Synthesis and Characterization of Some Novel Mannich Base Compounds
Dr. P. Sounthari Dr. P. R. Sivakumar
Dr. P. Sounthari Dr. P.R. Sivakumar Assistant Professor, PG & Research Department of Department of Chemistry, Chemistry, PSG College of Arts and Government Arts Science, Coimbatore- College (Autonomous), 641 014. Coimbatore - 641 018, Tamil Nadu, India.
ISBN 978-93-89631-02-9 ISBN 978-93-89631-04-3 (eBook) https://doi.org/10.34256/ioriip196
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Synopsis
The present study includes Synthesis of new Mannich base compounds based on some 1, 3, 5-triazine substituted uracil derivatives with formaldehyde and secondary amines. The title compounds were screened for their in vitro antimicrobial activity against Bacillus subtitle, Pseudonomous Aeruginosa, Staphylococcus aureoles and E.Colli and three fungal species Aspergillus niger, Candida Albicans and Aspergillus fumigatus using the disc diffusion method. Most of the synthesized compounds appeared with promising antimicrobial and antioxidant activity. The structure of the novel compounds were elucidated on the basis of IR, 1H and 13C NMR spectroscopy.
Authors
Dr. P. Sounthari was working as Assistant Professor in the Department Chemistry of CBM College Kovaipudur and PSG College of Arts and Science, Coimbatore. She has completed M.Sc from CBM College Kovaipudur, Coimbatore and Ph.D in Chemistry from PSGR Krishnammal College for Women, Coimbatore. She is a versatile teacher having three years of Experience in the field of teaching. She participated and presented many papers in National and International Conferences, Seminars and Workshops. She acts as Resource person in “Young student scientist’s programme” sponsored by the TNSCST organized by the PSG College of Arts and Science, Coimbatore. She has to her credit several articles and research papers published in various National and International Journals. Dr. P.R. Sivakumar, Research Scholar in PG & Research Department of Chemistry, Government Arts College, Coimbatore. He has completed M.Sc and Ph.D in Chemistry from Government Arts College, Coimbatore. He has completed B.Ed from Mother Terasa College, Salem. He participated and presented many papers in National and International Conferences, Seminars and Workshops. He has to his credit several articles and research papers published in various National and International Journals.
Contents
1 Introduction ...... 1 1.1 Introduction Green Chemistry ...... 1 1.2 Principles of Green Chemistry ...... 2 1.3 Green Chemistry - The Need of the Day...... 3 1.4 Scope of Green Chemistry ...... 4 1.5 Industrial Interest in Green Chemistry ...... 4 1.6 Green Chemistry in Education ...... 5 1.7 Microwave in Organic Synthesis ...... 5 1.8 Principles of Microwave Activation ...... 6 1.9 Applications of Microwave Chemistry ...... 8 1.9.1 Applications in Analytical Chemistry ...... 9 1.9.2 Applications in Chemical Synthesis ...... 10 1.9.3 Applications in Polymer Chemistry ...... 12 1.10 Various Types of Microwave Assisted Organic Reactions ...... 12 1.10.1 Microwave Assisted Reactions using Solvents ...... 12 1.10.2 Microwave assisted Reactions under Solvent-Free Condition...... 14 1.10.3 Microwave assisted Reactions using Solid Liquid Phase ...... 15 1.10.4 Microwave assisted Reactions on Mineral Supports in Dry Media ...... 17 References ...... 18 2 Schiff Bases - Interesting Range of Applications in Various Fields of Science ...... 21 2.1 Introduction ...... 21 2.1.1 Biological activity ...... 21 2.1.2 Antibacterial properties ...... 21 2.1.3 Antifungal properties ...... 22 2.1.4 Biocidal properties ...... 22 2.1.5 Antiviral properties ...... 22 2.1.6 Antimalarial properties ...... 23 2.1.7 Anticancer properties ...... 23 2.2 Introduction to Mannich Reaction ...... 23 2.2.1 Mannich reaction: A versatile and convenient approach to bioactive skeletons: ...... 25 2.2.2 Mannich reaction and its modern variants ...... 25 2.2.3 Application of Mannich reaction in bioactive molecule synthesis ...... 26 2.2.4 Synthesis of antimalarial molecules ...... 27 2.2.5 Synthesis of antitumour molecules ...... 27 2.2.6 Synthesis of antimicrobial agents ...... 28 2.2.7 Synthesis of anti-inflammatory molecules ...... 28 2.2.8 Synthesis of anticonvulsant molecules...... 28 2.3 Introduction to Heterocyclic Compounds ...... 29 2.3.1 Pyrimidine compounds ...... 30 2.3.2 Triazine derivatives...... 31 References ...... 33 3 Review of Literature ...... 38 References ...... 50 4 Scope of the Present Investigation ...... 53 References ...... 55 5 Experimental Methods ...... 56 5.1 Materials ...... 56 5.1.1 Procedure ...... 56 5.1.2 Antibacterial Activity ...... 57 5.1.3 Anti-Fungal Activity ...... 57 5.1.4 Antioxidant Activity ...... 58 5.1.5 Stage-I ...... 59 5.1.6 Stage-II ...... 62 5.1.7 Stage-III ...... 65 References ...... 69 6 Result and Discussion ...... 70 6.1 Physical Properties ...... 71 6.2 FT-IR Spectra ...... 71 6.3 NMR Spectra ...... 71 6.4 Antimicrobial and Antifungal activities ...... 71 6.5 Antioxidant activity ...... 72 7 Conclusion ...... 88
Chapter 1 Introduction
1.1 Introduction to Green Chemistry
‘Green Chemistry’ is the new branch of chemistry which involves pulling together tools, techniques and technologies. It is helpful to chemists and chemical engineers in research, development and production for development of more eco- friendly and efficient products which may also have significant financial benefits. It is now going to become an essential tool in the field of synthetic chemistry. The development of Green Chemistry redefines the role of a solvent: “An ideal solvent facilitates the mass transfer but does not dissolve”. In addition, a desirable green solvent should be natural, nontoxic, cheap and readily available with additional benefits of adding the reaction, separation or catalyst recycling [1, 2]. The term Green Chemistry was first used in 1991 by Prof. Paul T. Anastas to implement sustainable development in chemistry and chemical technology by industry, academia and Government [3]. In 1995 the annual US Presidential Green Chemistry Challenge was announced. In 1996 the Working Party on Green Chemistry was created, acting within the framework of International Union of Applied and Pure Chemistry. One year later, the Green Chemistry Institute (GCI) was formed in 20 countries to facilitate contact between governmental agencies and industrial corporations with universities and research institutes to design and implement new technologies. The first conference highlighting green chemistry was held in Washington in 1997. Since that time other similar scientific conferences have soon held on a regular basis. The first books and journals on the subject of green chemistry were introduced in the 1990s, including the Journal of Clean Processes and Green Chemistry sponsored by the Royal Society of Chemistry. Green Chemistry embodies two main components. First, it addresses the problem of efficient utilisation of raw materials and the concomitant elimination of waste. Second, it deals with the health, safety and environmental issues associated with the manufacture, use and disposal or reuse of chemicals. Green Chemistry incorporates a new approach to the synthesis, processing and application of chemical substances in such a manner as to reduce threats to health and the environment [4-9]. This new approach is also known as: • Environmentally Benign Chemistry • Clean Chemistry
© IOR INTERNATIONAL PRESS 2019 P.Sounthari and P.R. Sivakumar, Synthesis and Characterization of Some Novel Mannich Base Compounds, https://doi.org/10.34256/ioriip1981 1 Introduction
• Atom economy • Benign-by-Design Chemistry [4]
1.2 Principles of Green Chemistry
Green Chemistry is commonly presented as a set of twelve principles proposed by Anastas and Warner [1]. The principles comprise instructions for professional chemists to implement new chemical compound and new synthesis and technological processes.
Prevention It is to prevent waste than to treat or clean up waste after it has been created.
Atom Economy Synthetic methods should be designed to maximize the incorporation of all materials used in the process into the final product.
Less Hazardous Chemical Synthesis Whenever practicable synthetic methods should be designed to use and generate substances that possess little or no toxicity to human health and the environment.
Designing Safer Chemicals Chemical products should be designed to affect their desired function while minimizing toxicity.
Safer Solvents and Auxiliary The use of auxiliary substances should be made unnecessary wherever possible.
Design for Energy Efficiency Energy requirements of chemical processes should be recognized for their environmental and at low temperature and pressure.
Use of Renewable Feedstock’s A raw material or feedstock should be renewable rather than depleting whenever technically and practicable.
Reduce Derivatives Unnecessary derivatization (use of blocking groups, protection, deprotection) should be avoided whenever possible.
Catalysis Catalytic reagents (as selective as possible) are superior stoichiometric
2 Introduction reagents.
Design for Degradation Chemical products should be designed so that at the end of their function they break down into innocuous degradation products and do not persist in the environment.
Real-time analysis for pollution prevention Analytical methodologies need to be further developed to allow for real-time, in process monitoring and control prior to the formation of hazardous substances.
Inherently Safer Chemistry for Accident prevention Substances and the form of a substance used in a chemical process should be chosen to minimize the potential for chemical accidents, including releases, explosions and fires. These principles can motivate chemistry at all levels: research, education and public perception. The first principle describes the basic idea of green chemistry in protecting the environment from pollution. The remaining principles are focused on atom economy, toxicity, solvent and other media using consumption of energy, application of raw materials from renewable sources and degradation of chemical products to simple, nontoxic substances that are friendly for the environment.
1.3 Green Chemistry - The Need of the Day
Green Chemistry is no doubt a special contribution of chemists to the conditions for sustainable development incorporating an environmentally "benign by design" approach to all aspects of chemical industry. Sustainable development has becoming major economic, environmental, legal and social issue of this century. The word Green Chemistry was continued by Paul T Anastas, which means the judicious use of chemistry for prevention of pollution. It involves the designing of products and processes using environmentally safe alternatives that reduce the generation of hazardous substances. Green Chemistry is one of them, which involves modified engineering practices, bioremediation, ecofriendly reaction media and concept of atom economy leading to almost zero waste. Green strategies include the replacement of organic solvent by water, elimination of a solvent, the substitution of environmentally benign substances to replace toxic heavy metals, development of solid support reagents and catalysis for synthesis, launching of eco-friendly methods of organic synthesis, designing of products, which can be recycled or safely disposable, use of dry media reactions and many other important aspects. The overall strategy is to virtually eliminate toxic persistent substances from the environment by allowing no further release or by collecting and destroying the existing deposits. Harmful synthetic products either should be replaced by green products or should be synthesized friendly techniques. Green Chemistry has launched the concept
3 Introduction of atom economy. The objective is to conduct chemical reaction where all the atoms that go into process come out either incorporated in the products or marketable side products. It combines the goals of environmental benignity with synthetic elegance in the design of methods for producing compounds. Green Chemistry places special emphasis on the synthesis of new substances and the corresponding industrial process. The use of microorganism for the synthesis of drugs and chemical disposal with the help of genetically manipulated living system has been considered safe [10].
1.4 Scope of Green Chemistry
Newer, environmentally friendly, waste minimization, remediation (clean- up) and restoration strategies can be based on physical, chemical or biological approaches [11]. Examples of green chemistry or technology that have been developed encompass most all areas of chemistry including organic, biochemistry, inorganic, polymer, toxicology, environmental, physical, industrial etc. The principle of Green Chemistry can be applied broadly to areas like synthesis, catalysis, reaction conditions, analysis and monitoring extraction, separation, computational chemistry and process modeling etc [12]. An emerging area of increasing importance in green chemistry is that of analytical chemistry and all of its associated activities. Green Chemistry is also applicable to all sectors of the chemical industry ranging from pharmaceuticals and specially chemicals to the high volume of manufacture of bulk chemicals. The growing public sentiment in support of our environment, the focus of the industry has shifted to reduce or eliminate the use of water and organic solvents during manufacturing and processing. This involves 'closed loop system' leading to reduction and/or recycling, switching to "solvent free" processes or "solvent alternatives". The key to achieving the goal of reducing the generation of environmentally unfriendly waste and the use of toxic solvents and reagents is the widespread substitution of "Stiochiometric" technologies by greener, catalytic alternatives.
1.5 Industrial Interest in Green Chemistry
Many forward-looking companies are embracing green chemistry, not only to protect the environment and to create good public relations, but also because it is often beneficial to the bottom $ 100 and $ 150 billion per year to comply with environment regulations. In addition, cleaning up hazardous waste sites will cost hundreds of billions of dollars. In many companies, the cost of dealing with environment regulations often exceeds their expenditure for research. Larger companies budget close to $ 1 billion per year for environment compliance. If a company can significantly reduce this expenditure, then these funds can be spent in more productive areas and result in an improved bottom line. Thus, Green Chemistry (pollution prevention) is not only good for the environment but also for industry [13].
4 Introduction
1.6 Green Chemistry in Education
Convincing chemists to think in an environment friendly manner begins with education. The idea of including green chemistry in chemistry education was first put forward in 1994. Few Green Chemistry textbook have also been published [14]. Graduates, post graduates, teachers and researchers will find these books of immense use. Both Environment Protection Agency (EPA) and American Chemical Agency (ACS) have recognized the importance bringing Green Chemistry to the class room and the laboratory. Together they have launched a significant campaign to develop Green Chemistry educational materials and to encourage the ‘greening’ of the chemistry curriculum. Student involvement in Green Chemistry principles and practices is essential to the integration the environmentally benign technologies in academia and industry. ACS student Affiliate chapters may be recognized as “green” chapters by engaging in at least three green chemistry activities during the academic year. Suggestions for these activities include:
Hosting a Green Chemistry speakers • Organization an interdisciplinary Green Chemistry workshop on campus • Working with a local company on a Green Chemistry project • Developing a Green Chemistry activity with a local school • Converting a current laboratory experiment into a greener one • Organizing a Green Chemistry poster session on campus • Distributing a Green Chemistry Newsletter to the local community • Designing a Green Chemistry web page
Green Chemistry is the design of chemical products and processes that reduce or eliminate the use and generation of hazardous materials. One of the principles of Green Chemistry involves use of microwave to carry out the reaction [15]. Microwave assisted organic reactions are of great interest because of its advantages.
1.7 Microwave in Organic Synthesis
Microwave have been used to speed up chemical reactions in the laboratories which led scientists to investigate the mechanism of microwave dielectric heating and to identify the advantages of the technique for chemical synthesis [15-16]. During recent years, microwaves have been extensively used for carrying out chemical reactions and have become a useful non-conventional energy source for performing organic synthesis [17]. This is supported by a great number of publications in recent years, particularly in 2003, related to the application of microwaves as a consequence of a great availability of dedicated and reliable microwave instrumentation [18-23]. The first recorded application of microwave energy in organic synthesis is the aqueous emulsion polymerization of butyl acrylate, acrylic acid and methacrylic
5 Introduction acid using pulsed electromagnetic radiation. The start of the rapid growth of microwave assisted procedures in organic synthesis was ignited in 1986 by pioneering papers by Gedye and co-workers [9] and Giguere and coworkers [24]. During the last two decades, the activity in this new technique has experienced exponential growth and has been extensively reviewed. Kappe and Dallinger have reported the impact of microwaves on drug discovery. Even microwave-assisted reactions under solvent-free conditions promoted the synthesis of Zincke’s salt and its conversion to chiral pyridinium salts in water and microwave- assisted organic transformations using benign reaction media have also been reported. Moreover, Varma and co-workers have reported the drug discovery by using aqueous microwave chemistry [25-30].
1.8 Principles of Microwave Activation
In the electromagnetic spectrum the microwave radiation region is located between infrared radiation and radio-waves [29]. Telecommunication and microwave radar equipment occupy many of the band frequencies in this region. In order to avoid interference with these systems, the household and industrial microwave ovens operate at a fixed frequency of 2.45 GHz. The energy of the quantum involved can be calculated by the Planck’s law E = h ν and is found to be 0.3 cal mol–1.
Presently, organic transformations take place by either of the two ways.
Conventional heating: In this method of heating, reactants are slowly activated by a conventional external heat source. Heat is driven into the substance, passing first
6 Introduction through the walls of the vessel in order to reach the solvent and the reactants. This is a slow and inefficient method for transferring energy into the reacting system.
Microwave heating: Here, microwaves couple directly with the molecules of the entire reaction mixture, leading to a rapid rise in the temperature. Since the process is not limited by the thermal conductivity of the vessel, the result is an instantaneous localized superheating of any substance that will respond to either dipole rotation or ionic conductivity. Only the reaction vessel contents are heated and not the vessel itself; better homogeneity and selective heating of polar molecules might be achieved. The acceleration of chemical reactions by microwave exposure results from the interactions between the material and electromagnetic field leading to the thermal and specific (non-thermal) effects. For microwave heating, the substance must possess a dipole moment. A dipole is sensitive to external electric field and tries to align itself with the field by rotation. If submitted to an alternating current, the electric field is inversed at each alterance and therefore dipoles tend to move together to follow the inversed electric field. Such a characteristic induces rotation and friction of the molecules, which dissipates as internal homogeneous heating. The electric field of commonly used irradiation frequency (2450 MHz) oscillates 4.9 × 109 times per second. Thus, microwave heating is directly dependent on dielectric properties of a substance, dielectric constant (ε’) and dielectric loss (ε”). The ability of a material to convert electromagnetic energy into heat energy at a given frequency and temperature, is calculated using ε’’ / ε’ = tan δ (1)
where δ is the dissipation factor of the sample, ε” is the dielectric loss, which measures the efficiency with which heat is generated from the electromagnetic radiation and ε’ is the dielectric constant which gives the ability of a molecule to be polarized by an electric field. The high value of dissipation factor δ indicates large susceptibility to microwave energy [31]. The conduction mechanism leads, due to the much stronger interaction of ions with electric field, to the generation of heat. The ions will move under the influence of an electric field, resulting in expenditure of energy due to an increased collision rate, converting kinetic energy into heat. The heat generated by both mechanisms adds up resulting in a higher final temperature. Since the ability of a molecule to couple with the microwave radiation is a function of its molecular polarizability (i.e. a function of its dipole moment), only polar molecules interact with microwave energy. As a guide, compounds with high dielectric constants such as water, ethanol, acetonitrile, N, N-dimethylformamide (DMF), acetic acid, chloroform, dichloromethane, acetone, ethylene glycol etc., tend to heat rapidly under microwave irradiation, while less polar substances, such as aromatic and aliphatic hydrocarbons or compounds with no net dipole moment, such as carbon dioxide, carbon tetrachloride, diethyl ether etc., as well as highly ordered crystalline substances are poorly absorbing. Thus polar molecules in a non-polar solvent would absorb energy, but not the solvent or the reaction vessel, if it is made of teflon (μ = 2.1 at 22°C) or
7 Introduction ceramic or even pyrex (μ= 4.5–6.0). Sometimes it is possible to use mixtures comprising microwave active reactants and microwave inactive solvents. It has also been suggested that if microwave energy is absorbed by the solvent and not by the substrate, only modest rate increase will result relative to those observed with conventional energy. If, on the other hand, the microwave energy is absorbed selectively by a reactant, by a complex or by an intermediate during the rate determining step, then large rate increase will result.
