Isatin (1H-indole-2,3-dione) (I) was first discovered by Erdmann and Laurent in 1841, independently as a product from oxidation of indigo by nitric and chromic acids.
It is a unique molecule possessing both amide and keto carbonyl groups. Apart from this, it has an active hydrogen atom attached to nitrogen (or oxygen) and an aromatic ring which was substituted at 5- and 7-positions. It exists in a tautomeric form (II) and these functional characteristics play an important role in governing the various reactions of the molecule.
The C-3 carbonyl group of isatin is strongly electrophilic. As a result, isatins are readily involved in condensation and addition reactions with carbanion type nucleophiles into 3-substituted oxindoles. In general, there are three possibilities during condensation reactions.
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CHEMISTRY OF ISATIN
INTRODUCTION
Isatin (1H-indole-2,3-dione) (I) was first discovered by Erdmann1 and Laurent2 in 1841, independently as a product from oxidation of indigo by nitric and chromic acids.
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It is a unique molecule possessing both amide and keto carbonyl groups. Apart from this, it has an active hydrogen atom attached to nitrogen (or oxygen) and an aromatic ring which was substituted at 5- and 7-positions. It exists in a tautomeric form (II) and these functional characteristics play an important role in governing the various reactions of the molecule.
The C-3 carbonyl group of isatin is strongly electrophilic. As a result, isatins are readily involved in condensation and addition reactions with carbanion type nucleophiles into 3-substituted oxindoles3. In general, there are three possibilities during condensation reactions.
i) both the a, b-carbonyl groups, having varying in reactivity are involved,
ii) ring cleavage takes place and
iii) ring expansion occurs
A general observation reveals that the nature of final product always depends on the experimental conditions and substituents on nitrogen atom which may affect the electron density at a and b carbonyl carbon atoms respectively4.
Synthesis of Isatins
The Sandmeyer methodology :
The method developed by Sandmeyer is the oldest and the most frequently used for the synthesis of isatin. It consists of, reaction of aniline with chloral hydrate and hydroxylamine hydrochloride in aqueous sodium sulfate to form an isonitrosoacetanilide, which after isolation, when treated with concentrated sulfuric acid, furnishes isatin (1) in >75% overall yield (Guo and Chen, 1986). This method is applied mostly well to anilines with electron-withdrawing substituents, such as 2-fluoroaniline5.
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Scheme-1
In addition to the use of H2SO4 for the cyclization step, isonitrosoacetanilides is heated in BF3.Et2O at 90o C. After cooling the reaction mixture, addition of water allows isolation of the respective isatins. This methodology has been proved to be particularly effective for the preparation of benzo-oxygenated isatin derivatives6 7.
The Stolle Procedure
The most important alternative to Sandmeyer’s procedure is the method of Stolle. In this method anilines react with oxalyl chloride to form an intermediate chloro-oxalylanilide which can be cyclized in the presence of a Lewis acid, usually aluminium chloride or BF3.Et2O, although TiCl4 has also been used to give the corresponding isatin. This method has been used for the synthesis of 1-aryl8 and polycyclic isatins derived from phenoxazine, phenothiazine and dibenzoazepine9 as well as indoline10. In the case of dimethoxyanilines, spontaneous cyclization to yield dimethoxyisatins in the absence of a Lewis acid has been observed, as exemplified in the synthesis of melosatin A (2), albeit in very low yield (Scheme-2).
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Scheme-2
The Martinet Isatin Synthesis
The Martinet procedure for the synthesis of indole-2,3-diones involves the reaction of an aminoaromatic compound and either an oxomalonate ester or its hydrate in the presence of an acid to yield a 3-(3-hydroxy-2-oxindole)carboxylic acid derivative which after oxidative decarboxylation yields the respective isatin (3). This method was applied successfully for the synthesis of 5,6-dimethoxyisatin from 4-aminoveratrole whereas the use of 2,4-dimethoxyaniline was less successful11 (Scheme-3).
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Scheme-3
The Martinet procedure is readily applied to naphthylamines, thus yielding benzoisatin derivatives12.
The Gassman Procedure
A fundamentally different and general procedure developed by Gassman is another option for the synthesis of isatins13. This methodology consists in the formation and subsequent oxidation of an intermediate 3-methylthio-2-oxindole to give the corresponding substituted isatins (4) in 40-81% yield.
Two complementary methods for the synthesis of the 3-methylthio-2-oxindoles were developed, and the methodology of choice is dependent upon the electronic effect of substituents bonded to the aromatic ring. When electron-withdrawing groups are present, the oxindole derivative can be synthesized via N -chloroaniline intermediate, which further reacts with a methyl thioacetate ester to furnish an azasulfonium salt (Method 1, Scheme 4). In the case of electron-donating groups that destabilize the N -chloro intermediate, and thus give diminished yields of the azasulfonium salt, a second method of generation of this salt, by reaction of the chlorosulfonium salt with an appropriate aniline, gives better yield of the 3-methylthio-2-oxindoles.
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Scheme-4
Reactions of Isatin :
The reactive carbonyl group at position-3 undergoes typical reactions with the ketonic reagents such as hydroxylamine14, phenyl hydrazine15 and semicarbazide16. The carbonyl group at position-2 is less active and has less ketonic character compared with carbonyl group at C3.
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Schiff Bases :
Isatin reacts with a variety of aromatic amines17 in the presence of glacial acetic acid to yield Schiff bases (9) (azomethines, imines, anils).
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Mannich Reaction 18 :
Isatin reacts with formaldehyde and a variety of amines in the Mannich reaction to give their respective Mannich bases (10), in the absence of an amine, isatin and substituted isatin with formaldehyde give hydroxymethyl isatins (11).
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Other Reactions of Isatins
a) Electrophilic Substitution and Related Reactions :
Reaction of Isatin and haloisatins with chlorosulfonic acid gave 5-chlorosulfonylisatin which were then converted into sulfonamides19.
Nitration of isatin20, 7-methyl isatin, 4,7-dimethyl isatin21 and 1-ethyl isatin22 leads to the introduction of the nitro group into the 5-position. Nitration of 5-methyl isatin gave 5-methyl-7-nitro isatin24.
Pharmacology of Isatin25:
Isatins are endogeneous compounds identified in human and rat tissues. Isatin is a well known pharmacological agent having a range of action in the brain and also protective against certain types of infections.
Isatin contains indole nucleus as that of 5-HT transmitter and is expected to have CNS activity.
Physiologically CNS is divided into following parts26:
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The human brain has about 100 billion nerve cells, also called neurons. Neurons carry signals around the brain and between the brain and the rest of the body. Each neuron produces electrical signals, but chemicals called neurotransmitters are responsible for spreading them27.
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The important neurotransmitters of the central nervous system28
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The drug acting on CNS are divided into two types29:
CNS depressants
- General Anaesthetics
- Anxiolytic, sediative and hypnotic agents
- Antipsychotics
- Anticonvulsant (or) antiepileptic drugs
Central Nervous System Stimulants
- Analeptics
- Methylxanthines
- Central sympathomimetic agents (Psychomotor stimulants)
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