الفهرس 
Synthesis of phthalazinoneOnly 14 pages are availabe for public view
 |  | from | 224 |  |  |
| | | from | 224 | | |
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.