.5 equiv), and n-butylamine (390) (1.5 equiv)] under controlled microwave heating at 100°C for 5-10 min (Scheme A). Moreover, single crystal X-ray analysis of compounds 391a and 391b unambiguously confirmed the structure of these products 391-393 (Figure A).
A literature survey showed that the previously reported synthesis of melam (386) is a very sophisticated process therefore, we developed an easy, simple, and efficient synthesis of melam (386) (1.0 equiv) using cyanamide (387) (6.0 equiv) [or 2-cyanoguanidine (381) (3.0 equiv)] in the presence of piperidine (388) (1.5 equiv) as a solvent and a basic organocatalyst under controlled microwave heating at 100°C for 5 min (Scheme B).
This process is proved to be of high yields, short reaction times as well as simple work-up or isolation of the reaction final products without chromatographic separation.
Scheme A: Synthesis of 4-aryl-6-pipperidinyl/alkylamino-1,3,5-triazine-2-amines 391a-e, 392a-c and 393a-d.
Figure A: Single crystal X-ray structure of compounds 391a and 391b.
Scheme B: Novel synthesis of melam (386).
Part (2): Synthesis of Polyfunctionally Substituted Cinnolines via Visible-Light and Solventless Grinding as Green Techniques.
Our interest in developing a new synthesis of biologically active cinnoline derivatives prompted us to develop herein, for the first time, a synthesis of polyfunctionally substituted cinnolines 415a-t via a reaction of ethyl 1-aryl-5-cyano-4-methyl-6-oxo-1,6-dihydropyridazine-2-carboxylates 412 with nitrostyrenes 413 using visible light with EtOH/pip. at room temperature for 8 h or solventless grinding with mortar and pestle using a few drops of piperidine as a basic catalyst at room temperature for 5 min. (Scheme C) and expected phthalazines 416 were not formed. These compounds exhibited anti-cancer activities against both leukemia and melanoma cell lines.
It is notable that the visible-light mediated synthesis for cinnolines is of high efficiency process with high-yielding products. Moreover, solventless grinding is preferable to visible-light as it reduces time and increases yield.
Scheme C: Synthesis of cinnoline derivatives 415a-t.