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Abstract Nitrogen-containing heterocycles have received a great deal of interest in the biological and medicinal science and this justifies continuing efforts in the development of new efficient and mild synthetic strategies for their synthesis 1-4. A large variety of nitrogen containing heterocyclic compounds, phthalazines have received considerable attention because of their pharmacological properties and clinical applications. 5-12 The name phthalazine was first used by Lieberman. 13,14 The fundamental ring system of phthalazine is benzo[d]pyridazine 1. Derivatives of phthalazine are oxygenated derivatives, like, phthalazine-1- (2H)-one (2) and 2,3-dihydrophthalazine-1,4-dione (3). N N ( 1 ) N NH O ( 2 ) NH NH ( 3 ) O O Phthalazinone moiety exhibit two lactam-lactim tautomeric forms 2 and 2’. NH N O N N OH ( 2 ) ( 2’ ) A number of methods have been reported for the synthesis of phthalazine derivatives 15-21. ‐2‐ Nevertheless, the development of new synthetic methods for the efficient preparation of heterocycles containing phthalazine ring fragment is therefore an interesting challenge. Thus, the following survey deals with the synthesis, the chemical reactivity and applications of some phthalazinone derivatives. Synthesis of phthalazinone Hydrazine derivatives play a great role in the synthesis of phthalazinones. In most of the reported cases, the reaction involved the direct reaction between hydrazine derivatives with aromatic carbonyl compounds, acid anhydrides, acid imides and oxazines. The reaction usually proceeds via either direct condensation between hydrazine and the substrate or replacement of an oxygen atom by hydrazine’s nitrogen atom or both as shown in the following transformations: 1- from phthalimide derivatives Phthalazine-1-(2H)-one (2) was synthesized via the reaction of 3- hydroxy isoindolin-1-one (4) with hydrazine hydrate 22. NH O OH NH2NH2 N NH O 4 2 + Also, the reaction of phthalimide (5) with reducing agents gives phthalimidine 6 which react with hydrazine hydrate to yield phthalazine-1-(2H)-one (2).23 ‐3‐ NH O O Reduction N O NH N O 5 6 N2H4 2 4-Amino phthalazine-1-(2H)-one (8) was prepared via interaction between mono thiophthalimide 7 with hydrazine hydrate.24 NH S O NH2NH2 NH N NH2 O 7 8 + 2- from benzofuran derivatives Ozonolysis of 2-phenyl-3-ethylbenzofuran (9) gave stable crystalline ozonide. Treatment of the latter with phenyl hydrazine afforded 2-phenyl-4-ethyl phthalazinone (10).25 N N O 10 (i) O3 (ii) C6H5NHNH2 C2H5 C6H5 O C2H5 C6H5 9 3- from O-acylbenzoic acid Phthalazinone derivatives 12 can be obtained from the reaction of oacylbenzoic acid 11 with hydrazine derivatives 26-40 namely hydrazine hydrate, hydrazine acetate salts and methally hydrazine in alcohol or acetic acid. ‐4‐ Also, it has been reported that acid 11 reacted with semicarbazide, thiosemicarbazide and acylhydrazines in pyridine forming phthalazinone derivatives.41 OH O + NH2NHR2 N N R1 R2 R1 O 11 12 O R1 H alkyl aryl R2 H aryl NH2CO NH2CS CH3 CH3COO 4- from naphthalene 1-(2H)-Phthalazinone (2) is prepared from the oxidation of naphthalene 13 subsequent by a treatment with hydrazine and then decarboxylation.42 [ O ] COOH COCOOH NH2NH2 NH N COOH O - CO2 NH N 13 O 2 5- from benzoxazones 2-Amino-4-(aryl)-5,6,7,8-tetrabromo-1-(2H)phthalazinone (15) can be prepared from the reaction of benzoxazones 14 with hydrazine hydrate 43 in boiling pyridine. N O Br Br Br Br Ar O 14 NH2NH2 N N Br Br Br Br Ar O NH2 15 ‐5‐ 6- from phthalide Phthalazinones 17 and 18 were prepared 44-47 from the reaction of phthalide derivatives 16 with hydrazine hydrate or phenylhydrazine respectively. O O CHRR1 N2H4 NH N O CHRR1 R = Styryl, Ph R1= COOH, H, Ph PhNHNH2 NH N O CHRR1 Ph R = Acetyl R1= COOEt 16 17 18 7- from phthalic acid derivatives Treatment of diethyl phthalate 19a, sodium phthalate 19b, or phthalic anhydride 20 with hydrazine hydrate furnished 4-hydroxyphthalazine-1- 2H-one (21) 48 . COOX COOX O O 19a,b O 20 NH N O OH 19 21 a b X C2H5 Na ‐6‐ On the other hand, fused phthalazines comprise a very interesting class of compounds because of their significant biological activities. The following presentation presents a systematic and comprehensive survey on methods of preparation, chemical reactions and applications of fused phthalazines. These compounds proved to be useful precursors for the synthesis of variety of otherwise difficulty accessible, synthetically useful and novel heterocyclic systems. 1. Tricyclic fused phthalazines 1.1. 5,6,6 Ring system 1.1.1. Imidazolo[4,5-g]phthalazine Treatment of 6,7-dichlorophthalazine-5,8-dione (22) with sodium azide in AcOH at room temperature yielded the 6-azido-7- chlorophthalazine 23 gives 6-amino derivative 24 by reducing of the azide group with sodium borohydride in EtOH. The amino group of (24) was acetylated with acetic anhydride in the presence of H2SO4 to give 6- acetamido-7-chlorophthalazine 25. 