Advantages
In the past, microwave chemistry was often used only when all other options to perform a particular reaction had failed or when exceedingly long reaction times or high temperatures were required to complete a reaction. This practice is now slowly changing and due to the growing availability of microwave reactors in many laboratories, routine synthetic transformations are now also being carried out by microwave heating. Microwave include following advantages, over the conventional heating. • Uniform heating occurs throughout the material • Process speed is increased • High efficiency of heating • Reduction in unwanted side reaction • Purity in final product, • Improve reproducibility • Environmental heat loss can be avoided • Reduce wastage of heating reaction vessel • Low operating cost
1.9 Applications of Microwave Chemistry
Microwave chemistry is applicable in various industries such as the biotechnology, pharmaceuticals, petroleum, plastics, chemicals etc., and major applications have been developed in the field of analytical chemistry and chemical
8 Introduction synthesis. Due to the successful development of commercial instrumentation, microwave dielectric heating is now being increasingly applied in chemical reactions. However, most of these applications have been limited to small-scale use in laboratories and have not been extended to the production level. The major industrial applications of microwave chemistry can be segmented as:
1.9.1 Applications in Analytical Chemistry
The various applications of microwave radiation in analytical chemistry are:
Ashing
Ashing is used in various analytical laboratories to determine the ash content in a sample, for the purpose of process and quality control. Microwave heating is extensively used for ashing in the petroleum and fuels, plastics, pharmaceuticals and food industries. In most of these industries, microwave powered muffle furnaces, which are specifically meant for laboratory use, are used for ashing. These microwave muffle furnaces have proven to be more efficient (about 97%) compared to conventional muffle furnaces. They can reach high temperatures ranging between 1,000°C and 1,200°C and can also process a large number of samples simultaneously [33].
Digestion
Digestion is the process by which samples are broken down to their basic constituents for chemical analysis. Microwave digestion systems are used in analytical laboratories for sample decomposition and preparation. It involves the heating of microwave-absorbing reagents inside a pressurized, microwave-transparent container, in contrast to conventional open vessel digestion. Pressurization allows higher temperatures to be achieved in short period and it increases the speed of digestion. Rapid heating accelerates the reaction rate exponentially and results in an approximately 100-fold decrease in the time required for the process of digestion at 175°C, compared to such a process conducted at 95°C. Microwave radiation has now become the technology of choice for sample preparation trace and ultra-trace metals analysis and is being used in the digestion of even the toughest organic or inorganic samples in diverse industries [34].
Extraction
Microwave extraction has proved to be more effective and efficient than its conventional counterpart, the Soxhlet extraction method. The Soxhlet extraction, which is a standard technique, is a continuous solvent extraction method. Extraction systems are used to conduct routine solvent extractions of soils, sediments, sludge,
9 Introduction polymers and plastics, pulp and paper, biological tissues, textiles and food samples. Experiments have proved that microwaves, in comparison with the Soxhlet extraction, use a lesser volume of solvent and sample and perform extraction at a much faster rate. For example, it has been observed that about 500 microwave extractions can be performed for a given solvent, compared to just 32 Soxhlet extractions [34].
Moisture analysis
Application of microwave assisted moisture analysis has been extended to food and beverage, chemical, environmental, organic and pharmaceutical industries and has been found to be highly effective in reducing testing time. Microwave moisture analysis is specifically applied at product development stages such as process and quality control, testing of raw materials, intermediate and finished products [34].
1.9.2 Applications in Chemical Synthesis
Application of microwave radiation in chemical synthesis encompasses its use in the acceleration of chemical synthesis. Microwave enhanced synthesis allows organic chemists to work faster, generate higher yields, and increase product purity. In addition, due to the availability of high capacity microwave apparatus, the yields of the experiments have now easily scaled up from milligrams to kilograms, without the need to alter reaction parameters. Microwave organic synthesis is the main component of microwave-assisted chemical synthesis.
Organic synthesis
Organic synthesis is the preparation of a desired organic compound from available starting materials. Microwave assisted organic synthesis has been the one of the most researched applications of microwaves in chemical reactions. Chemists have successfully conducted a large range of organic reactions. These include [35]
1. Diels-Alder reaction 2. Heck reaction 3. Suzuki reaction 4. Mannich reaction 5. Hydrogenation of [beta]-lactams 6. Hydrolysis 7. Dehydration 8. Esterification 9. Cycloaddition reaction 10. Epoxidation 11. Reductions 12. Condensations 13. Protection and deprotection
10 Introduction
14. Cyclisation reactions
Microwave-assisted organic synthesis is being widely applied in the pharmaceuticals industry, particularly for developing compounds in the lead optimization phase of drug development. In this phase, chemists use diverse synthetic techniques to develop candidate drugs from lead compounds. Based on reaction conditions, organic synthesis reactions can be conducted in the following ways:
❖ Organic synthesis at atmospheric pressure ❖ Organic synthesis at elevated pressure ❖ Organic synthesis in dry media
Inorganic synthesis
Synthesis of organometallic and coordination compounds
Microwave radiation has been successful in accelerating the reaction rate for the generation of organometallic and coordination compounds, which are produced by generating covalent bonds between organic compounds and metals.
Synthesis of intercalation compounds
Applications of microwave chemistry for intercalation compounds have been tested recently. Intercalation compounds comprise organic or organometallic compounds that are incorporated between layers of oxides and sulphides. Conventional heating methods for the preparation of intercalation compounds, such as the intercalation of pyridine or its derivatives are slow and have limitations w.r.t. the yield obtained.
Synthesis of ceramic products
Microwave processing of ceramic materials has reached a high degree of maturity. In ceramic production industry, the removal of solvent or moisture is a critical step in the generation of ceramic products. Initially, the use of microwaves was limited to the effective removal of solvents from solid samples. It is estimated that for materials with a water content below 5%, microwave drying is efficient than conventional drying methods. However, over the past few years, the utility of microwaves has increased due to other advantages. It has been proven that microwave heating provides better uniform heating than conventional heating methods. Ceramics are widely used in electrical components, sanitary-ware industries, and in many other industries.
11 Introduction
1.9.3 Applications in Polymer Chemistry
Polymer chemistry, including ceramic processing forms the single-largest application area of microwave chemistry. The use of polar reactants in polymerization reaction results in controlled synthesis and a combination of this with direct heating of reactants makes microwave heating an economically viable option. Curing is a polymerization process, which transforms a liquid resin to a solid, creating the maximum physical properties attainable from the materials. Using microwave radiation in curing has greatly increased the rate of the reactions. It has been found that the rate of a curing reaction, using microwaves, is not dependent on the power applied but on the way the pulse is applied [36, 37]
1.10 Various Types of Microwave Assisted Organic Reactions
The microwave-assisted organic reactions have been broadly classified into two categories: • Microwave-assisted reactions using solvents • Microwave-assisted reactions using solvent-free conditions.
1.10.1 Microwave Assisted Reactions using Solvents
In the case of the microwave-assisted reactions using (organic) solvents, the reactants are usually dissolved in the solvent, which often couples effectively with microwaves and thus acts as the energy transfer medium. The use of aqueous media for organic reactions [38-42] is also under active investigation and temperatures of up to 100°C and above have been employed for the syntheses often intended to exploit the hydrophobic effect. Water has a dielectric constant 78 at 25°C which decreases to 20 at 300°C; the latter value being comparable with that of the solvents, such as acetone, at ambient temperature [43-46]. Thus, water at elevated temperature can behave as a pseudo-organic solvent [47] and is a possible environmentally benign replacement for organic solvents. In addition to the environmental advantages [48,49] of using water instead of the organic solvents, isolation of the products is often facilitated by the decrease of the solubility of the organic material upon post-reaction cooling [50]. Microwave irradiation is applicable not only to the solvent phase chemistry, but also to the solid-phase organic synthesis. Following are the example of microwave assisted reaction using solvents.
Hydrolysis
Hydrolysis of benzyl chloride with water in microwave oven gives 97 % yield of benzyl alcohol in 3 min. The usual hydrolysis in normal way takes about 35 min [51].
12 Introduction
C H CH Cl 푀푊, 3 푚푖푛 C H CH OH 6 5 2 + H O → 6 5 2 benzyl chloride 2 benzyl alcohol 97 %
Oxidation
Oxidation [52] of toluene with KMnO4 under normal conditions of refluxing takes 10-12 hr compared to reaction in microwave conditions, which takes only 5 min and the yield is 40%.
Esterification
A mixture of benzoic acid and n- propanol on heating in a microwave oven for 6 min in presence of catalytic amount of conc [53]. Sulfuric acid gives propylbenzoate.
C H COOH Conc H So C H COOC H 6 5 + nC H OH 2 4 6 5 3 7 benzoic acid 3 7 MW 6 min propylbenzoate
Decarboxylation
Conventional decarboxylations of carboxylic acids involve refluxing in quinoline in presence of copper chromate and the yields are low [54]. However, in the presence of microwaves decarboxylation takes place in much shorter time.
Cycloaddition
1, 3-Dipolar cycloadditions [55] are important reactions in organic synthesis. Cycloaducts were prepared by carrying out the reaction between an azide and a substituted amide in toluene. This reaction was carried out under microwave irradiation at 120 W at 75°C for 1 h. The product was isolated in 70–80 % yield.
13 Introduction
N-Acylations
N-Acylations were carried out using secondary amines and isocyanate in dichloromethane under microwave irradiation (8–10 min), yielding the product in 94 % yield [56].
1.10.2 Microwave assisted Reactions under Solvent-Free Conditions
Microwave-assisted solvent-free organic synthesis (MASFOS) has been developed as an environmentally friendly process as it combines the selectivity associated with most reactions carried out under microwaves with solvent and waste- free procedures in which organic solvents are avoided throughout all stages [57]. In these environmentally conscious days, the research and development are directed towards devising cleaner processes. Environmental hazards and the subsequent degradations are instrumental for the rapid evolution of green chemistry concept involving benign reagents and conditions. The MASFOS reactions are of three types:
❖ Reactions using neat reactants; ❖ Reactions using solid-liquid phase transfer catalysis (PTC); ❖ Reactions using solid mineral supports.
For carrying out reactions with neat reactants i.e without the use of a solvent or a support (heterogeneous reactions) at least one of the reactants at the reaction temperature should normally be liquid. In such a set-up, either the solid is partially soluble in the liquid phase or the liquid is adsorbed onto the surface of solid with the reaction occurring at the interface. There is also another possibility, namely that both the reactants are solid [58] Following are the Examples of Microwaves assisted Reactions with neat reactants.
14 Introduction
Aromatic Nucleophilic Substitutions
Formation of Substituted Triazines [59, 60] Aromatic nucleophilic substitutions are carried out using sodium phenoxide and 1,3,5-trichlorotriazine under microwave irradiation (6 min). The products, 1,3,5-triarlyoxytriazines are obtained in 85–90% yields.
Deacetylation
Aldehydes, phenol and alcohols are protected by acetylation. After the reaction, the deacetylation of the product is carried out usually under acidic or basic conditions the process takes long time and the yields are low [61]. Use of microwave irradiation reduces the time of deacetylation and the yields are good.
1.10.3 Microwave assisted Reactions using Solid Liquid Phase
Solid liquid phase transfer catalysis (PTC) has been described as an effective method in organic synthesis and is under active investigation. This method is specific for anionic reactions as it involves anionic activation. A catalytic amount of a tetralkylammonium salt or a cation complexing agent is added to the mixture (in equimolar amounts) of both pure reactants. Reactions occur in the liquid organic phase, which consists here only of the electrophilic R-X. The presence of an additional liquid component is disadvantageous as it induces a dilution of reactants and consequently a decrease in reactivity. The electrophile R-X is therefore both the reactant and the organic phase for the reaction. Following are the Example of Microwave assisted Reaction using Solid Liquid Phase
15 Introduction
O-Alkylation
Preparations of ethers were carried out from β-naphthol using benzyl bromide and 1-utyl-3-methylimidazolium tetrafluoroborate under microwave irradiation (6-12 min) the products were isolated in 75-90% yields.
N-Alkylations
N-Alkylations under microwave irradiation using phase transfer catalysts occupy a unique place in organic chemistry [62]. Bogdal and co-workers reported the synthesis of N-alkyl phthalimides using phthalimide, alkyl halides, potassium carbonate and TBAB giving products in 45–98% yields.
Oxidations
Chakraborty reported the oxidation of secondary alcohol and benzyl alcohols using phase transfer catalysts [63]. Oxidation of secondary alcohols to acetone derivatives was carried out using PCC, tetrabutylammonium bromide and dichloromethane under microwave irradiation (6–8min), products were isolated in 70– 99% yields.
Knoevenagel Condensation
Knoevenagel condensation is a well known organic reaction, other applied in
16 Introduction the synthesis of unsaturated acids, which are used as precursors for perfumes, flavonoids and as building blocks of many heterocycles [64]. Gupta and Wakhloo studied knoevenagel condensation between carbonyl compounds and active methylene compounds, such as malonic acid, using tetrabutylammonium bromide, potassium carbonate in water forming unsaturated acids in excellent yield and purity under microwave irradiation.
1.10.4 Microwave assisted Reactions on Mineral Supports in Dry Media
Solid supports are often very poor conductor of heat but behave as very efficient microwave absorbents. This, in turn results in very rapid and homogeneous heating. Consequently, they display very strong specific microwave effect with significant important in temperature homogeneity and heating rates enabling faster reactions and less degradation of final products as compared to the classical heating. Following are the Example of the Microwave Activation with Supported Reagents.
N-Alkylation
N-Alkylation was carried out between piperidines and chloroalkanes in the presence of silica as the solid support under microwave irradiation (6-10 min) [65]. N- Alkyl products were isolated in 79-99% yields.
S-Alkylation
S-Alkylation was studied and accomplished by carrying out the reaction between mercaptobenzene and alkyl halides using potassium carbonate and alumina under microwave irradiation (4-10 min). Products were isolated in 70-89 % yields [66].
17 Introduction
References
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18 Introduction
19. Mingos D.M.P, Baghurst D.R, Kingston H.M, Hazel S.J, ACS and Washington D. C, 455, 1997. 20. Nuchter M, Ondruschka B, Jungnickel A and Muller U, J Phys. Org. Chem., 13, 579–586, 2000. 21. Nuchter M, Ondrushka B and Lautenschlager W, Synth. Commun., 37, 1277– 1283, 2001. 22. Vanderhoff J.W, Chem. Abstr. 3, 432- 413, 1969. 23. Gedye R, Smith F, Westaway K, Ali V, Baldisera L, Laberge L and Rousell J, Tetrahedron Lett., 27; 279–282, 1986. 24. Giguere R.J, Bray T.L, Duncan S.M and Majetich G, Tetrahedron Lett., 27, 4945–4948, 1986. 25. Li C.J, Chem. Rev., 93, 2023–2035 1993. 26. Kappe C.O and Dallinger D, Nat. Rev. Drug Discovery, 5, 51–63, 2006. 27. Polshettiwar V and Varma R.S, Acc. Chem. Res., 41, 629–639, 2008. 28. Polshettiwar V and Varma R.S, Chem. Soc. Rev., 37, 1546–1557, 2008. 29. Galema S.A, Halstead B.S.J and Mingos D.M.P, Chem. Soc. Rev., 2, 213– 232, 1998. 30. Trotzki R, Nuchter M and Ondruschka B, Green Chem., 5, 285–290 2003. 31. Kingston H.M, Jassie L.B, ACS, Washington D.C, 2, 110–122, 1988. 32. Glasnov T.N, and Kappe C.O, Microwave-assisted synthesis under continuous-flow conditions. Macromolecular Rapid Communications, 28(4), 395–410, 2007. 33. Qinhan J, Feng L, Hanqi Z, Liwei Z, Yanfu H and Daqian S, Applications of microwave techniques in analytical chemistry. Trends in Analytical Chemistry, 18, 479-484, 1999. 34. Gupta M, Paul S and Gupta R, General characteristics and applications of microwaves in organic synthesis, Acta Chim Slov., 56, 749–764, 2009. 35. Berteaud A.J and Badot J.C, High temperature microwave heating in refractory materials. J Microwave Power, 11, 315-320, 1976. 36. Akyel C and Bilgen E, Microwave and radio-frequency curing of polymers: Energy requirements, cost and market penetration. Energy, 14, 839-851, 1989. 37. Breslow R, Acc. Chem. Res. 24, 159–164, 1991. 38. Grieco P.A, Aldrichimica Acta. 24, 59–66, 1991. 39. Bose A.K, Manhas M.S, Banik B.K and Robb E.W, Res. Chem. Interme, 20, 1–11, 1994. 40. Bose A.K, Banik B.K, Lavlinskaia N and Manhas M.S, Chem. Tech., 27, 18– 24, 1997. 41. Lubineau A, Auge J and Queneau Y, Synthesi., 741–760, 1994. 42. Grieco P.A, Brandes E.B, McCann S and Clark J.D, J. Org.Chem., 54, 5849– 5851, 1989. 43. Laurent R, Laporterie A, Dubac J, Balam J, Lefeuvre S and Audhuy M, J. Org. Chem.,57, 7099–7102, 1992. 44. Blokzijl W, Engberts J and Angew B.F.N, Chem., Int. Ed., 32, 1545–1579, 1993.
19 Introduction
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20 Chapter 2 Schiff Bases - Interesting Range of Applications in Various Fields of Science
2.1 Introduction
Schiff bases are condensation products of primary amines and carbonyl compounds and they were discovered by a German chemist, Nobel Prize winner, Hugo Schiff in 1864 [1]. Structurally, Schiff base (also known as imine or azomethine) is an analogue of a ketone or aldehyde in which the carbonyl group (C=O) has been replaced by an imine or azomethine group [2].
2.1.1 Biological activity
Schiff bases are characterized by an imine group –N=CH-, which helps to clarify the mechanism of transamination and racemization reaction in biological system [1].
2.1.2 Antibacterial properties
Mortality increase caused by infectious diseases is directly related to the bacteria that have multiple resistance to antibiotics. The development of new antibacterial drugs enriched by innovatory and more effective mechanisms of action is clearly an urgent medical need [3]. Schiff bases are identified as promising antibacterial agents. For example, N-(Salicylidene)-2-hydroxyaniline is active against Mycobacterium tuberculosis [4].
