DESIGN AND SYNTHESIS OF N, O-CONTAINING HETEROCYCLES

Abstract

The thesis entitled “Design and synthesis of N, O-containing heterocycles” is reported in five chapters. The present work is aimed to design and synthesis of N and O containing heterocyclic compound via different novel methodology involving C―C, C―O, C―N bonds formation using different reactions like knoevenagel condensation, Aza Michael addition with sequential dehydrogenation, oxiadative C―C bond cleavage and Ullman type reaction. The synthesized compounds were characterization through different analytical techniques such as 1H NMR, 13C NMR, HRMS and x-ray diffraction and their biological evaluations were reported as calcium calmodulin dependent protein kinase applications. Chapter 1. Introduction Heterocyclic compounds are widely distributed in nature. All living things are made up of genetic material and this genetic material are made up of DNA, Which contains heterocycles moities like purine and pyrimidine as base. Beside these naturally occurring alkaloids such as morphine, vinblastine, papaverine, phenazine; anibiotics such as penicillin, cephalosporin moieties contains heterocyclic rings. Vitamin B complex contains corrin and benzimidazole heterocyclic rings. There are many of natural product having heterocyclic rings such as ascorbic acid, chlorophyll, hemoglobin, ATP, soft drinks, dyes, amino acid. The colour of flowers due to anthocyanin which is the large class of flavonoid family. Consequently the design of structurally diverse heterocyclic compound is one of the driving forces for the development of organic chemistry. The ability to create new heterocyclic compounds in an involuntary and efficient manner is fundamental in many fields; for instance, in the industry heterocyclic compounds are used in making cosmetics, textiles, plastics, lubricants and paints. Moreover they are most extensively used in pharmaceuticals, because 90% of the medicines like analgesic, antitumor, anticancer, antihypertensive drugs are made up of heterocyclic compounds. Therefore, the precise synthesis of heterocyclic compounds is one of the main aims for an organic chemist. Natural product is a substance or compounds, created via living organism such as - plants, fruits and microorganisms, etc. exclusively found in nature, formed with metabolism. For the development in the field of organic chemistry, Natural products have participated a vital role by providing confronting synthetic targets in drug development and drug synthesis. Directly and indirectly, a huge percentage of drugs in modern medicine are originated from natural sources. Traditionally significant concept for the natural products is that it is applied as a therapeutic agent in different disease such as Cancer infectious disease and reduced pain Flavonoids, Carotenoids, Chromenes, coumarins, alkaloids and quinolines etc. are considered as a significant part of natural products and usually utilized around the world due to their assorted pharmacological properties. In Particular, flavonoids, chromene and quinoline have occupied a considerable interest, owing to its diverse pharmacological, therapeutic and chemo-sensor applications.Chapter 2. PhI(OAc)2 mediated an efficient Knoevenagel reaction and their synthetic application for coumarin derivatives In this chapter, We describe the synthesis and stereospecific characterization of ethyl-2-cyano-3-phenylacrylate and different type of substituted coumarins by Knoevenagel reaction and cyclization process using different type of active methylene compounds and benzaldehyde or salicylaldehyde in the presence of phenyl iododiacetate (PIDA) as mediator. Optimization of the reaction conditions and screening of PIDA 1.0 equivalent was found to be best in ethanol solvent for the reaction. The method needs no base and features wide substrate scope and good functional group tolerance with environmentally benign and high yields (80-92%) under mild reaction conditions.Scheme: 2 Synthesis of ethyl-2-cyano-3-phenylacrylate and coumarins using active methylene compounds and aldehyde. All synthesized compounds were fully characterized by 1H-NMR, 13C-NMR, FTIR and HRMS. Chapter 3. Synthesis of 3-nitro-N, 2-diphenyl-2H-chromen-4-amines and their Pharmacological activities against Calcium/Calmodulin dependent Protein Kinase IV (CaMKIV) Inhibitors. In this chapter, A potassium tertiary butoxide mediated Aza-Michael addition with sequential dehydrogenation reaction of substituted 3-nitrochromene with aniline or N-phenyl urea is reported using DMF as solvent. The most important feature of this method is here molecular oxygen (O2) used as oxidant through the oxidative C(sp2)-H amination. This strategy signifies an attractive, cost-effective and operationally convenient tool for synthesis of a wide range of 3-nitro-N, 2-diphenyl-2H-chromen-4- amine derivatives with good to high yields at room temperature. This methodology can be applied to a gram scale synthesis with good to excellent yield (75–90%), a natural product with a broad range of biological activities.All Synthesized compounds were fully characterized by 1H NMR, 13C NMR, FTIR, HRMS and single crystal (XRD). We report activity of aminated chromene compound againts Calcium/calmodulin dependent protein kinase IV (CaMKIV) phosphorylates various transcription activators and subsequently regulates cellular activities which triggered by CaMKK-CaMKIV signalling. However, abnormal expression of CaMKIV is often associated with cancer and neurodegenerative diseases. Here, we have synthesized and characterized a series of 3-nitro-2-phenyl-2H-chromenes and tested their inhibition potential and binding affinity with the CaMKIV. Among the synthesised compounds, the IC50 value (50% of ATPase activity) for compounds D19 and D22 was observed as 12.22±1.12 μM and 16.10± 1.30 μM, respectively. The fluorescence binding and dot-blot assay further complements inhibitory potential, indicating a better binding affinity. These compounds were tested against human cancerous cells (HepG2) and we observed a significant inhibition of cell viability, induced apoptosis and lowered the tau-phosphorylation. In cell viability studies, the IC50 values for compounds D19 and D22 was 18.33±1.12 and 26.22±1.30 μM, respectively. These results suggested that compounds D19 and D22 are non-toxic to the normal cells and specifically inhibits the proliferation of cancerous cells. Chapter 4. SeO2 mediated synthesis of selected heterocycles by oxidative C―C bond cleavage of acetophenone derivatives In this chapter a series of various heterocycles like benzoxazole, benzothiazole, benzimidazole and quinazolinone were designed and efficiently synthesized via SeO2- mediated oxidative C―C cleavage using acetophenone with various O-substituted anilines. The reaction likely involves sequential C―N, C―O and C―S bond formation followed by C(CO)−C(alkyl) bond cleavage. This method provided good-to-excellent product yields in shorter reaction time. The reaction has a number of advantages over existing procedures, for example, it is inexpensive, tolerates various functional groups under mild reaction conditions.All synthesized compounds were fully characterized by 1H-NMR, 13C-NMR, FT-IR, HRMS. Chapter 5. Cu (0) and Cu (I) oxide catalysed cyclisation of halo-betti base via ullmann couling: synthesis of fused banzo-xanthene and oxazine. In this chapter, An operationally simple copper (I) and copper (0)-catalyzed cyclization of halo Betti base has been developed in 2-ethoxy ethanol in basic medium at 130 0C and 100 0C leads to the corresponding Benzo-xenthene and oxazine with high selectivity. By this reagent combination, Iodide, bromide and chloride can be replace by oxygen and C―O bond formed without any ligand involving with good to excellent yield. The reaction is companionable with numerous electron-withdrawing or electrondonating groups. All synthesized compounds were fully characterized by 1H-NMR, 13CNMR, FT-IR, HRMS.