1-Alkyl/ aryl-2-methyl-1Himidazo[ 4,5-g]- phthalazine-4,9-diones (26a-g) were prepared directly by the cyclization of 25 with alkyl/ aryl amines in ethanol. 49, 1-1. Synthesis of nanostructured materials: In general, there are two approaches to nanoparticle production that are commonly referred to as ‘top-down’ and ‘bottom-up’ Fig.1.1. ‘Top-down’ nanoparticles are generated from the size reduction of bulk materials. They generally rely on physical, the combination of physical and chemical, electrical or thermal processes for their production. Such methods include high-energy milling, mechano-chemical processing, electro-explosion, laser ablation, sputtering and vapour condensation. ‘Bottom-up’ approaches generate nanoparticles from the atomic or molecular level and thus are predominantly chemical processes. Commonly used techniques are crystallization/precipitation, sol gel methods, chemical vapour deposition and self-assembly routes. Some processes may use a combination of both. Fig. 1.1: Schematic of the two general nanoparticle production techniques. Both approaches may be performed in all three states of matter, i.e., vapour, solid or liquid (or combination of these) and the limits to the physical size of nanoparticles produced by either approach are converging and may overlap. The choice of particle size, from a product design perspective, is directly influenced by process economics, capability to supply and the adequacy and type of performance required in the target application. Nanoparticles have a size dimension up to 100 nm and thus represent a ‘bridge’ between the quantum and ‘real’ world (micro and macro). Process routes Top-down Bottom-up High-energy milling Chemical mechanical milling Vapour phase condensation Electro-explosion Laser ablation Sputtering Crystallization Sol-gel Chemical vapour deposition Self-assembly 1-2. Applications of nanostructured materials: Nanomaterials have attracted intensive attentions in the recent years for their wide-range of promising applications. These applications can be represented in the field of adsorption, separation, catalysis, supporting-materials, opticelectric devices, petroleum and chemical industries. owing to their well-defined large surface areas and high thermal stability, and tunable pore surface characters, etc.(5) Not only the electronic, magnetic and optical properties but also chemical, electrochemical and catalytic properties of nanostructured materials are very different from those of the bulk form and depend sensitively on size, shape and composition.(6) Main application areas of nanoparticles are as additives to polymers used in the transport (automotive and aerospace) sector (vehicle parts for lighter weight and higher performance), packaging (including food and biomedical) to protect and preserve the integrity of the product by controlling the barrier, mechanical, optical and respiration properties, textiles (increased strength, water resistance, self cleaning, fade resistance) and personal care products (UV protection, deep penetration skin cream emulsions). Many of these functionalities can be interchanged from one application to another. For example, similar technology used for transparent UV protective coatings such as sunscreens in personal care. Products can be also used for UV protection in food packaging, paints, textiles, plastics used in outdoor use and protection of wood without altering the optical properties.(4) In the communications and information technology sectors, nanoparticles are used for increasing the efficiency of electronics by increasing the information storage capacity whilst reducing the size and weight of devices and components. Additionally, dispersions of nanoparticles in different matrices are used for chemical–mechanical planarisation (CMP) of hard drives and high surface area carbons are used in energy storage devices such as supercapacitors.(7) Other important areas include inks and ink printable electronic circuitry. The paper industry has employed nanoparticle technology for improving fillers and coatings.(8) Moreover in medical sector, nanomaterials are so promising it can involves orthopedic therapy at which nanostructure materials such as ceramics, metals, polymers, and composites can act as new and effective constituents of bone materials, because bone is also made up of nanosized organic and mineral phases in what is called osseointegration.(9) As can be seen from this overview, nanoparticles are being designed and delivered into a broad and ever-increasing range of applications. |