N-(salicylidine)-2-hydroxyaniline as the example of bio active Schiff base
© IOR INTERNATIONAL PRESS 2019 P.Sounthari and P.R. Sivakumar, Synthesis and Characterization of Some Novel Mannich Base Compounds, https://doi.org/10.34256/ioriip1982 21 Schiff Bases - Interesting Range of Applications in Various Fields of Science
Schiff bases containing 2,4-dichloro-5-fluorophenyl moieties also take part in effective inhibition of bacterial growth [5]. On the other hand, the compounds obtained from furylglyoxal and p-toluidene show antibacterial activity against: Escherichia coli, Staphylococcus aureus, Bacillus subtilis and Proteus vulgaris. Isatin derived Schiff bases present anti-HIV and antibacterial activity. Other Schiff bases derivatives, which possess antibacterial activity, are: benzimidazole, thiazole, pyridine, glucosamine, pyrazolone, hydrazide, thiazolidiones, indole, thiosemicarbazone, p-fluorobenzaldehyde [6]
2.1.3 Antifungal properties
Fungal infections usually are not only limited to the contamination of surface tissues. Recently, there was a considerable increase in the incidence of systemic fungal infections, which are potentially life threatening [7] Exploration and development of more effective antifungal agents is necessity, and the individual Schiff bases are considered to be promising antifungal medicines [8]. Some of them, such as imine derivatives of quinazolinones possess antifungal properties against Candida albicans, Trichophyton rubrum, T. mentagrophytes, Aspergillus niger and Microsporum gypseum [9].
2.1.4 Biocidal properties
Schiff bases obtained by the synthesis of o-aminobenzoic acid and β-keto esters have found biocidal use against S. epidermidis, E. coli, B. cinerea and A. niger. By contrast, Schiff bases of isatin derivatives are used in the destruction of protozoa and parasites [10].
2.1.5 Antiviral properties
The use of vaccines may lead to the eradication of pathogens known viruses, such as smallpox, poliomyelitis (polio), whether rubella. Although there are many therapeutic ways to work against viral infections, currently available antiviral agents are not fully effective, which is likely to cause a high rate of mutation of viruses and the possibility of side effects. Salicylaldehyde Schiff bases derived from 1-amino-3- hydroxyguanidine tosylate are good material for the design of new antiviral agents [4]. Isatin Schiff base ligands are marked by antiviral activity, and this fact is very useful in the treatment of HIV [10]. In addition, it was also found that these compounds have anticonvulsant activity and may be included in the anti-epileptic drugs [11]. Gossypol derivatives also present high antiviral activity. Increasingly, gossypol, often used in medical therapy is replaced by its derivatives, because of their much lower toxicity [12]. Schiff bases have obtained acceptable results for Cucumber mosaic virus, whose effectiveness was estimated at 74.7% [6].
22 Schiff Bases - Interesting Range of Applications in Various Fields of Science
2.1.6 Antimalarial properties
Malaria is a disease which when is neglected causes serious health problems. Human malaria is largely caused by four species of the genus Plasmodium (P. falciparum, P. vivax, P. ovale and P. malariae). The search for new drugs, vaccines and insecticides for the prevention or treatment of this disease is a priority. Schiff bases are interesting compounds, which could be part of antimalarial drugs. For example, the compound with such effect is Ancistrocladidine, which is a secondary metabolite produced by plants of the family Ancistrocladaceae and Dioncophyllaceae, and presenting an imine group in a molecular chain [4].
Ancistrocladaceae- antimalarial activity of bioactive Schiff base
Cryptolepine, valid indolchinoline alkaloid, isolated from African plant Cryptolepis sanguinolenta, also used in the treatment of malaria, is the product of multi-stage reaction, in which Schiff base is involved [12].
2.1.7 Anticancer properties
Some Schiff bases have a high antitumor activity. Imine derivatives of N- hydroxy-N’-minoguanidine block ribonucleotide reductase in tumor cells, so that they are used in the treatment of leukemia [13]. Schiff bases of PDH [N-(1-phenyl-2- hydroxy-2-phenyl ethylidine)-2′,4′-dinitrophenyl hydrazine], PHP [N-(1-phenyl-2- hydroxy-2-phenyl ethylidine)-2′-hydroxy phenyl imine] and HHP [N-(2-hydroxy benzylidine)-2′-hydroxy phenyl imine] reduce the average tumor weight (reduction in tumor growth increases with increasing dose) and decrease the growth of cancer cells in mice EAC cells. In addition, they have ability to rebuild depleted haematological parameters, such as hemoglobin, red blood cells (RBC) and white blood cells (WBC) towards the right content. They also show protective effect on hematopoietic system [14].
2.2 Introduction to Mannich Reaction
Mannich reaction is an organic reaction which consists of an amino alkylation of an acidic proton placed next to a carbonyl functional group with formaldehyde and ammonia or any primary or secondary amine. The final product is
23 Schiff Bases - Interesting Range of Applications in Various Fields of Science a β-amino-carbonyl compound also known as a Mannich base [15]. Reactions between aldimines and α-metheylene carbonyl are also considered Mannich reactions because these imines form between amines and aldehydes. The reaction is named after chemist Carl Mannich.
R H H R R H R R
N H + C O + CH N C C -H2O R H R O R H H O
Mannich reaction is an example of nucleophilc addition of an amine to a carbonyl group followed by dehydration to the Schiff base. The Schiff base is an electrophile which introduced in the second step in electrophilic addition with a compound containing an acidic proton (which is, or had become an enol). The Mannich reaction is also considered a condensation reaction [16, 17]. In the Mannich reaction, ammonia or primary or secondary amines are employed for the activation of formaldehyde. Tertiary amines lack an N-H proton to form the intermediate imine. Α-CH-acidic compounds (nucleophiles) include carbonyl compounds, nitriles, acetylenes, aliphatic nitro compounds, α-alkyl-pyridines or imines. It is also possible to use activated phenyl groups and electron-rich heterocycles such as furan, pyrrole and thiophene. Indole is a particularly active substrate the reaction provides gramine derivatives [18, 19]. Mannich reaction is employed in the organic synthesis of natural compounds such as peptides, nucleotides, antibiotics and alkaloids (e.g. Tropinone). Other application are in agro chemicals such as plant growth regulators [20]. Paint and polymer chemistry, catalysis and crosslinking. Mannich reaction is also used in the synthesis of medicinal compounds e.g. rolitetracycline (Mannich base of tetracycline), fluoxetine (antidepressant), tramadol and tolmetin (anti-inflammatory drug) [17].
Studies on the chemistry of Mannich base are of interest in various areas of application • A large number of aminoalkyl derivatives have been prepared in order to correlate their structure and reactivity with their pharmacological activity. Particularly noteworthy are some general studies such as those concerning cytostatic Mannich bases derived from bis-[2-chloroethyl]-amine [21], melamine, or ethylenediamine [22] and those regarding Mannich base derivatives possessing antimicrobial [22-24] or cardiotonic [25] activity. • Mannich base represents easily obtainable intermediate for the synthesis of other compounds such as heterocycles, amino-alcohols, etc. • Finally, Mannich base have been investigated as potential biological agents, as dyes for synthetic fibers, as reactive dyes and also as surface active compounds.
24 Schiff Bases - Interesting Range of Applications in Various Fields of Science
2.2.1 Mannich reaction: A versatile and convenient approach to bioactive skeletons:
The development of new drugs and target specific delivery agents with enhanced efficacy to counter the multi-drug resistant (MDR) tumours and microbial strains. The modification of existing drug molecules offers a cost and time effective convenient strategy to achieve new bioactive skeletons. Mannich reaction provides a suitable method to introduce aminoalkyl substituent into a molecule. In several instances, the Mannich derivatives exhibit better activity than the corresponding parent analogues vide infra. Moreover, the presence of Mannich side chain increases the solubility and hence the bioavailability of the drug molecule [26].
2.2.2 Mannich reaction and its modern variants
Mannich reaction [27] is one of the most fundamental and important, C-C bond forming reactions in organic synthesis. Mannich reaction withstands a large diversity of functional groups and hence it has been witnessing a continuous growth in the field of Organic Chemistry. The surge of literature on Mannich reaction provides an outstanding evidence for the diversity and applications of the reaction [28-32]. The Mannich reaction and its variants offer a robust method for the preparation of the aminocarbonyl and several other derivatives [33,34]. The following scheme depicts the synthesis of β-aminocarbonyl compounds by Mannich reaction.
O R1 O R3 R4 H R2 1 + N + CH O R 2 2 R3 R H N R4 R1, R2 =alkyl or β-Amino carbonyl derivative R3, R4=cyclic or acyclic amine
However, the classical Mannich reaction has limitations such as lack of selectivity, competitive aldol reactions, etc. To overcome these limitations, modern variants of Mannich reaction utilize performed imines, enolates, appropritate use of catalyst and reaction conditions, etc [35-37] Several chiral auxiliaries and chiral catalysts are often employed to carry out asymmetric Mannich-type reaction [38]. Apart from this, basic nanocrystalline magnesium oxide, [39] recyclable copper nanoparticles, poly(amidoamine) catalysed reactions and microwave-assisted Mannich reactions have also been reported recently. Hayashi et al. discovered high pressure asymmetric Mannich-type reaction in frozen water medium. Cimarelli et al. reported three component Mannich reactions under neat condition for the synthesis of diaminoalkylnaphthols [40].
25 Schiff Bases - Interesting Range of Applications in Various Fields of Science
2.2.3 Application of Mannich reaction in bioactive molecule synthesis
The Mannich reaction and its variants are often employed to access diverse molecules whose applications are ranging from bioactive skeletons to material science. The aminocarbonyl Mannich products are useful in the construction of β- peptides and β-lactams, which are present in several bioactive molecules such as taxol (antitumour agent), bestatine (immunological response modifier) and SCH48461(anti- cholesterol agent) [41]. Tramadol, osnervan and moban are bioactive β-aminocarbonyl derivatives with analgesic, antiparkinson and neuroleptic properties. It is believed that the solubility of the Mannich derivatives increases in water due to protonation of basic amine nitrogen atom [42].
CH O 3
OH OH CH3 N N CH 3 Tramado lOsnervan (Analgesic) (Antiparkinsonic)
HO H3C O OH N N H3C N O N H OH Moban Mulundocandin Mannich analogue (Neuroleptic) (Antifungal activity with increased aqueous solubility)
Mannich reaction was useful for the preparation of zolpidem, a hypnotic drug used for the treatment of insomnia [43]. The Mannich bases are obtained by the condensation reaction of C-H acidic substrates (ketones, phenols, etc.,), amine (cyclic or acyclic) and aldehyde. The Mannich bases are an important class of molecules with significant biological activity. The cationic surfactant molecules obtained from Mannich bases possess excellent fungicidal property along with good biocidal property against Gram-positive and Gram-negative bacteria [44]. The quinoline derived Mannich base possessvasorelaxing properties [45]. Such molecules are useful in the treatment of hypertension. 1,2,4-Triazole derived Mannich bases exhibited anticancer activity [46] The isothiazolopyridine derived Mannich bases were found to be 2 to 10 times more potent than the reference drug acetyl salicylic acid [47]. The Mannich reaction is useful for the synthesis of ferrocenyl derived
26 Schiff Bases - Interesting Range of Applications in Various Fields of Science aminohydroxylnaphthoquinones [48]. These products exhibited good activity against Toxoplasma gondii and atovaquone resistant strain of T.gondii.
2.2.4 Synthesis of antimalarial molecules
Malaria is one of the most widespread infectious diseases in the world. Though effective antimalarial drug like chloroquine exists, drug resistance has become a great challenge. The development of new inexpensive antimalarial drugs is vital in developing countries to counter multi-drug resistant has Plasmodium falciparum [49]. The discovery of new molecular skeletons is always in need to circumvent the drug resistance and to provide good antimalarial activity. In 1997, analogues, a quinoline based di-Mannich bases and screened their activity against multi-drug resistant strains of Plasmodium falciparum. The ex vivo antimalarial activity of the Mannich bases tested in serum were found to be greater than those of amodiaquine, chloroquine or pyronaridine.
R2N R2N OH HO Z
HN HN
Y NR2 Y NR2
X N X N
X=CF3,Cl; Y=H,Me; NR2=NEt2,pyrrolidinyl, X=Cl,CF3; Y=H,Me; Z=H,Me; NR2=piperidinyl, Piperidinyl, 2=methyl piperidinyl, pyrrolidinyl,3-methyl piperidinyl, 4-methylpiperazinyl 3, 5-dimethylpiperidinyl
2.2.5 Synthesis of antitumour molecules
Highly drug-resistant tumour cells limit the success rate of the cancer chemotherapy. The use of doxorubicin, an anthracycline chemotherapeutic agent causes multi-drug resistance in tumour cells. The anthracycline synthetic analogue 4, 11-dihydroxy naphthoindole-5, 10-dione Mannich base showed significant activity against multi-drug resistant tumour cell lines [50].
O OH NH2
N H O OH 4,11-Dihydroxynaphtho[2,3-f]indole-5,10-dione Mannich bases (Anticancer activity)
27 Schiff Bases - Interesting Range of Applications in Various Fields of Science
2.2.6 Synthesis of antimicrobial agents
The development of new antimicrobial agents is needed to counter the increasing number of multi-drug resistant (MDR) strains [51]. The multiple mechanisms operating in the bacteria makes them highly resistant to widely used antibacterial drugs and hence newer generation antibiotics are in need to evade the drug resistance mechanism. The Mannich reaction has been useful in the preparation of various antimicrobial molecules [52]. Lorand et al. studied the antibacterial properties of unsaturated Mannich ketones [53]. The presence of Mannich side chain increases the water solubility of the unsaturated Mannich etones.
(CH2)n Ar
R O
n=1,2,3,4 R = amine; Ar = aryl (exhibit antibacterial activity)
2.2.7 Synthesis of anti-inflammatory molecules
Antiinflammatory drugs are used to treat pain and inflammation. Ibuprofen is a well-known non-steroidal anti-inflammatory drug. Prolonged use of ibuprofen leads to ulceration and nephrotoxicity.The carbonyl derivative of non-steroidal anti- inflammatory properties with minimal side effects. Sujith et al. reported the Mannich reaction of ibuprofen triazole derivatives with formaldehyde and secondary amine [54].
N NH
N S N
Ar Ibuprofen triazole derivative
2.2.8 Synthesis of anticonvulsant molecules
Anticonvulsant molecules are used to treat epileptic seizures, bipolar disorder and neuropathic pain. The currently available antiepileptic drugs phenytoin, mephobarbital induce side effects such as sedation and hypnosis. There is ever- mounting need for new anti-convulsant agents to control all kinds of fits, with minimal or no side effects [55].
28 Schiff Bases - Interesting Range of Applications in Various Fields of Science
2.3 Introduction to Heterocyclic Compounds
Heterocyclic compounds are organic compounds containing at least one carbon atom and at least one element other than carbon, such as sulfur, oxygen or nitrogen within a ring structure. The name comes from the Greek word “heteros” which means “different.” A variety of atoms, such as N, O, S, Se, P, Si, B can be incorporated in to ring structures. By far the most numerous and most important heterocyclic systems are those of five and six members. Heterocyclic make up an exceedingly important class of compounds more than half of all known organic compounds are heterocycles. Almost all the compounds we know as drugs, vitamins, and many other natural products are heterocycles. Since in hetrocycles non-carbons usually are considered to replace carbon atoms, they are called heteroatoms e.g. different from carbon and hydrogen. A ring with only heteroatoms is called homocyclic compound and heterocycles are the counterparts of homocyclic compounds. Thus incorporation of oxygen, nitrogen, sulfur or an atom of a related element into an organic ring structure in place of a carbon atom gives rise to a heterocyclic compound. These structures may comprise either simple aromatic rings or nonaromatic rings. The heterocyclic compounds usually possess a stable ring structure which does not readily hydrolyzed or depolymerized. Heterocycles with three atoms in the ring are more reactive because of ring strain. Those containing one heteroatom are in general, stable. Those with two hetero atoms are more likely to occur as reactive intermediates. Heterocyclic chemistry is one of the most interesting, applied branches of organic chemistry and of utmost practical and theoretical importance. As a result, a great deal of research carried out in chemistry is devoted to heterocyclic chemistry. It is vast and expanding area of chemistry because of obvious application of compounds derived from heterocyclic rings in pharmacy, medicine, agriculture, plastic, polymer and other fields. Heterocyclic compounds are widely distributed in nature. By virtue of their therapeutic properties, they could be employed in the treatment of infectious diseases. Many heterocyclic compounds synthesized in laboratories have been successfully used as clinical agents. Nitrogen-containing heterocyclic compounds have maintained the interest of researchers through decades of historical development of organic synthesis [56]. Nitrogen-containing heterocycles have been used as medicinal compounds for centuries, and form the basis for many common drugs such as Morphine, Captopril and Vincristine (cancer chemotherapy). Nitrogen containing heterocycles occur in a diversity of natural products and drugs and are of great importance in a wide variety of applications. Aromatic nitrogen heterocycles may contain another heteroatom, such as the oxygen in isoxazoles, oxazoles, 1,3,4-oxadiazoles, and 1,2,4-oxadiazoles. Among the drugs containing aromatic five-membered nitrogen heterocycles are cholesterol-reducing Atorvastatin, anti-inflammatory Celecoxib, antiulcerative Cimetidine, antifungal Fluconazole, and antihypertensive Losartan.
29 Schiff Bases - Interesting Range of Applications in Various Fields of Science
2.3.1 Pyrimidine compounds
Heterocyclic compounds are abundant in nature and are of great significance to life because their structural subunits exist in many natural products such as vitamins, hormones, and antibiotics [57, 58]. Hence, they have attracted considerable attention in the design of biologically active molecules [59, 60] and advanced organic chemistry [61, 62]. Also in the family of heterocyclic compounds nitrogen containing Heterocycles are an important class of compounds in the medicinal chemistry and also contributed to the society from biological and industrial point which helps to understand life processes [63] A totally unsaturated six membered-ring containing nitrogen is known as azine [64] or pyridine, with two nitrogen atoms it is known as diazine [65] and with a nitrogen at 1,2-position, it is known as pyridazine, at 1,3- position as pyrimidine and at 1,4-position as pyrazine. However, the current review intends to focus on the significance of pyrimidines class of antimicrobial agents along with clinical and in-vitro applications of pyrimidine derivatives to facilitate the development of more potent as well as effective antimicrobial agents. Pyrimidines [66] are the heterocyclic aromatic compounds similar to benzene and pyrimidine containing two nitrogen atoms at positions 1 and 3 of the six membered rings. Heterocycles containing pyrimidine moiety are of great interest because they constitute an important class of natural and non-natural products, many of which exhibit useful biological activities and clinical applications [67] Substituted purines and pyrimidines occur very widely in living organisms and were some of the first compounds studied by the organic chemists [68] Pyrimidines are biologically very important heterocycles and represent by far the most important of the diazine family with uracil [69] and thymine [70] being constituents of ribonucleic acid (RNA) and deoxyribonucleic acid (DNA) and with cytosine [71]. In addition to this, pyrimidines skeleton is also present in many natural products such as vitamin B1 (thiamine) and many synthetic compounds, such as barbituric acid [72] and Veranal [73] which are used as hypnotics [74]. The presence of Pyrimidine base in thymine, cytosine, and uracil, which are the essential building blocks of nucleic acids DNA and RNA, is one possible reason for their widespread therapeutic applications. The Pyrimidines represent one of the most active classes of compounds possessing wide spectrum of biological activities like signification vitroactivity against unrelated DNA and RNA, viruses including polio herpes viruses, diuretic, antitumor, anti-HIV, and cardiovascular [75]. Dihydropyrimidinones (DHPMs) are well known compounds, possess wide range of biological activities and their applications in the field of research have stimulated the discovery of a wide range of synthetic methods for their preparation and chemical transformations. In case of Nucleic acids, the pyrimidine nucleus is known to be present in three bases, out of five major bases such as cytosine which is found in DNA and RNA, uracil in RNA and thymine in DNA. Due to their involvement as bases in DNA and RNA, they became very important in synthetic organic chemistry [76].
30 Schiff Bases - Interesting Range of Applications in Various Fields of Science
Nucleic acids containing pyrimidine bases
2.3.2 Triazine derivatives
The triazine structure is a heterocyclic ring, analogous to the six-membered benzene ring but with three carbons replaced by nitrogens. The three isomers of triazine are distinguished from each other by the positions of their nitrogen atoms, and are referred to as 1,2,3-triazine, 1,2,4-triazine, and 1,3,5-triazine. Other aromatic nitrogen heterocycles are pyridines with 1 ring nitrogen atom, diazines with 2 nitrogen atoms in the ring and tetrazines with 4 ring nitrogen atoms. Triazines are weaker bases than pyridine.
1,3,5-Triazines (or s-triazines) are a class of compounds well known for a long time, and still continue the object of considerable interest, mainly due to their applications in different fields, including the production of herbicides and polymer photostabilisers [77]. Some 1,3,5-triazines display important biological propertiesfor example hexamethylmelamine (HMM, 1) and 2-amino- 4-morphlino-s-triazine (2) are used clinically due to their antitumor properties to treat lung breast and ovarian cancer, respectively [78]. Hydroxymethylpentamethylmelamine (HMPMM, 3) is also the hydroxylated metabolite which corresponds to the major active form of HMM 3. More recently, significant aromatase inhibitory activity were observed for 1,3,5-triazines of general structure 4. For the similar general structure 5 antitumor activity in human cancer and murine leukemia cell lines were observed [79]. The 1,3,5-triazine 6 presents potential use as siderophore (microbial iron shelter) mediated drug [80] and the general structure 7 presents potent corticotrophin-releasing factor1 receptor antagonist activity [81]. The compounds of type 8 show potent activity against leukotriene C4 (LTC4) antagonist, which possess a protective effect on HCl.ethanol- induced gastric lesions [82]. More recently it was discovered that the compound 9 is a potent corticotrophin-releasing factor1 receptor antagonist [83]. Among several
31 Schiff Bases - Interesting Range of Applications in Various Fields of Science other 1,3,5-triazine substituted polyamines tested, the substrate 10 presents a good in vitro activity against the protozoan parasite Trypanosoma brucei, the causative organism of Human African Trypanosomasis [84].
Select examples of biologically active compounds containing the 1,3,5-triazine unit.
HMM HMPMM R1, R2 = morpholine, imidazole 1 2 3 4
R-dimethylamine 2,6- dimethyl-morpholine 7 5 6
8 9
32 Schiff Bases - Interesting Range of Applications in Various Fields of Science
10
The diverse biological activities observed for different molecules containing the 1,3,5-triazine unit have been further explored in order to discover other new potential molecules through the synthesis of libraries by combinatorial approaches.
References
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37 Chapter 3 Review of Literature
Sunil G. Sanghani et al have investigated a series of Mannich bases were prepared by the reaction of 7-methyl-2-(p-methyl phenyl)imidazo[1,2-a]pyridine with secondary amines and p-formaldehyde in appropriate solvent. The newly synthesized compounds were characterized by elemental analysis, IR, 1H NMR and mass spectra. All the synthesized compounds were tested for their antibacterial activities against Gram positive and Gram negative bacteria and antifungal activities [1].
2-(p-methylphenyl)-7-methyl imidazo[1,2-a]pyridine
Lingappa et al has prepared the new series of 3-(4,6-disubstituted-2- thiomethylpyrimidyl)-4-amino-5-mecapto-1,2,4-triazoles have been synthesized. These triazoles on reaction with aldehyde in the presence of acid catalyst forms Schiff’s base. These Schiff’s bases can exist both in the thiol as well as in the thione tautomeric form. However when these compounds are subjected to Mannich reaction, Mannich base are obtained rather than the S-Mannich bases. The structures of the new compounds have been confirmed by spectral and analytical data. Few of these Mannich base have been evaluated for their possible antifungal and antibacterial activity. Most of the test compounds show significant antifungal and antibacterial activity [2]. Huseyin Istanbullu et al have studied the design, synthesis, characterization, and cytotoxic activity of a series of uracil C-Mannich bases. Among them, one hybrid compound (1), a molecular combination of the potential antimetabolite substituted uracil and nitrogen mustard, having potential alkylating capability was prepared as a Mannich base. The other compound was synthesized with the replacement of chlorines in the ethyl chains with hydroxyl groups for testing for anticancer activity. Some of Mannich bases having several amino groups with different pKa values were also synthesized and investigated in terms of cytotoxic activity. Their chemical structures were confirmed by means of their UV, IR, 1H NMR, 13C-NMR, and MS data.
© IOR INTERNATIONAL PRESS 2019 P.Sounthari and P.R. Sivakumar, Synthesis and Characterization of Some Novel Mannich Base Compounds, https://doi.org/10.34256/ioriip1983 38 Review of Literature
Compounds 6 with diethylamine and 8 with piperazine are reported for the first time in the literature and compounds 1, 4, and 5 containing nitrogen mustard, pyrolidine, and diethanolamine, respectively, as amine function are reported for first time with detailed spectral data herein. Morpholine, piperidine, and dimethylamine were used in Mannich reactions for the synthesis of compounds 2, 3 and 7. The biological activities using MTT assays on 3 human cell lines: HeLa (cervix adenocarcinoma), MCF7 (breast adenocarcinoma), and A431 (skin epidermoid carcinoma). While compounds 2-8 have the potential to deaminate, forming ortho-quinone methides, which would be capable of alkylating cellular thiols, compound 1 has the potential to give aziridinium ion for nucleophilic alkylation. Our results are discussed in terms of the significance of these compounds in pharmaceutical use [3].
Compound R Groups Compound R Groups 1 R1=R2= -CH2CH2Cl 5 R1=R2= -CH2CH2OH 2 R1=R2= -C2H4OC2H4 6 R1=R2= -CH2CH3 3 R1=R2= -C5H10 7 R1=R2= -CH3 4 R1=R2= -C4H8 8 R1=R2= -C2H4NHC2H4
Shaker Youssifa et al have synthesized several 6-substitued-1-methyl- 2,5,7,8-tetrahydro-2-thiopyrimido[4,5-d]pyrimidine-4-ones and ethyl-7-amino-5- aryl-1-methyl-4-oxo-1,2,3,4-tetrahydro-2-thiopyrido[2,3-d]pyrimidines-6- carboxylates were synthesized by treatment of 6-amino-1-methyl-2-thiouracil with primary amines and formalin (40%) and with ethyl 3-aryl-2-cyanoacrylate respectively. 8-Substituted-7-hydroxy-3-methyl-2-thioxanthines were synthesized by the treatment of 6-amino-1-methyl-5-nitroso-2-thiouracil with benzylidene-anilines. Elemental and spectral analyses were performed for the new compounds [4].
6-amino-1-methyl-2-thiouracil R=-C6H5, -C6H4-4-CH3, -C6H4-4-NO2, -C6H4-4-OCH3, -naphthyl-2, -C2H5, -C6H4-3-OCH3, -C6H4-3-Cl
39 Review of Literature
Haiffaa Y. Hussin have been prepared some acetylenic amine derivatives containing nitrogen bases (cytosine, uracil) were synthesized through Mannich reaction which involved reaction of N-propargyl cytosine or uracil with paraformaldehyde and secondary amines. The structures of synthesized compounds have been confirmed depending on the physical and spectral data [5].
Synthesized acetylenic amines derivatives
Tomasz Pospieszny et al have synthesized six new 2-o-(m- and p-) chlorobenzylthio-6-methyl-5-piperidino-(or morpholino-) methyluracils. The structures of these compounds were confirmed by spectroscopic (FT-IR, UV-Vis, 1H NMR, 13C NMR, and HMBC) and elemental analyses. Estimation of pharmacotherapeutic potential has been made for synthesized compounds on the basis of prediction of activity spectra for substances (PASS) [6].
X = CH2, o-C X = O, o-Cl X = CH2, m-CI X = O, m-CI X = CH2, m-CI X = O, m-CI X = CH2, p-CI X = O, p-CI
Govindu et al have been prepared the synthesis, as well as spectroscopic characterization, biological evaluation and docking studies of a novel class of N'-((1- (piperidin/morpholin/ thiomorpholin/ methylpiperazine)-1H-imidazol-4-yl) methylene)-3-(4-substituted phenyl-[1,2,4] triazolo [4,3-c] pyrimidine-8- carbohydrazide derivatives are described. All the synthesized compounds were characterized by elemental analysis FTIR, 1H-NMR, 13C NMR, and Mass spectral data. All the synthesized compounds were exhibits antimicrobial activities. Further the docking studies were carried out based on mycobacterial studies for the model
40 Review of Literature compounds against Transaminase BioA enzyme and the results found are moderate [7].
X= CH2, O, S, NCH3 R= H, CH3, OCH3, NO2, CF3 pyrimidines containing imidazole Mannich bases derivatives
Hironao Sajiki et al have been reported the reaction of 5-halogenouracil and uridine derivatives with active methylene compounds under basic conditions produced diverse and selective C-C bond formation products by virtue of the nature of the carbanions. Three different types of reactions such as the regioselective C-C bond formation at the 5 and 6-positions of uracil and uridine derivatives and the formation of fused heterocycle derivatives 2,4-diazabicyclo[4.1.0]heptane and 2,4-diazabicyclo- [4.1.0]nonane via dual C-C bond formations at both the 5- and 6-positions were due to the different active methylene compounds used as reagents [8]
R=CO2Et, CN 2,4-diazabicyclo[4.1.0]heptane 2,4-diazabicyclo[4.1.0]nonane (cyclopropane) (cyclopentane)
Navgeet Kaur et al have investigated a series of pyrimidines bearing a pyronyl side chain in the 4-position is described. These unreported compounds are obtained starting from commercially available dehydro acetic acid (DHA), aromatic aldehydes and S-benzylisothiouronium chloride (SBT). A series of compounds were
41 Review of Literature prepared and tested for their antimicrobial activity. These synthesized compounds showed mild activity against gram +ve bacteria and very less activity against gram - ve bacteria. Compounds 6-(4-Fluorophenyl)-4-(4-hydroxy-6-methyl-2-oxo-2H- pyran-3-yl)-2-S-benzylthio pyrimidine, 6-(2-Thiophene)-4-(4-hydroxy-6-methyl-2- oxo-2H-pyran-3-yl)-2-S-benzylthiopyrimidine, 6-(4-Pyridyl)-4-(4-hydroxy-6- methyl-2-oxo-2H-pyran-3-yl)-2-S-benzylthio pyrimidine showed mild activity against gram +ve Bacillus subtilis bacteria while against gram -ve Pseudomonas aeruginosa compound 6-(2-Thiophene)-4-(4-hydroxy-6-methyl-2-oxo-2H-pyran-3- yl)-2-S-benzylthiopyrimidine showed minor activity [9].
Ar = Ph, 4-FC6H4, 3-ClC6H4, 4-BrC6H4, 4-OH-3-Et- C6H3, 3-OCH3-4-OH- C6H3, (CH3)2NC6H4, (C2H5)2NC6H4, 2-Thienyl, 4-Pyridyl
Caurino Cesar Bombardieri et al have synthesized some new Mannich bases was accomplished by the condensation of secondary amines and formaldehyde with the following compounds: (1) 2-pyrrolidone, (2) 2,4-thiazolidinedione, (3) hydantoin, (4) 5,5-dimethylhydantoin, (5) uracil, (6) ethylnitramine, and (7) n- butylnitramine [10]. Firouzeh Nematia et al have prepared Three-component Mannich-type reaction of acetophenon, aromatic aldehydes, and aromatic amines is catalyzed by 2,4,6-trichloro[1,3,5]triazine at ambient temperature in EtOH and solvent-free conditions to give various β-amino ketones in high yields [11].
The Mannich reaction using TCT.
Desai Sweta D et al have prepared ten compound which were synthesized in a series of 2,4,6-trichloro-1,3,5-s-triazine analogues which in substitution with
42 Review of Literature anisole, 4-hydroxy coumarin and different N-substituted piperazine derivatives on the C-6 position of s-triazine ring. The title compounds were screened for their in vitro antimicrobial activity against two gram negative bacteria (E. coli, K. pneumoniae), two gram-positive bacteria (S. aureus, B. subtilis) and two fungal species (C. albicans and S. cerevisiae) using the disc diffusion method. Most of the synthesized compounds appeared with promising antimicrobial activity. The structure of the novel compounds were elucidated on the basis of IR, 1H NMR and elemental analysis [12]. Marwa F. Balaha et al have investigated that dihydrofolate reductase (DHFR) is the primary target enzyme for antifolate drugs and 1,3,5-triazine derivatives containing various amino groups at position 2, 4 or 6 have been known as potent anticancer drugs, two series of tri-amino-substituted 1,3,5-triazine derivatives were designed, synthesized and evaluated as cytotoxic agent against non-small cell lung cancer(A549). The first series are N2-(4-phenylthiazol-2-yl)-1,3,5-triazine-2,4,6- triamine analogs and the second series are 4-((4,6-Diamino-1,3,5-triazin-2-yl)amino)- 4H-1,2,4-triazole-3-thiol analogs. Out of twenty two synthesized compounds there were thirteen compounds showed a higher cytotoxic activity against A549 cell line than methotrexate and four compounds were equipotent to methotrexate. Compounds N2-(4-(4-nitrophenyl)thiazol-2-yl)-1,3,5-triazine-2,4,6-triamine,N2,N4-dicyclohexyl- N6-(4-phenylthiazol-2-yl)-1,3,5-triazine-2,4,6-triamine,4-((4,6-Diamino-1,3,5-triazin -2-yl) amino)-5-phenyl-4H-1,2,4-triazole-3-thiol and 4-((4,6-bis (cyclohexylamino)- 1,3,5-triazin-2-yl)amino)-5-phenyl-4H-1,2,4-triazole-3-thiol showed the highest cytotoxic activity with IC50 values of 50, 42, 62 and 28 nM respectively. Molecular docking study was performed to interpret the comparative differences in the binding interactions of the synthesized novel compounds at molecular level as inhibitors of human dihydrofolate reductase (hDHFR) and to understand the structure activity relationships. The excellent anticancer activity of synthesized analogs presented in this study needs further investigation as highly promising cytotoxic lead agents against lung cancer [13].
Where, R=H or R=C6H11 R=H or R=C6H11 X= H, Cl, OCH3, CH3, NO2 Y= H, CH3, CH2CH3, C4H9, C6H5
R=H or R=C6H11 Chemical structure of target 1, 3, 5-triazine derivative and model compounds
43 Review of Literature
Sonika Jain et al have investigated a study directed towards exploring the temperature-dependent reactivity of the chlorine atoms of 2,4,6-trichloro-s-triazine (TCT) in the nucleophilic displacement reaction, allowed a facile replacement of its chlorine atoms in succession with (i) N-amino methyl substituted isatin-3-hydrazones, (ii) N1-substituted-4-aminobenzene sulphonamides, and (iii) 8-amino-4-oxo-N- benzyl-azacarbazole to produce the corresponding 2,4,6-trisubstituted-s-triazine, namely; 2-(N-amino methyl substituted isatin-3-hydrazinyl)-4-(N1-substituted-4̍- aminobenzenesulfonamidyl)-6-(8̍-amino-4̍-oxo-N-benzylazacarbazolyl)-1,3,5- triazine derivatives in acceptable yields. The compounds prepared were further evaluated for their antibacterial activity against E.coli and B. subtilis and antifungal activities against A. niger and A. flavus, and some of them showed promising activity profile [14]. Anton V. Dolzhenko have reported that the present review summarizes information on the synthetic approaches to thiazolo[3,2-a][1,3,5]triazines and polyfused systems bearing this heterocyclic core since the first report on this structure in 1887. The methods allowing access to the heterocyclic systems comprising isomeric thiazolo[3,4-a][1,3,5]triazine scaffold are also included in the review. Data concerning potential applications of the thiazolo[1,3,5]triazines, particularly as biologically active agents are discussed [15]. Anton V. Dolzhenko have reported that the present review summarizes information on the synthetic approaches to compounds with pyrimido[1,2- a][1,3,5]triazines, 1,3,5-triazino[2,1-b]quinazolines (benzofused pyrimido[1,2- a][1,3,5]triazines), and other polyfused heterocyclic systems bearing these scaffolds. Data concerning potential applications of the pyrimido[1,2-a][1,3,5]triazines, particularly as biologically active agents are also discussed [16].
R = Me, Et, n-Pr, i-Pr, i-Bu, c-Hexyl, n-C8H17, n-C18H37, allyl, Bn, HO2CCH2, Ph Synthesis of pyrimido[1,2-a][1,3,5]triazines using Mannich condensation
Vineeta sareen et al have prepared 2,4,6-Trichloro-1,3,5-Triazine has been reacted selectively with nucleophilic reagents, 6-Fluoro-2-aminobenzothiazole,phenyl thioureas and different substituted thioureas to give 2-(6-fluorobenzothiazole-2ʹ- ylamino)-4-(phenylthioureido)-6-(substituted thioureido)-1,3,5-triazine. These compounds are evaluated for their antimicrobial activity. The structures of all these compounds have been confirmed by IR, 1H NMR, mass spectral data and elemental analysis. Benzothiazoles, s-triazines and thioureas exhibit various biological activites [17].
44 Review of Literature
R = 2-FC6H4, 4-FC6H4, 2-Cl-5-CF3C6H3, 2-ClC6H4, 2-NO2C6H4, 4-OCH3C6H4, 2- CF3C6H4, CH2=CH-CH2, NH2, 4-NO2C6H4
Abha Bishnoi et al have prepared 1-(4-Substituted phenyl)-3- (substituted)propan-1-(1H-benzo[d]imidazole-2-yl)hydrazine and 1-(4-substituted phenyl)-3-(substituted)propan-1-(5H-[1,2,4]triazino[5,6-b]indol-3-yl) hydrazine have been synthesized by the fusion of triazine and benzimidazole derivatives with mannich bases. The synthesized compounds have been characterization and screened against ITCC5226 sclerotium rolfsii and ITCC0482 Macrophomina phaseolina and MTCC739 Escherichia coli, Bacillus subtilis, Staphylococcus aureus, Pseudomonas aeruginosa and Candida albicans [18]. Carlos A. M. Afonso et al have investigated some several specific synthetic protocols were developed for the preparation from cyanuric chloride of a range of symmetric and non-symmetric di- and tri-substituted 1,3,5-triazines containing alkyl, aromatic, hindered, chiral and achiral hydroxyalkyl, ester and imidazole groups via sequential nucleophilic substitution of the C-Cl bond by C-O, C-N and C-S bonds [19]. Sherine N. Khattab et al have synthesized three series of 4,6-dimethoxy-, 4,6-dipiperidino- and 4,6-dimorpholino-1,3,5-triazin-2-yl) amino acid derivatives were synthesized and characterized. A preliminary study for their monoamine oxidase inhibitory activity showed that compounds 2-(4,6-Dimethoxy-1,3,5-triazin-2- ylamino)-3-phenylpropanoic acid, 2-(4,6-Di(piperidin-1-yl)-1,3,5-triazin-2-ylamino)- 3-methylbutanoic acid, and 2-(4,6-Dimorpholino-1,3,5-triazin-2-ylamino)-3- methylbutanoic acid had MAO-A inhibition activity comparable to that of the standard clorgyline, with apparently more selective inhibitory activity toward MAO-A than MAO-B and no significant acute toxicity [20].
I II Planned modification and newly designed MAO inhibitors. I = (4,6-dimethoxy-
45 Review of Literature
1,3,5- triazin-2-yl) amino acid derivatives; X = O; II is (4,6-dimorpholino-1,3,5- triazin-2-yl) amino acid derivatives or X = CH2; II is (4,6-dipiperidino-1,3,5- triazin-2-yl) amino acid derivatives.
Hala M. Gareeb Alzahawi has prepared some Shiff bases were syuthesized using phenyl alanine with aniline by microwave irradiation. A series of mannich base were prepared by the reaction of Schiff bases with uracil in the presence of formaldehyde. The newly synthesized compounds were characterized on the basis of elemental analysis, IR and 1H NMR. All the synthesized compounds were tested for their antibacterial activites and antifungal activities [21].
R= 4-OH,4-COOH, 2-COOH, 2-Cl Phenyl alanine derivatives Jason p. Dworkin have reported Pseudouridine is a modified base found in all tRNA and rRNA. Hence, it is reasonable to think that pseudouridine was important in the early evolution, if not the origin, of life. Since uracil reacts rapidly with formaldehyde and other aldehydes at the C-5 position, it is plausible that pseudouridine could be synthesized in a similar way by the reaction of the C-5 of uracil with the C-1 of ribose. The determining factor is whether the ribose could react with the uracil faster than ribose decomposes. However, both rates are determined by the amount of free aldehyde in the ribose. Various plausible prebiotic reactions were investigated and none showed pseudouridine above the detection limit (<0.01%). Only unreacted uracil and ribose decomposition products could be observed. Thus the rate of addition of ribose to uracil is much slower than the decomposition of ribose under any reasonable prebiotic conditions. Unless efficient non-biological catalysts for any of these reactions exist, pseudouridine would not have been synthesized to any significant extent without the use of biologically produced enzymes [22]. H.Ighachane et al have investigated in order to create novel potent antifungal agents, the antifungal effects of 1,4-disubstitued 1,2,3-triazole derivatives on plant pathogenic fungi were evaluated for bioactivity against two of the most devastating fungal Verticillium dahliae Klep (Vd) and Fusarium oxysporum f.sp. albedinis (Foa) using the mycelia growth rate method and sporulation. Some of the compounds showed definite activities in vitro against the tested fungi at 20 μg/ml. For instance, benzyl and adenine substituted compound can be used as a good starting point for further optimization [23].
46 Review of Literature
R=Benzyl, TBRB (2’,3’,5’-tri-O-benzoylribofuranose) R1= CO2Et, Uracil, Thymine, Azauracil, 5-F-uracil, 5-Cl-uracil, 5-I-uracil, 5-Br- uracil, adenine R2= H, CO2Et
Hamid Hussein Eissa have reported the present study includes synthesis of Aso derivative were prepared by coupling reaction between diazonium salt and salicylaldehyde. Aso-schiff bases were prepared by the condensation by 3-formyl-4- hydroxy phenylazo benzene with 1,3-Docarbonylphenyl dihydrazide, Pyridine-2,6- Dicarbohydrazide and 2,4-diamino -6-methyl -1,3,5-triazine. The Schiff base ligands were checked by different spectral technique (GC-MS, 1H-NMR, IR, Elemental Analysis, and UV-Vis). The second part of this work includes studding the effect of the some bacteria. The results show that disappearance of amine group, carbonyl group and appearance imino group. As results show too that their activities were found to vary from moderate to very strong [24]. Savalia RV et al have reported that Schiff base synthesis is usually acid- catalyzed and usually require refluxing the mixture of aldehydes (or ketone) and amine in organic medium. However, assistance of microwave irradiation for synthesis of schiff base is introduced now a day. The method was also compared with conventional method for determination of production efficiency and production economic. Characterization of these Schiff base were done by TLC and IR spectra. It was concluded that the microwave irradiation method is very rapid, reliable and economic method for production of Schiff base [25]. Muhammad Aqeel Ashraf et al have prepared three new series of biologically active amino substituted Schiff bases with general formula, R1N=CHR2. Here R1 = 2-amino-benzthiazole, 4-amino-salicylic acid and 4-aminophenol. R2=4- chlorobenzaldehyde, 2-chloro-benzaldehyde, salicylaldehyde, vanillin and benzaldehyde were synthesized by the reaction of three different amino substituted compounds and substituted aldehydes in ethanol. Such compounds were characterized by different physico-chemical techniques like, melting point, elemental analysis, multinuclear NMR (1H, 13C). The free ligands and their metal complexes have been screened for their in vitro biological activities against bacteria, fungi and yeast. The metal complexes show more potent activities compared with Schiff base ligands [26]. Hosam A. Saad et al have investigated the rapid and efficient solvent-free synthesis of 4-amino-3-mercapto-6-[2-(2-thienyl) vinyl]-1,2,4-triazin-5(4H)-one under microwave irradiation is described. Some new fused heterobicyclic nitrogen systems such as 1,2,4-triazino[3,4-b][1,3,4]thiadiazinones, 1,3,4-thiadiazolo[2,3-
47 Review of Literature c][1,2,4]triazinone and pyrazolo[5,1-c]-[1,2,4]triazine-7-carbonitrile, have been synthesized by treatment of 4-amino-3-mercapto-6-[2-(2-thienyl)vinyl]-1,2,4-triazin- 5(4H)-one with bifunctional oxygen and halogen compounds, CS2/KOH and malononitrile via heterocyclization reactions, in addition to some uncondensed triazines. Structures of the products have been deduced from their elemental analysis and spectral data (IR, 1H-NMR, 13C-NMR). Select new synthesized compounds were screened as anticancer agents with some showing activity as cytotoxic agents against different cancer cell lines [27]. Akbar Sowkath et al have synthesized a schiff base (SB) between salicylaldehyde and 2, 4-diamino-6-phenyl-1,3,5-triazine was prepared. Thus synthesised SB is characterised by various analytical techniques like Fourier transform infrared (FTIR) spectroscopy, nuclear magnetic resonance (NMR) spectroscopy. The initiating efficiency of SB towards the ring opening polymerization (ROP) of Caprolactone (CL) was carried out. The poly (caprolactone) (PCL) formation was confirmed by gel permeation chromatography (GPC), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA) measurements. The scanning electron microscopy confirmed the surface morphology of PCL [28]. Wenling Qin et al have reported a short biography of the Italian naturalized chemist Hugo Schiff and an outline on the synthesis and use of his most popular discovery: the imines, very well known and popular as Schiff Bases. Recent developments on their “metallo-imines” variants have been described. The applications of Schiff bases in organic synthesis as partner in Staudinger and hetero Diels-Alder reactions, as “privileged” ligands in the organometallic complexes and as biological active Schiff intermediates/targets have been reported as well [29].
Madurahydroxy lactone Schiff bases. (Antibacterial Schiff bases)
Antifungal Schiff bases derived from 2,4-dichloro-5-fluorophenyl scaffold
48 Review of Literature
Modified 3-hydroxyguanidines antiviral Schiff base
Felicia N. Ejiah et al have reported the dependence of electronic absorption spectra antimicrobial property on the substituent position was investigated using three Schiff bases derived from salicylaldehyde and isomeric aminobenzoic acids in three solvents of different polarities. The absorption maxima in all three solvents exhibited dependence on the position of substituent with the absorption maxima undergoing a red shift as solvent polarity increased. The in vitro antibacterial activity of the compounds against some clinically important bacteria namely Escherichia coli (ATCC 25922), Pseudomonas aeruginosa (ATCC 27853), Staphylococcus aureus (ATCC 25923), Enterococcus feacalis (ATCC 29212) was determined in N, N”- dimethylformamide and 1,4-dioxane using the agar dilution method. The results revealed that the ortho and meta substituted Schiff bases exhibited better antimicrobial activity in the non-polar solvent [30]. Mohammad Arshad et al has prepared 1,2,4-Triazines are the six membered heterocyclic compounds possessing three nitrogen in its structure with general formula C3H3N3. 1,2,4-Triazines and its derivatives have been found to exhibit the variety of biological applications such as antifungal, anti-HIV, anticancer, antiinflammatory, analgesic and antihypertensive, cardiotonic, neuroleptic, nootropic, antihistaminergic, tuberculostatic, antiviral, anti-protozoal, estrogen receptor modulators, antimalarial, cyclin-dependent kinase inhibitors, antimicrobial and antiparasitic activities [31]. Jigna parekh et al have investigated that the following Schiff bases have been synthesized: (1) 4-[(2-chlorobenzylidene) Amino]benzoic acid, (2) 4-[(furan-2- ylmethylene)amino]benzoic acid, (3) 4-[(3-phenylallylidene)amino]benzoic acid, (4) 4-[(2-hydroxybenzylidene)amino]benzoic acid, (5) 4-[(4-hydroxy-3- methoxybenzylidene)amino] benzoic acid and (6) 4-[(3-nitrobenzylidene) amino] benzoic acid. They were screened as potential antibacterial agents against a number of medically important bacterial strains. The antibacterial activity was studied against A. faecalis ATCC 8750, E. aerogenes ATCC 13048, E. coli ATCC 25922, K. pneumonia NCIM 2719, S. aureus ATCC 25923, P. vulgaris NCIM 8313, P. aeruginosa ATCC 27853 and S. typhimurium ATCC 23564. The antibacterial activity was evaluated using the Agar Ditch method. The solvents used were 1,4-dioxane and dimethyl sulfoxide. Different effects of the compounds were found in the bacterial strains investigated and the solvents used, suggesting, once again, that the antibacterial activity is dependent on the molecular structure of the compound, the solvent used and the bacterial strain under consideration. In the present work, 1,4-dioxane proved to be a good solvent in inhibiting the above stated bacterial strains [32].
49 Review of Literature
′ 푹 − 퐂퐇퐎 + 퐑 − 퐍퐇ퟐ → 퐑 − 퐂퐇 = 퐍 − 퐑′
R’-NH2 is 4-aminobenzoic acid
compounds 1 2 3 4 5 6
R
References
1. Sunil Sanghani G and Kalpesh Ganatra J, Synthesis and biological evaluation of some novel Mannich bases, Archives of Applied Science Research, 2 (5), 444-450, 2010. 2. Lingappa B, Girisha K.S, Balakrishna Kalluraya N, Satheesh rai N and Nalilu Suchetha Kumari, Regioselective reaction; Synthesis of novel Mannich base derived from 3-94,6-disubstituted-2-thiomrthylpyrimidyl)-4-amino-5- mercapto-1,2-4-triazoles and their antimicrobial properties, Indian journal of Chemistry, 47B, 1858-1864, 2008. 3. Huseyin ˙istanbullu, Istvan zupko, Vildan alptuzun and Ercin erciyas, Synthesis and cytotoxic evaluation of uracil C-Mannich bases, Turk J Chem., 36 , 583 – 592, 2012. 4. Shaker Youssifa and Fatmah Agilib, One-pot Synthesis of Fused 2- Thiouracils: Pyrimidopyrimidines, Pyridopyrimidines and Imidazolopyrimidines, Z. Naturforsch., 63b, 860 – 864, 2008. 5. Haiffaa Y. Hussin, Synthesis of some Acetylenic Amines Derivatives by Mannich Reaction, Jou. Raf. Sci., 20(4), 52- 57, 2009. 6. Tomasz Pospieszny,Marcin Szymankiewicz, and ElzbietaWyrzykiewicz, Thio Analogs of Pyrimidine Bases: Synthesis, Spectroscopic Study, and In Silico Biological Activity Evaluation of New 2-o-(m- andp- )Chlorobenzylthio-6-Methyl-5- Piperidino- (Morpholino) Methyluracils, International Scholarly Research Network, 2011. 7. Govindu G, Raveendra Reddy P, Rajesh D and Ravindranath L.K, Synthesis, characterization, biological evaluation and docking studies of pyrimidine- imidazole mannich base derivatives as transaminase Bioainhibitors, Der Pharma Chemica, 7(10), 362-371, 2015. 8. Hironao Sajiki, Yusuke Iida, Kanoko (Yasunaga) Ikawa, Yoshinari Sawama, Yasunari Monguchi, Yukio Kitade, Yoshifumi Maki, Hideo Inoue and Kosaku Hirota, Molecules 2012, 17, 6519-6546.
50 Review of Literature
9. Navgeet Kaur, Ajay K, Aggarwal, Neha Sharma and Balram Choudhary, Synthesis and In-vitro Antimicrobial Activity of Pyrimidine Derivatives, International Journal of Pharmaceutical Sciences and Drug Research, 4(3), 199-204, 2012. 10. Caurino Cesar Bombardieri and Alfred Taurins, Mannich condensation of compounds containing acidic imino groups, Can.J.Chem., 2016. 11. Firouzeh Nemati , Mohammad A. Bigdeli , Gholam Hossein Mahdavinia and Hossein Kiani, 2,4,6-Trichloro[1,3,5]triazine (TCT)-catalyzed onepot Mannich-type reaction: three component synthesis of β-amino carbonyl compounds, Green Chemistry Letters and Reviews, 3(2), 89-92, 2010. 12. Desai Sweta D and Mehta Arvind G, Design, Synthesis, Characterization and Biological Evaluation of Various Nsubstituted Piperazine Annulated s- Triazine Derivatives, Research Journal of Chemical Sciences, 4(5), 14-19, 2014. 13. Marwa F. Balahaa, Mervat H. El-Hamamsy, Nabawya A. Sharaf El-Dinc, Nageh A and El-Mahdy, Synthesis, Evaluation and Docking Study of 1, 3, 5- Triazine Derivatives as Cytotoxic Agents against Lung Cancer, Journal of Applied Pharmaceutical Science, 6(4), 028-045, 2016. 14. Sonika Jain, Anamika Sharma, Meenakshi Agrawal, Swapnil Sharma, Jaya Dwivedi, and Kishore D, Synthesis and Antimicrobial Evaluation of Some Novel Trisubstituted s-Triazine Derivatives Based on Isatinimino, Sulphonamido, and Azacarbazole, Journal of Chemistry, 2013. 15. Dolzhenko, Anton V, Synthetic Routes towards Thiazolo[1,3,5]triazines (Review). Heterocycles. 83 (4), 695 -738, 2011. 16. Dolzhenko, Anton V, Synthetic routes towards pyrimido[1,2- a][1,3,5]triazines (Review). Heterocycles. 83(7), 1489-1525, 2011. 17. Vineeta sareen, Vineeta Khatri, Prakash Jain and Kanti Sharma, Synthesis of 2-(6-fluorobenzothiozole-2’-ylamino)-4-(phenylthioureido)-6-(substituted thioureido)-1,3,5-triazine as antimicrobial agent, Indian Journal of Chemistry,1288-1290, 2005. 18. Abha Bishnoi, Suruchi Singh, Anil K Tiwari, Archna Rani, Sapna Jain and Tripathi C.K.M, Synthesis and antimicrobial activity of some new 1,2,4- triazine and benzimidazole derivatives,Indian Journal of Chemistry, 53B, 325- 331, 2014. 19. Carlos A.M, Afonso, Nuno M.T, Lourenço and Andreia de A. Rosatella, Synthesis of 2,4,6-Tri-substituted-1,3,5-Triazines, Molecules, 11, 81-102, 2006. 20. Sherine N. Khattab , Hosam H. Khalil, Adnan A. Bekhit , Mohamed Mokbel Abd El-Rahman, Ayman El-Faham and Fernando Albericio, Molecules, 20, 15976-15988, 2015. 21. Hala M . Gareeb Alzahawi, Synthesis , characterization and antimicrobial activity of shiff and mannich bases of uracil derivatives, Kirkuk University Journal /Scientific Studies (KUJSS), 11(1), 124-130, 2016.
51 Review of Literature
22. Jason P. Dworkin, Attempted prebiotic synthesis of pseudouridine, Origins of Life and Evolution of the Biosphere 27,345–355, 1997. 23. Ighachane H, H.El ayadi, My.H.Sedra and Lazrek H.B., Biological Evaluation of 1, 4-Disubstituted 1,2,3-Triazole Derivatives as Plant Pathogenic Fungus Inhibitors, Medicinal Chemistry, 4 (8), 2014. 24. Hamid Hussein Eissa, Synthesis and characterization of new azo-schiff bases and study biological activity, Journal of Current Research in Science, 1(2), 96- 103, 2013. 25. Savalia R.V, Patel A.P, Trivedi P.T, Gohel H.R and Khetani D.B, Rapid and Economic Synthesis of Schiff Base of Salicylaldehyde by Microwave Irradiation, Research Journal of Chemical Sciences, 3(10), 97-99, 2013. 26. Muhammad Aqeel Ashraf, Karamat Mahmood and Abdul Wajid, Synthesis, Characterization and Biological Activity of Schiff Bases, International Conference on Chemistry and Chemical Process, 10, 2011. 27. Hosam A. Saad, Mohamed M. Youssef and Mosselhi A. Mosselhi, Microwave Assisted Synthesis of Some New Fused 1,2,4-Triazines Bearing Thiophene Moieties With Expected Pharmacological Activity, Molecules, 16, 4937- 4957. 2011. 28. Akbar Sowkath, Mansur Ahmed, Anbarasan R, Synthesis, spectral characterization and application of Triazine based Schiff base and its Cu- complex, International Journal of Emerging Technologies and Engineering, 2348–8050, 2014. 29. Wenling Qin, Sha Long, Mauro Panunzio and Stefano Biondi, Schiff Bases: A Short Survey on an Evergreen Chemistry Tool, 18, 12264-12289, 2013. 30. Felicia N. Ejiah, Tolulope M. Fasina, Oluwole B. Familoni and Folashade T. Ogunsola, Substituent effect on spectral and antimicrobial activity of Schiff bases derived from aminobenzoic acids, Advances in Biological Chemistry, 3, 475-479, 2013. 31. Mohammad Arshad, Taki Ahmed Khan and Meraj Alam Khan, 1,2,4-triazine derivatives: Synthesis and biological applications, International Journal of Pharma Sciences and Research, 5(4), 2014. 32. Jigna Parekh, Pranav Inamdhar, Rathish Nair, Shipra Baluja and Sumitra Chanda, Synthesis and antibacterial activity of some Schiff bases derived From 4-aminobenzoic acid, J. Serb. Chem. Soc. 70 (10), 1155–1161, 2005.
52 Chapter 4 Scope of the Present Investigation
The Mannich reaction is an organic reaction which consists of an amino alkylation of an acidic proton placed next to a carbonyl functional group with formaldehyde and ammonia or any primary or secondary amine. The final product is a β-amino-carbonyl compound is known as a Mannich base. Reactions between aldimines and α-methylene carbonyls are also considered as Mannich reactions because these imines form between amines and aldehydes. In the past few decades, Mannich bases of heterocyclic molecules have been grabbing the attention of the synthetic chemists for their wide range of antimicrobial properties. They possess many interesting pharmacological properties. Mannich bases have several biological activities such as antimicrobial, cytotoxic, anticancer, analgesic and diuretic activities [1-3]. They are the versatile synthetic intermediates formed by Mannich Reaction and find great use in medicinal chemistry. The significance of the Mannich reaction was first recognised by Carl Mannich and since then it developed into a vital reaction in the synthesis of various Pharmaceuticals and Natural products. Mannich reaction has gained popularity in synthetic chemistry over the past decades because it is one of the most important and fundamental reactions in organic chemistry, since it affords synthetically and biologically important β-amino carbonyl compounds. These compounds are useful building blocks for molecules with applications in pharmaceutical and material sciences. The development of new synthetic methods leading to β-amino carbonyl compounds or their derivatives has attracted much attention. Mannich bases have gained importance due to their application in pharmaceutical chemistry. They have been encountered with antibacterial, anticancer, analgesic and anti-inflammatory, anticonvulsant, antimalarial, antiviral, and CNS depressant activities [5]. Schiff bases, named after Hugo Schiff, are formed when any primary amine reacts with an aldehyde or a ketone under specific conditions. Structurally, a Schiff base (also known as imine or azomethine is a nitrogen analogue of an aldehyde or ketone in which the carbonyl group (C=O) has been replaced by an imine or azomethine group. Compounds containing an azomethine group (-CH=N-), known as Schiff bases are formed by the condensation of a primary amine with a carbonyl compound.
© IOR INTERNATIONAL PRESS 2019 P.Sounthari and P.R. Sivakumar, Synthesis and Characterization of Some Novel Mannich Base Compounds, https://doi.org/10.34256/ioriip1984 53 Scope of the Present Investigation
Schiff bases of aliphatic aldehydes are relatively unstable and are readily polymerizable while those of aromatic aldehydes, having an effective conjugation system, are more stable. Schiff bases have number of applications viz., preparative use, identification, detection and determination of aldehydes or ketones, purification of carbonyl or amino compounds, or protection of these groups during complex or sensitive reactions. They also form basic units in certain pigments, dyes and catalysts [6]. In organic synthesis, Schiff base reactions are useful in making carbon-nitrogen bonds. They appear to be an important intermediate in a number of enzymatic reactions involving interaction of an enzyme with an amino or a carbonyl group of the substrate. Schiff bases have also been shown to exhibit a broad range of biological activities, including antifungal, antibacterial, antimalarial, antiproliferative, anti- inflammatory, antiviral, and antipyretic properties. Imine or azomethine groups are present in various natural, natural-derived, and non-natural compounds. The imine group present in such compounds has been shown to be critical to their biological activities. Green chemistry is the design of chemical products and processes that reduce or eliminate the use and generation of hazardous materials. One of the principles of green chemistry involves use of microwave to carry out the reaction [7]. Microwave assisted organic reactions are of great interest because of its advantages. The promotion of microwave assisted reactions in organic chemistry has improved the speed, reduced cost, reduced energy spent making it a sustainable process and is widely heralded as “green chemistry” measures [8] whose applications are promoted today to minimize the use of non-renewable resources as well as polluting solvent, to reduce generation of secondary products which are often toxic and to reduce the emission of harmful gases. Microwave assisted reactions in organic chemistry achieve the same by ensuring facilitation of faster reactions under bulk conditions as well as promoting reduction of reaction time [9-11].
s-Triazine derivatives represent an important class of compounds due to their potential to be biologically active. They are known to be anti-protozoals, [12] anticancer agents, estrogen receptor modulators, antimalarials, cyclindependent kinase modulators, [13] and antimicrobials. Cyanuric chloride, an inexpensive, easily available reagent, of low toxicity and less corrosive than other similar reactants, has been widely used in organic reactions. 1,3,5-triazines (or s-triazines) are a class of compounds well known for a long time and still continue the object of considerable interest mainly due to their application in different fields, including the production of herbicides and polymer photostabilizers. Some 1, 3, 5-triazines display important biological properties; for example hexamethylmelamine (HMM) & 2-amino-4- morpholino-s-triazine are used clinically due to their antitumor properties to treat lung, breast and ovarian cancer, respectively [14]. The diverse biological activities observed for different molecule containing the 1,3,5-triazine unit have been further explored in order to discover other new potential molecules through the synthesis of libraries by combinatorial approaches. Certain 1,3,5-triazine derivatives are also used as chiral
54 Scope of the Present Investigation stationary phases, for example, the chiral solvating agent for the determination of enantiomeric excess by NMR spectroscopy and determination of absolute configuration by circular dichroism. The aim of the project is to synthesize new Mannich base compounds based on some 1, 3, 5-triazine substituted uracil derivatives with formaldehyde and secondary amines for their varied pharmacological applications. The synthesized compounds will be characterized by TLC, physical properties, elemental analysis, IR, 1H and 13C NMR spectroscopy and screened for their biological and pharmacological activities.
References
1. F.Aydoğan,Z. Turgut, N.Öcal, Turk. J. Chem., 26, 159, 2002. 2. Katica D. Vesna K. Vlado G.M and Dora B. Aleksandra, Molecules., 6, 815- 824, 2001. 3. Koechel D.A, Rankin G.O, J Med Chem., 21(8), 764-9, 1978. 4. Risch, N and Westermann B. Angew. Chem. Int. Ed, 37, 1044-1070, 1998. 5. Knabe, J, Buch, H.P and Schmitt W. Derivatives of barbituric acid cytostatic and CNS activities of chiral barbiturate mannich-bases. Arch. Pharm. Chem. Life Sci., 316, 1051-1053, 1983. 6. Hollink E, Simanek, E.E and Bergbreiter D.E, Tetrahedron Lett. 46, 2005. 7. Joshi U.J, Gokhale K.M, Kanitkar A.P, Green chemistry: need for the hour, Ind. J . Edu. 168-174, 2011. 8. Prasad D, Preetam A and Nath M, Microwave-assisted green synthesis of dibenzo[a,j]xanthenes using p-dodecylbenzenesulfonic acid as an efficient Bronsted acid catalyst under solvent-free conditions Original Research Article. Comptes Rendus Chimie, 15(8), 675-678, 2012. 9. Wang S, Cheng C, Wu F, Jiang B, Shi F, Tu S and Li, G, Microwave-assisted multi-component reaction in water leading to highly regioselective formation of benzo[f]azulen-1-ones. Tetrahedron, 67(25), 4485-4493, 2011. 10. Tucker J.L, Green chemistry: cresting a summit toward sustainability, Org Process Res Dev, 14, 2010. 11. Erdmenger T, Guerrero-Sanchez C, Vitz J, Hoogenboom R and Schubert U.S, Recent developmentsin the utilization of green solvents in polymer chemistry. Chem Soc Rev, 39, 3317-3333, 2010. 12. Balini A, J. Med. Chem., 48, 5570, 2005. 13. Kuo G.H, J. Med. Chem., 48, 4535, 2005. 14. Hedayatullah M, Lion C and Slimane A.B, Heterocycles, 51, 1986.
55 Chapter 5 Experimental Methods
5.1.Materials
o-Amino benzoic acid, p-Amino benzoic acid, o-Amino phenol, p-Amino phenol, Salicylaldehyde, Dicynodiamide, Uracil, Formaldehyde, piperazine, petroleum benzene, ethyl acetate, Hydrochloric acid and Ethanol.
5.1.1 Procedure 1. Synthesis of 5, 6-disubstituted -1, 3, 5-triazine (T1-T4)
The different 5, 6-disubstituted -1, 3, 5-triazine were synthesized using microwave oven as Green synthesis irradiation for appropriate time (2-3 minutes). After complete conversion, the mixture was extracted with ice cold water and washed with water and dried. It is then recrystallized with ethanol.
2. Synthesis of Schiff bases derived from Uracil and different 5,6- disubstituted 1,3,5-Triazine (S1-S4)
Different 5, 6-disubstituted 1, 3, 5-Triazine (0.01M) was dissolved in 20ml of 1:1 HCl. To this equimolar concentration of Uracil (0.01M) was added. The contents were subjected to microwave irradiation in Pyrex beaker at an interval of (30 seconds) at 800W for about 10-15 minutes. The progress of the reaction was monitored by TLC. After the completion of the reaction, the product obtained was extracted with ice cold water, washed with water and dried. It is then recrystallized with ethanol.
3. Synthesis of Mannich base derived from synthesised different Schiff base compounds, Formaldehyde and piperazine (M1-M4)
A mixture of synthesized Schiff base compounds, formaldehyde and piperazine was dissolved in 50 ml of ethanol. This solution was refluxed for 4-19 hours. The progress of the reaction was monitored by TLC. After the completion of the reaction, the product obtained was extracted with ice cold water, washed with water and dried. It is then recrystallized with ethanol.
© IOR INTERNATIONAL PRESS 2019 P.Sounthari and P.R. Sivakumar, Synthesis and Characterization of Some Novel Mannich Base Compounds, https://doi.org/10.34256/ioriip1985 56 Experimental Methods
5.1.2 Antibacterial Activity Sensitivity Studies Preparation of inoculum
The inoculums for the experiment were prepared in fresh Nutrient broth from preserved slant culture. The inoculums were standardized by adjusting the turbidity of the culture to that of McFarland standards. The turbidity of the culture may be adjusted by the addition of sterile saline or broth (if excessive or by further incubation to get required turbidity.
Preparation of sterile swabs
Cotton wool swab on wooden applicator or plastics were prepared and sterilized by autoclaving or dry heat (only for wooden swabs) by packing the swabs in culture tubes, papers or tins etc.
Sterilization of forceps
Sterilize forceps by dipping in alcohol and burning off the alcohol
Experiment
The standardized inoculums is inoculated in the plates prepared earlier (aseptically) by dipping a sterile in the inoculums removing the excess of inoculums by passing by pressing and rotating the swab firmly against the side of the culture tube above the level of the liquid and finally streaking the swab all over the surface of the medium 3 times rotating the plate through an angle of 60º after each application. Finally pass the swab round the edge of the agar surface. Leave the inoculums to dry at room temperature with the lid closed. Each Petri dish is divided into 4 parts, in each part samples disc such as M1, M2, M3 and M4– 100 µg discs (discs are soaked overnight in sample solution) and (Std) Ciprofloxacin 10µg, was placed in the plate with the help of sterile forceps. Then Petri dishes are placed in the refrigerator at 4ºC or at room temperature for 1 hour for diffusion. Incubate at 37 ºC for 24 hours. Observe the zone of inhibition produced by different samples. Measure it using a scale and record the average of two diameters of each zone of inhibition.
5.1.3 Anti-Fungal Activity Sensitivity Studies Preparation of inoculum
The inoculums for the experiment were prepared in fresh sabouraud’s broth from preserved slant culture. The inoculums were standardized by adjusting the
57 Experimental Methods turbidity of the culture to that of McFarland standards. The turbidity of the culture may be adjusted by the addition of sterile saline or broth (if excessive or by further incubating to get required turbidity.
Preparation of sterile swabs
Cotton wool swab on wooden applicator or plastics were prepared and sterilized by autoclaving or dry heat (only for wooden swabs) by packing the swabs in culture tubes, papers or tins etc.
Sterilization of forceps
Sterilize forceps by dipping in alcohol and burning off the alcohol
Experiment
The standardized inoculums is inoculated in the plates prepared earlier (aseptically) by dipping a sterile in the inoculums removing the excess of inoculums by passing by pressing and rotating the swab firmly against the side of the culture tube above the level of the liquid and finally streaking the swab all over the surface of the medium 3 times rotating the plate through an angle of 60º after each application. Finally pass the swab round the edge of the agar surface. Leave the inoculums to dry at room temperature with the lid closed. Each Petri dish is divided into 4 parts, in each part samples disc such as M1, M2, M3 and M4 (100µg) discs (discs are soaked overnight in sample solution) and (Std) Flucanaazole 10µg, was placed in the plate with the help of sterile forceps. Then Petri dishes are placed in the refrigerator at 4º C or at room temperature for 1 hour for diffusion. Incubate at 28 º C for 48hours. Observe the zone of inhibition produced by different samples. Measure it using a scale and record the average of two diameters of each zone of inhibition.
5.1.4 Antioxidant Activity Procedure DPPH radical scavenging activity
The DPPH is a stable free radical and is widely used to assess the radical scavenging activity of antioxidant component. This method is based on the reduction of DPPH in methanol solution in the presence of a hydrogen donating antioxidant due to the formation of the non radical form DPPH-H. The free radical scavenging activity of all the extracts was evaluated by 1, 1- diphenyl-2-picryl-hydrazyl (DPPH) according to the previously reported method. Briefly, an 0.1mM solution of DPPH in methanol was prepared, and 1mL of this solution was added to 3 mL of the solution of all extracts in methanol at different concentration (50,100,200,400 & 800μg/mL).The mixtures were shaken vigorously
58 Experimental Methods and allowed to stand at room temperature for 30 minutes. Then the absorbance was measured at 517 nm using a UV-VIS spectrophotometer (Genesys 10S UV: Thermo electron corporation). Quercetein was used as the reference. Lower absorbance values of reaction mixture indicate higher free radical scavenging activity. The capability to scavenge the DPPH radical was calculated by using the formula DPPH scavenging effect (% inhibition) = {(A0 –A1)/A0)*100} A0 is the absorbance of the control reaction, and A1 is the absorbance in presence of all of the extract samples and reference. All the tests were performed in triplicates and the results were averaged [1, 2].
5.1.5 STAGE-I Synthesis of 5, 6 – Disubstituted - 1, 3, 5 – Triazines
1. Synthesis of (2,4-diamino-5-(2-carboxy phenyl)-6-(2-hydroxy phenyl))- 1,3,5 –triazine (T1)
o-amino benzoic acid (0.01M) was dissolved in 20ml of 1:1 HCl. To this equimolar concentration (0.01M) of dicyanodiamide and salicylaldehyde was added. The contents were subjected to microwave irradiation in Pyrex beaker at an interval of (30 seconds) at 300W for about 3 minutes. The progress of the reaction was monitored by TLC. After the completion of the reaction, the product obtained was extracted with ice cold water, washed with water and dried. It is then recrystallized with ethanol.
CN HO
H2N N C H + COOH +
NH O
NH2 o-amino benzoic acid Dicyano diamide Salicylaldehyde
HCl -H2O
HO
O
N H2N
N N OH
NH2 (2,4-diamino-5-(2-carboxy phenyl)-6-(2-hydroxy phenyl))-1,3,5-triazine
59 Experimental Methods
2. Synthesis of (2,4-diamino-5-(4-carboxy phenyl)-6-(2-hydroxy phenyl))- 1,3,5 –triazine (T2) p-amino benzoic acid (0.01M) was dissolved in 20ml of 1:1 HCl. To this equimolar concentration (0.01M) of dicyanodiamide and salicylaldehyde was added. The contents were subjected to microwave irradiation in Pyrex beaker at an interval of (30 seconds) at 300W for about 3 minutes. The progress of the reaction was monitored by TLC. After the completion of the reaction, the product obtained was extracted with ice cold water, washed with water and dried. It is then recrystallized with ethanol.
COOH CN HO
H2N N + C H +
NH O
NH2 p-amino benzoic acid Dicyano diamide Salicylaldehyde
HCl -H2O
O OH
H2N N
N N OH
NH2 (2,4-diamino-5-(4-carboxy phenyl)-6-(2-hydroxy phenyl))-1,3,5-triazine
3. Synthesis of (2,4-diamino-5,6-bis(2-hydroxy phenyl))-1,3,5–triazine (T3)
o-amino phenol (0.01M) was dissolved in 20ml of 1:1 HCl. To this equimolar concentration (0.01M) of dicyanodiamide and salicylaldehyde was added. The contents were subjected to microwave irradiation in Pyrex beaker at an interval of (30 seconds) at 300W for about 3 minutes. The progress of the reaction was monitored by TLC. After the completion of the reaction, the product obtained was extracted with ice cold water, washed with water and dried. It is then recrystallized with ethanol.
60 Experimental Methods
CN HO
H2N N + C H +
OH NH O
NH2
o-amino phenol Dicyano diamide Salicylaldehyde
HCl -H2O
HO
H2N N
N N OH
NH2 (2,4-diamino-5,6-bis-(2-hydroxy phenyl))-1,3,5-triazine
4. Synthesis of (2,4-diamino-5-(4-hydroxy phenyl)-6-(2-hydroxy phenyl))- 1,3,5 –triazine (T4)
p-amino phenol (0.01M) was dissolved in 20ml of 1:1 HCl. To this equimolar concentration (0.01M) of dicyanodiamide and salicylaldehyde was added. The contents were subjected to microwave irradiation in Pyrex beaker at an interval of (30 seconds) at 300W for about 3 minutes. The progress of the reaction was monitored by TLC. After the completion of the reaction, the product obtained was extracted with ice cold water, washed with water and dried. It is then recrystallized with ethanol. OH CN HO
H2N N + C H +
NH O
NH2
p-amino phenol Dicyano diamide Salicylaldehyde
HCl -H2O
OH
H2N N
N N OH
NH2 (2,4-diamino-5-(4-hydroxy phenyl)-6-(2-hydroxy phenyl))-1,3,5- triazine
61 Experimental Methods
5.1.6 Stage-II Synthesis of Schiff Base Compounds
1. Synthesis of 2-[4-Amino-2-(2-hydroxy-phenyl)-6-(2-oxo-2,3-dihydro- 1H-pyrimidin-4-ylideneamino)-2H-[1,3,5]-triazin-1-yl]-benzoic acid (S1)
(2,4-diamino-5-(2-carboxy phenyl)-6-(2-hydroxy phenyl))-1,3,5–triazine (0.01M) was dissolved in 20ml of 1:1 HCl. To this equimolar concentration of Uracil (0.01M) and 10 ml of ethanol was added. The contents were subjected to microwave irradiation in Pyrex beaker at an interval of (30 seconds) at 800W for about 15 minutes. The progress of the reaction was monitored by TLC. After the completion of the reaction, the product obtained was extracted with ice cold water, washed with water and dried. It is then recrystallized with ethanol.
HO
O NH
H2N N
O N O + H N N OH
Uracil NH2 (2,4-diamino-5-(2-carboxy phenyl)-6-(2- hydroxy phenyl))-1,3,5 -triazine
HCl -H2O
HO
O O
HN NH N N
N N OH
NH2 2-[4-Amino-2-(2-hydroxy-phenyl)-6-(2-oxo-2,3-dihydro-1H-pyrimidin-4-ylideneamino)- 2H-[1,3,5]triazin-1-yl]-benzoic acid
62 Experimental Methods
2. Synthesis of 4-[4-Amino-2-(2-hydroxy-phenyl)-6-(2-oxo-2,3-dihydro- 1H-pyrimidin-4-ylideneamino)-2H-[1,3,5]-triazin-1-yl]-benzoic acid (S2)
(2,4-diamino-5-(4-carboxy phenyl)-6-(2-hydroxy phenyl))-1,3,5 –triazine (0.01M) was dissolved in 20ml of 1:1 HCl. To this equimolar concentration of Uracil (0.01M) and 10 ml of ethanol was added. The contents were subjected to microwave irradiation in Pyrex beaker at an interval of (30 seconds) at 800W for about 17 minutes. The progress of the reaction was monitored by TLC. After the completion of the reaction, the product obtained was extracted with ice cold water, washed with water and dried. It is then recrystallized with ethanol.
O OH
NH +
H2N N O N O H
N N OH Uracil
NH2 (2,4-diamino-5-(4 -carboxy phenyl)-6-(2-hydroxy phenyl))-1,3,5 -triazine
HCl -H2O
O OH
O
HN NH
N N
N N OH
NH2 4-[4-Amino-2-(2-hydroxy-phenyl)-6-(2-oxo-2,3-dihydro-1H-pyrimidin-4- ylideneamino)-2H-[1,3,5]triazin-1-yl]-benzoic acid
3. Synthesis of 4-[4-Amino-1,6-bis-(2-hydroxy-phenyl)-1,6-dihydro- [1,3,5]triazine-2-ylimino]- 3,4-dihydro-1H-pyrimidin-2-one (S3)
2,4-diamino-5,6-bis(2-hydroxy phenyl))-1,3,5–triazine (0.01M) was dissolved in 20ml of 1:1 HCl. To this equimolar concentration of Uracil (0.01M) and 10 ml of ethanol was added. The contents were subjected to microwave irradiation in
63 Experimental Methods
Pyrex beaker at an interval of (30 seconds) at 800W for about 9 minutes. The progress of the reaction was monitored by TLC. After the completion of the reaction, the product obtained was extracted with ice cold water, washed with water and dried. It is then recrystallized with ethanol.
NH HO
+ H2N N O N O H
N N OH
Uracil NH2 (2,4-diamino-5,6-bis(2-hydroxy phenyl))-1,3,5 -triazine
HCl -H2O
O
HO HN NH
N N
N N OH
NH2 4-[4-Amino-1,6-bis-(2-hydroxy-phenyl)-1,6-dihydro-[1,3,5]triazin-2- ylimino]-3,4-dihydro-1H-pyrimidin-2-one
1. Synthesis of 4-[4-Amino-6-(2-hydroxy-phenyl)-1-(4-hydroxy-phenyl)- 1,6-dihydro-[1,3,5]triazin-2-ylimino]-3,4-dihydro-1H-pyrimidin-2-one (S4)
2,4-diamino-5-(4-hydroxy phenyl)-6-(2-hydroxy phenyl))-1,3,5–triazine (0.01M) was dissolved in 20ml of 1:1 HCl. To this equimolar concentration of Uracil (0.01M) and 10 ml of ethanol was added. The contents were subjected to microwave irradiation in Pyrex beaker at an interval of (30 seconds) at 800W for about 9 minutes. The progress of the reaction was monitored by TLC. After the completion of the reaction, the product obtained was extracted with ice cold water, washed with water and dried. It is then recrystallized with ethanol.
64 Experimental Methods
OH
NH
O N O + H2N N H
N N OH
Uracil NH2 (2,4-diamino-5-(4-hydroxy phenyl)-6-(2- hydroxy phenyl))-1,3,5 -triazine
HCl -H2O
OH
O
HN NH
N N
N N OH
NH2 4-[4-Amino-6-(2-hydroxy-phenyl)-1-(4-hydroxy-phenyl)-1,6-dihydro-[1,3,5]triazin- 2-ylimino]-3,4-dihydro-1H-pyrimidin-2-one
5.1.7 Stage-3 Synthesis of Mannich Base Compounds
1. Synthesis of 2-[4-Amino-2-(2-hydroxy-phenyl)-6-(2-oxo-1-piperazin-1- ylmethyl-2,3-dihydro-1H-pyrimidin-4-ylideneamino)-2H-[1,3,5]triazin- 1-yl]-benzoic acid (M1)
A mixture of synthesized 2-[4-Amino-2-(2-hydroxy-phenyl)-6-(2-oxo-2,3- dihydro-1H-pyrimidin-4-ylideneamino)-2H-[1,3,5]-triazin-1-yl]-benzoic acid (S1), formaldehyde and piperazine was dissolved in 50 ml of ethanol. This solution was refluxed for 9 hours. The progress of the reaction was monitored by TLC. After the completion of the reaction, the product obtained was extracted with ice cold water, washed with water and dried. It is then recrystallized with ethanol.
65 Experimental Methods
HO O O HN NH O N HN N + C + NH N N OH H H
NH2 Formaldehyde Piperazine 2-[4-Amino-2-(2-hydroxy-phenyl)-6-(2-oxo-2,3- dihydro-1H-pyrimidin-4-ylideneamino)-2H- [1,3,5]triazin-1-yl]-benzoic acid
-H2O
HO HN O O N CH2 N NH N N
N N OH
NH2 2-[4-Amino-2-(2-hydroxy-phenyl)-6-(2-oxo-1-piperazin-1-ylmethyl-2,3-dihydro- 1H-pyrimidin-4-ylideneamino)-2H-[1,3,5]triazin-1-yl]-benzoic acid
2. Synthesis of 4-[4-Amino-2-(2-hydroxy-phenyl)-6-(2-oxo-1-piperazin-1- ylmethyl-2,3-dihydro-1H-pyrimidin-4-ylideneamino)-2H-[1,3,5]triazin- 1-yl]-benzoic acid (M2)
A mixture of synthesized 4-[4-Amino-2-(2-hydroxy-phenyl)-6-(2-oxo-2,3- dihydro-1H-pyrimidin-4-ylideneamino)-2H-[1,3,5]-triazin-1-yl]-benzoic acid (S2), formaldehyde and piperazine was dissolved in 50 ml of ethanol. This solution was refluxed for 9 hours. The progress of the reaction was monitored by TLC. After the completion of the reaction, the product obtained was extracted with ice cold water, washed with water and dried. It is then recrystallized with ethanol.
66 Experimental Methods
O OH
O
HN NH O HN N N + C + NH H H N N OH
NH2 Formaldehyde Piperazine 4-[4-Amino-2-(2-hydroxy-phenyl)-6-(2-oxo-2,3- dihydro-1H-pyrimidin-4-ylideneamino)-2H- [1,3,5]triazin-1-yl]-benzoic acid
-H2O
O OH HN O N
CH2 N NH
N N
N N OH
NH2 4-[4-Amino-2-(2-hydroxy-phenyl)-6-(2-oxo-1-piperazin-1-ylmethyl-2,3-dihydro-1H-pyrimidin-4- ylideneamino)-2H-[1,3,5]triazin-1-yl]-benzoic acid
3. Synthesis of 4-[4-Amino-1,6-bis-(2-hydroxy-phenyl)-1,6-dihydro- [1,3,5]triazin-2-ylimino]-1-piperazin-1-ylmethyl)-3,4-dihydro-1H- pyrimidin-2-one (M3)
A mixture of synthesized 4-[4-Amino-1,6-bis-(2-hydroxy-phenyl)-1,6- dihydro-[1,3,5]triazine-2-ylimino]- 3,4-dihydro-1H-pyrimidin-2-one (S3), formaldehyde and piperazine was dissolved in 50 ml of ethanol. This solution was refluxed for 10 hours. The progress of the reaction was monitored by TLC. After the completion of the reaction, the product obtained was extracted with ice cold water, washed with water and dried. It is then recrystallized with ethanol.
67 Experimental Methods
O
HO HN NH O HN
N N + C + NH H H N N OH
Formaldehyde Piperazine NH2 4-[4-Amino-1,6-bis-(2-hydroxy-phenyl)-1,6- dihydro-[1,3,5]triazin-2-ylimino]-3,4- dihydro-1H-pyrimidin-2-one
-H2O
HN O N HO CH2 N NH
N N
N N OH
NH2 4-[4-Amino-1,6-bis-(2-hydroxy-phenyl)-1,6-dihydro-[1,3,5]triazin-2-ylimino]-1-piperazin-1- ylmethyl-3,4-dihydro-1H-pyrimidin-2-one
4. Synthesis of 4-[4-Amino-6-(2-hydroxy-phenyl)-1-(4-hydroxy-phenyl)- 1,6-dihydro-[1,3,5]triazin-2-ylimino]-1-piperazin-1-ylmethyl-3,4- dihydro-1H-pyrimidine-2-one (M4)
A mixture of synthesized 4-[4-Amino-6-(2-hydroxy-phenyl)-1-(4- hydroxy-phenyl)-1,6-dihydro-[1,3,5]triazin-2-ylimino]-3,4-dihydro-1H- pyrimidin-2-one (S4), formaldehyde and piperazine was dissolved in 50 ml of ethanol. This solution was refluxed for 19 hours. The progress of the reaction was monitored by TLC. After the completion of the reaction, the product obtained was extracted with ice cold water, washed with water and dried. It is then recrystallized with ethanol.
68 Experimental Methods
OH
O
HN NH
N N O HN
+ C + N N OH NH H H
NH2 4-[4-Amino-6-(2-hydroxy-phenyl)-1-(4-hydroxy-phenyl) Formaldehyde Piperazine 1,6-dihydro-[1,3,5]triazin-2-ylimino]-3,4-dihydro-1H-pyrimidin-2- one
-H2O
OH
HN O
N CH2 N NH
N N
N N OH
NH2 4-[4-Amino-6-(2-hydroxy-phenyl)-1-(4-hydroxy-phenyl)-1,6-dihydro- [1,3,5]triazin-2-ylimino]-1-piperazin-1-ylmethyl-3,4-dihydro-1H-pyrimidin-2- one
References
1. Halliwell B, Gutteridge JMC and Aruoma OI. The deoxyribose method: a simple test to be assay for determination of rate constants for reaction of hydroxyl radicals. Ana Biochem 165, 215-219, 1987. 2. Srinivasan R, Chandrasekar MJN, Nanjan MJ and Suresh B, Antioxidant activity of Caesalpinia digyna root. J Ethnopharmacol, 113: 284-291, 2007.
69 Chapter 6 Result and Discussion
Heterocyclic compounds are abundant in nature and are of great significance to life because their structural subunits exist in many natural products such as vitamins, hormones, and antibiotics. Hence, they have attracted considerable attention in the design of biologically active molecules and advanced organic chemistry. Heterocycles are an important class of compounds in the medicinal chemistry and also contributed to the society from biological and industrial point which helps to understand life processes. Mannich reaction have been employed in the organic synthesis of natural compounds such as peptides, nucleotides, antibiotics, and alkaloids (e.g. tropinone), other applications were in agro chemicals such as plant growth regulators, also used in the synthesis of medicinal compounds e.g. rolitetracycline, flaoxetine and tolmetin (anti-inflammatory drugs). The recent Mannich bases and its derivatives are of great importance in medicinal chemistry because of their wide variety of application of multifaceted reaction in the synthesis of antimalarial, antitumour, antimicrobial, antitubercular, anti-inflammatory and anticonvulsant molecules. They have been used in paint and polymer chemistry as hardeners, cross linkers, reaction accelerators. However, the most important applications are in the field of pharmaceutical products. Heterocyclic Schiff bases have been extensively investigated due to their wide range of applications including catalysts, medicine, crystal engineering and anti- corrosion agent. Schiff bases are studied widely due to their synthetic flexibility, selectivity and sensitivity towards the central metal atom; structural similarities with natural biological compounds and also due to presence of azomethine group (-N=CH- ) which imports in elucidating the mechanism of transformation and racemization reaction biologically .They exhibit a broad spectrum biological activity including bactericidal, fungicidal, antipyretic, antitumour, antitubercular, anticancer and sterease inhibitory activities and antiviral, antimicrobial and anti-inflammatory activities. As a result of these useful properties, a large number of Schiff bases with 1,2,4-triazine core have been developed. Pyrimidines represent an important class of heterocycles and their structural framework is not only a key constituent of nucleic bases, alkaloids, and numerous pharmacophores with variety of potent biological activities. The activities include anticancer, antiviral, antibacterial, antifungal, antiprotozoal, antihypertensive, antihistaminic, anti-inflammatory and central nervous activities. The presence of © IOR INTERNATIONAL PRESS 2019 P.Sounthari and P.R. Sivakumar, Synthesis and Characterization of Some Novel Mannich Base Compounds, https://doi.org/10.34256/ioriip1986 70 Result and Discussion
Pyrimidine base in uracil, thymine, and cytosine, which are the essential building blocks of nucleic acids DNA and RNA, is one possible reason for their wide spread therapeutic applications. They represent one of the most active classes of compounds possessing wide spectrum of biological activities like signification vitro activity against unrelated DNA and RNA viruses, including polio herpes viruses, diuretic, antitumor, anti-HIV, and cardiovascular. Uracil chemically known as 2,4 dihydroxy pyrimidine has become a popular topic due to its various uses. The chemistry of Uracil and its derivatives is particularly interesting because of their potential application in medicinal chemistry. Similarly, substituted 1,3,5-triazines and their derivatives play important roles in medicinal, agricultural and industrial fields. s-Triazine nucleus has been found to be privileged scaffold with extensive array of biological activities such as antimicrobial, antiprotozoal, anticancer, antimalarial, antiviral, NNRTI’s and anti-angiogenic. Several reports appeared that s- triazine nucleus is a potential scaffold for therapeutic agent against diseases caused by bacteria, malaria and cancer. The aim of the project is to synthesize new Mannich base compounds based on some 1, 3, 5-triazine substituted uracil derivatives with formaldehyde and secondary amines for their varied pharmacological applications. The synthesized compounds will be characterized by TLC, physical properties, elemental analysis, IR, 1H and 13C NMR spectroscopy and screened for their biological and pharmacological activities.
6.1 Physical Properties
The physical properties of synthesised Mannich bases (M1-M4) were presented in Table-1-3. The Molecular weight, Melting point and Yields are noted.
6.2 FT-IR Spectra
FT-IR Spectra was recorded for the Mannich bases in the range 400-4000 cm-1 and presented in the Figures. The vibration bands were tabulated in Tables-4,5 and 6.
6.3 NMR Spectra
NMR spectra were recorded for the Mannich base in the range 1H NMR – 1- 20 ppm C13 - 20-220 ppm using DMSO as a solvent and presented in the Figures. The Chemical shift was tabulated in Tables-7 and 8.
6.4 Antimicrobial and Antifungal activities The Antimicrobial screening results of the synthesized compounds are showed in the table 9-14.
71 Result and Discussion
A series of novel compounds were synthesized and tested for their antibacterial activities against the Bacillus subtitles, Staphylococcus aureoles, E.Colli and Pseudonomous Aeruginosa and Antifungal activities against Aspergillus niger, Candida Albicans, Candida Trophicalis and Aspergillus fumigatus. Antibacterial and Antifungal activity of the synthesized 5,6 disubstituted 1,3,5-triazine compounds (stage-I) are showed in the table 9 and 10. According to the results, T1 and T2 compound exhibited high activity against Bacillus subtitles, Staphylococcus aureoles and Pseudomonas Aeruginosa whereas T3 exhibited moderate activity against Bacillus subtitles, Staphylococcus aureoles and Pseudomonas Aeruginosa. T4, T1 and T2 exhibited high activity against Aspergillus niger, Candida albicans and Candida trophicalis whereas T3 showed good activity against Candida albicans and Candida trophicalis. Antibacterial and Antifungal activity of the synthesized Schiff base compounds (stage-II) are showed in the table 11 and 12. According to the results, S1 and S4 exhibited high activity against E.coli, and Pseudomonas aeruginosa whereas S2 and S3 exhibited moderate activity towards E.coli, Staphylococcus aureus and Pseudomonas aeruginosa. S2 and S4 exhibited high activity against Candida tropicalis and Candida albicans whereas S2 and S3 showed moderate activity against Aspergillus niger, Candida albicans and Candida tropicalis. Antibacterial and Antifungal activity of the synthesized Mannich base compounds (stage-III) are showed in the table 13 and 14. According to the results, compound M3 exhibited good activity against Bacillus subtitles and Pseudonomous Aeruginosa and poor activity against Staphylococcus aureoles and E.Colli. M4 compound showed good activity against Bacillus subtitles, Staphylococcus aureoles and Pseudonomous Aeruginosa. Compounds M1 and M2 exhibited a moderate activity towards Bacillus subtitles, Staphylococcus aureoles, E.Colli and Pseudonomous Aeruginosa. Compounds M3 and M4 exhibited good activity against Aspergillus niger and moderate activity against Candida Albicans and Aspergillus fumigatus. M1 and M2 compounds showed a moderate activity towards Aspergillus niger, Candida Albicans and Aspergillus fumigatus
6.5 Antioxidant activity
Since the antioxidants are gaining a lot of importance as panacea for a large number of lifestyle diseases like aging, cancer, diabetes, cardiovascular and other degenerative diseases, it is of immense significance to establish some new antioxidants by a convenient synthetic methodology. Although a number of methods such as ORAC, ABTS, DMPD, FRAP, TRAP, TBA, superoxide radical scavenging, hydroxyl radical scavenging, nitric oxide radical scavenging, xanthine oxidase, cytochrome C, reducing power method, etc. available, the DPPH method is very common and proved as the best. A series of novel compounds were synthesized were tested for their antioxidant activity against different concentration like 10, 20, 40 and 80. The DPPH is a stable free radical and is widely used to assess the radical scavenging activity of
72 Result and Discussion antioxidant component. Compound M4 showed moderate antioxidant activity of all the synthesized derivatives. Compounds M1, M2 and M3 showed good activities which were similar to reference antioxidant compounds. Also all the compounds showed good scavenging activities. On comparing all the three compounds, M2 showed highest antioxidant property which was similar to the standard compound.
Stage-I Table 1. Physical Properties S.No Properties T1 T2 T3 T4 1. Physical state Solid Solid Solid Solid 2. Melting point oC 190 196 205 210 3. Molecular weight 310 310 282 282 4. Yield 84% 86% 85% 82% 5. Stability Stable under Stable under Stable under Stable under ordinary ordinary ordinary ordinary conditions conditions conditions conditions 6. Molecular formula C16H15N5O3 C16H15N5O3 C15H15N5O2 C15H15N5O2 7. % composition C = 59.07 C = 59.07 C = 60.60 C = 60.60 O = 14.76 O = 14.76 O = 5.05 O = 5.05 N = 21.53 N = 21.53 N = 23.56 N = 23.56 H = 4.61 H = 4.61 H = 10.77 H = 10.77
Stage-II Table 2. Physical Properties S.No Properties S1 S2 S3 S4 1. Physical state Solid Solid Solid Solid 2. Melting point 179 195 168 228 oC 3. Molecular 419 419 391 391 weight 4. Yield 78% 75% 80% 70% 5. Stability Stable under Stable under Stable under Stable under ordinary ordinary ordinary ordinary conditions conditions conditions conditions 6. Molecular C20H17N7O4 C20H17N7O4 C19H17N7O3 C19H17N7O3 formula 7. % composition C = 57.27 C = 57.27 C = 58.31 C = 58.31 O = 15.27 O = 15.27 O = 12.27 O = 12.27 N = 23.38 N = 23.38 N = 23.38 N = 23.38 H = 4.05 H = 4.05 H = 4.05 H = 4.05
73 Result and Discussion
Stage-III Table 3. Physical Properties S.No Properties M1 M2 M3 M4 1. Physical state Solid Solid Solid Solid 2. Melting point 198 182 124 128 oC 3. Molecular 517 517 489 489 weight 4. Yield 49% 47% 48% 45% 5. Stability Stable under Stable under Stable under Stable under ordinary ordinary ordinary ordinary conditions conditions conditions conditions 6. Molecular C25H27N9O4 C25H27N9O4 C24H27N9O3 C24H27N9O3 formula 7. % C = 58.02 C = 58.02 C = 58.89 C = 58.89 composition O = 12.37 O = 12.37 O = 9.81 O = 9.81 N = 24.37 N = 24.37 N = 25,76 N = 25,76 H = 5.22 H = 5.22 H = 5.52 H = 5.52
Stage-I Table 4. FT-IR Spectrum of 1,3,5-Triazine compounds Absorption Band T1 T2 T3 T4 -OH 3333 3351 3663 3374 C-H ( Ar str) 3039 3037 3046 3178 C=O 1693 1699 - - N-H (bending) 1627 1602 1628 1610 C=C 1459 1427 1458 1469 C-N 1320 1375 1363 1370 C-O 1060 1018 1138 1154
Stage-II Table 5. FT-IR Spectrum of Schiff base compounds Absorption Band S1 S2 S3 S4 -OH 3322 3418 3467 3747 C-H ( Ar str) 3040 2614 2979 3035 C=O 1689 1704 1729 1720 C=N 1626 1612 1642 1643 N-H (bending) 1574 1503 1606 1601 C=C 1458 1403 1469 1463 C-N 1320 1243 1357 1362 C-O 1060 1014 1018 1022
74 Result and Discussion
Stage-III Table 6. FT-IR Spectrum of Mannich base compounds Absorption Band M1 M2 M3 M4 -OH 3398 3451 3860 3396 C-H ( Ar str) 3040 3057 3125 3047 C=O 1726 1786 1725 1721 C=N 1626 1698 1636 1614 N-H (bending) 1616 1612 1516 1502 C=C 1453 1410 1402 1450 C-N 1365 1367 1294 1361 C-O 1108 1038 1001 1027
Table 7. 1H NMR Spectrum of Mannich base compounds S.No Assignment M1 M2 M3 M4 1 COOH at C-25 12.92 (s) 13.81 (s) _ _ 2 OH at C-13 12.68(s) 13.73 (s) 13.39 (s) 13.76 (s) 3 NH 9.98 (br, s) 9.68 (s) 9.63 (s) 9.71 (s) 4 NH2 at C-8 8.98(s) 8.95 (s) 8.88 (s) 8.96 (s) 5 Aromatic 6.99-7.99 (m) 6.77-7.61 (m) 6.81-7.58 (m) 6.86-7.61 (m) protons 6 CH2 at C-14 5.34 (s) 5.69 (s) 4.91 (s) 5.52 (s) 7 CH2 at C-18 2.21 (t) 3.52 (t) 2.85 (t) 1.92-2.03 (t) &C-15 8 CH2 at C-16 2.83 (t) 4.01 (t) 3.52 (t) 3.33-3.61 (t) &C-17
Table 8. C13 NMR Spectrum of Mannich base compounds S.No Assignment M1 M2 M3 M4 1 C=O at C-25 178.12 172.01 - - 2 C=O at C-13 166.79 168.91 161.02 161.59 3 C=N at C-8 164.72 161.23 160.13 160.84 3 C-N at C-7 160.23 160.65 160.07 159.16 & C-9 4 C-O at C-4 152.11 151.02 156.02 158.65 5 C-C at C-1 121.45 120.09 119.38 119.67 & C-2 6 Aromatic Carbons 116.08-134.05 116.46-134.93 115.88- 116.03- 141.01 132.37 7 C-14 69.01 70.52 69.43 67.21 8 C-16 & C-17 51.02 50.12 49.55 52.19 9 C-15 &C-18 58.09 58.23 59.03 59.05
75 Result and Discussion
Table 9. Antibacterial Activities of 5,6 disubstituted 1,3,5-Triazine Compounds (Stage-1) S.No Organism Control Sample Concentration/ Zone of Inhibition in diameter Ofluxacin T1 T2 T3 T4 1. Bacillus subtitles 17 16 17 16 14 2. Staphylococcus 16 14 13 13 12 aureoles 3. E.Colli 16 10 10 10 R 4. Pseudonomous 15 14 14 12 R Aeruginosa
Table 10. Antifungal Activities of 5,6 disubstituted 1,3,5-Triazine Compounds (Stage-1) S.No Organism Control Sample Concentration/ Zone of Inhibition in diameter Ketoconezole T1 T2 T3 T4 1. Aspergillus niger 16 16 10 R 14 2. Candida Albicans 18 16 16 16 16 3. Candida Trophicalis 18 14 16 16 14
Table 11. Antibacterial Activities of Schiff base Compounds (Stage-II) S.No Organism Control Sample Concentration/ Zone of Inhibition in diameter Amikacin S1 S2 S3 S4 1. Staphylococcus 17 10 10 12 10 aureoles 2. E.Colli 17 14 10 08 13 3. Pseudonomous 17 13 10 11 10 Aeruginosa
Table 12. Antifungal Activities of Schiff base Compounds (Stage-II) S.No Organism Control Sample Concentration/ Zone of Inhibition in diameter Ketoconezole S1 S2 S3 S4 1. Aspergillus niger 15 12 12 10 10 2. Candida Albicans 15 13 12 10 13 3. Candida Trophicalis 15 13 13 12 14
76 Result and Discussion
Table 13. Antibacterial activities of Mannich base compounds (Stage-III) S.No Organism Control Sample Concentration/ Zone of Inhibition in diameter Ciprofloxacin M1 M2 M3 M4 (10μg/disc) 1. Bacillus subtitles 33 14 11 32 30 2. Staphylococcus 31 20 12 R 24 aureoles 3. E.Colli 31 11 10 R 19 4. Pseudonomous 36 13 12 32 26 Aeruginosa
Table 14. Antifungal Activities of Mannich base Compounds (Stage-III) S.No Organism Control Sample Concentration/ Zone of Inhibition in diameter Flucanazole M1 M2 M3 M4 (10μg/disc) 1. Aspergillus niger 23 14 13 22 23 2. Candida Albicans 40 17 22 20 20 3. Aspergillus fumigatus 32 11 20 17 13
Table 15. Antioxidant Activity of Mannich base compounds (Stage-III) Compounds DPPH Ic 50 Value M1 1.623 M2 1.542 M3 1.850 M4 2.018 Qucertein (Standard) 1.465
77 Result and Discussion
STAGE- I
Fig. 1 FTIR spectral studies of (2,4-diamino-5-(2-carboxy phenyl)-6-(2-hydroxy phenyl))-1,3,5–triazine (T1)
Fig. 2 FTIR spectral studies of (2,4-diamino-5-(4-carboxy phenyl)-6-(2-hydroxy phenyl))-1,3,5–triazine (T2)
78 Result and Discussion
Fig.3 FTIR spectral studies of (2,4-diamino-5,6-bis(2-hydroxy phenyl))-1,3,5– triazine (T3)
Fig.4 FTIR spectral studies of (2,4-diamino-5-(4-hydroxy phenyl)-6-(2-hydroxy phenyl))-1,3,5–triazine (T4)
79 Result and Discussion
STAGE-II
Fig.5 FTIR spectral studies of 2-[4-Amino-2-(2-hydroxy-phenyl)-6-(2-oxo-3,4- dihydro-1H-pyrimidin-4-ylideneamino)-2H-[1,3,5]-triazin-1-yl]-benzoic acid (S1)
O OH
O
HN NH
N N
N N OH
NH2
Fig.6 FTIR spectral studies of 4-[4-Amino-2-(2-hydroxy-phenyl)-6-(2-oxo-2,3- dihydro-1H-pyrimidin-4-ylideneamino)-2H-[1,3,5]-triazin-1-yl]-benzoic acid (S2)
80 Result and Discussion
Fig.7 FTIR spectral studies of 4-[4-Amino-1,6-bis-(2-hydroxy-phenyl)-1,6- dihydro-[1,3,5]triazine-2-ylimino]- 3,4-dihydro-1H-pyrimidin-2-one (S3)
OH
O
HN NH
N N
N N OH
NH2
Fig.8 FTIR spectral studies of 4-[4-Amino-6-(2-hydroxy-phenyl)-1-(4-hydroxy- phenyl)-1, 6-dihydro-[1,3,5]triazin-2-ylimino]-3,4-dihydro-1H-pyrimidin-2-one (S4)
81 Result and Discussion
STAGE-III
Fig.9 FTIR spectral studies of 2-[4-Amino-2-(2-hydroxy-phenyl)-6-(2-oxo-1- piperazin-1-ylmethyl-2,3-dihydro-1H-pyrimidin-4-ylideneamino)-2H- [1,3,5]triazin-1-yl]-benzoic acid (M1)
Fig.10 FTIR spectral studies of 4-[4-Amino-2-(2-hydroxy-phenyl)-6-(2-oxo-1- piperazin-1-ylmethyl-2,3-dihydro-1H-pyrimidin-4-ylideneamino)-2H- [1,3,5]triazin-1-yl]-benzoic acid (M2)
82 Result and Discussion
Fig.11 FTIR spectral studies of 4-[4-Amino-1,6-bis-(2-hydroxy-phenyl)-1,6- dihydro-[1,3,5]triazin-2-ylimino]-1-piperazin-1-ylmethyl)-3,4-dihydro-1H- pyrimidin-2-one (M3)
Fig.12 FTIR spectral studies of 4-[4-Amino-6-(2-hydroxy-phenyl)-1-(4-hydroxy- phenyl)-1, 6-dihydro-[1,3,5]triazin-2-ylimino]-1-piperazin-1-ylmethyl-3,4- dihydro-1H-pyrimidine-2-one (M4)
83 Result and Discussion
Fig.13 1H NMR spectral studies of 2-[4-Amino-2-(2-hydroxy-phenyl)-6-(2-oxo-1- piperazin-1-ylmethyl-2,3-dihydro-1H-pyrimidin-4-ylideneamino)-2H- [1,3,5]triazin-1-yl]-benzoic acid (M1)
Fig.14 1H NMR spectral studies of 4-[4-Amino-2-(2-hydroxy-phenyl)-6-(2-oxo-1- piperazin-1-ylmethyl-2,3-dihydro-1H-pyrimidin-4-ylideneamino)-2H- [1,3,5]triazin-1-yl]-benzoic acid (M2)
84 Result and Discussion
Fig.15 1H NMR spectral studies of 4-[4-Amino-1,6-bis-(2-hydroxy-phenyl)-1,6- dihydro-[1,3,5]triazin-2-ylimino]-1-piperazin-1-ylmethyl)-3,4-dihydro-1H- pyrimidin-2-one (M3)
Fig.16 1H NMR spectral studies of 4-[4-Amino-6-(2-hydroxy-phenyl)-1-(4- hydroxy-phenyl)-1,6-dihydro-[1,3,5]triazin-2-ylimino]-1-piperazin-1-ylmethyl- 3,4-dihydro-1H-pyrimidine-2-one (M4)
85 Result and Discussion
STAGE-III
Fig.17 C13 NMR spectral studies of 2-[4-Amino-2-(2-hydroxy-phenyl)-6-(2-oxo- 1-piperazin-1-ylmethyl-2,3-dihydro-1H-pyrimidin-4-ylideneamino)-2H- [1,3,5]triazin-1-yl]-benzoic acid (M1)
Fig.18 C13 NMR spectral studies of 4-[4-Amino-2-(2-hydroxy-phenyl)-6-(2-oxo- 1-piperazin-1-ylmethyl-2,3-dihydro-1H-pyrimidin-4-ylideneamino)-2H- [1,3,5]triazin-1-yl]-benzoic acid (M2)
86 Result and Discussion
Fig.19 C13 NMR spectral studies of 4-[4-Amino-1,6-bis-(2-hydroxy-phenyl)-1,6- dihydro-[1,3,5]triazin-2-ylimino]-1-piperazin-1-ylmethyl)-3,4-dihydro-1H- pyrimidin-2-one (M3)
Fig.20 C13 NMR spectral studies of 4-[4-Amino-6-(2-hydroxy-phenyl)-1-(4- hydroxy-phenyl)-1,6-dihydro-[1,3,5]triazin-2-ylimino]-1-piperazin-1-ylmethyl- 3,4-dihydro-1H-pyrimidine-2-one (M4)
87 Chapter 7 Conclusion
Uracil is a synthetically versatile substrate that can be used to prepare a large variety of hetrocyclic compounds and as a raw material for drug synthesis. Uracil chemically known as 2,4 dihydroxy pyrimidine has become a popular topic due to its various uses. The synthetic versatility of Uracil has led to the extensive use of this compound in organic synthesis. These compounds are gaining importance because of their role in several pharmacological properties like Antibacterial, Antifungal and Antimalarial activity. The 1, 3, 5-Triazine moiety is a structural element in Antimalarial, Anticancer, Antifungal, Anticonvulsant, Antibacterial and Antiviral compounds. The results of FT-IR, 1H NMR,13C NMR are tabulated and the structure of Mannich bases are assigned on the basis of the spectral studies. The 1H NMR and 13C NMR spectrum confirms the position of H & C and structural details of the compounds. The IR spectroscopy result confirms the presence of functional groups in the proposed compounds. Mannich base compounds were prepared and tested for Antibacterial and Antifungal activities. According to the results, compound M3 exhibited good activity against Bacillus subtitles and Pseudonomous Aeruginosa and poor activity against Staphylococcus aureoles and E.Colli. M4 compound showed good activity against Bacillus subtitles, Staphylococcus aureoles and Pseudonomous Aeruginosa. Compounds M1 and M2 exhibited a moderate activity towards Bacillus subtitles, Staphylococcus aureoles, E.Colli and Pseudonomous Aeruginosa. Compounds M3 and M4 exhibited good activity against Aspergillus niger and moderate activity against Candida Albicans and Aspergillus fumigatus. M1 and M2 compounds showed a moderate activity towards Aspergillus niger, Candida Albicans and Aspergillus fumigatus. A series of novel compounds were synthesized were tested for their antioxidant activity against different concentration like 10, 20, 40 and 80. The DPPH is a stable free radical and is widely used to assess the radical scavenging activity of antioxidant component. Compound M4 showed moderate antioxidant activity of all the synthesized derivatives. Compounds M1, M2 and M3 showed good activities which were similar to reference antioxidant compounds. Also all the compounds
© IOR INTERNATIONAL PRESS 2019 P.Sounthari and P.R. Sivakumar, Synthesis and Characterization of Some Novel Mannich Base Compounds, https://doi.org/10.34256/ioriip1987 88 Conclusion showed good scavenging activities. On comparing all the three compounds, M2 showed highest antioxidant property which was similar to the standard compound.
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