1. CHEMISTRY OF ISATIN

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.

 

 

It is a unique molecule possessing both amide and ketocarbonyl groups. Apart from this, it has an active hydrogen atom attached to nitrogen (or oxygen) and an aromatic ring which should substitute 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.

1. Both the , -carbonyl groups, having varying reactivity are

involved,

1. Ring cleavage takes place and

2. Ring expansion occurs

A general observation has been that the nature of final product always depends on the experimental conditions and substituents at nitrogen atom which may affect the electron density at  and  carbonyl carbon atoms respectively4.

 

In nature, isatin is found in plants of the genus Isatis5, in Calanthe discolor LINDL6 and in Couroupita guianensis Aubl7, and has also been found as a component of the secretion from the parotid gland of Bufo frogs8, and in humans as it is a metabolic derivative of adrenaline9-11. Substituted isatins are also found in plants, for example the melosatin alkaloids (methoxy phenylpentyl isatins) obtained from the Caribbean tumorigenic plant Melochia tomentosa12-14 as well as from fungi 6-(3'-methylbuten-2'-yl)isatin was isolated from Streptomyces albus15 and 5-(3'-methylbuten-2'­-yl)isatin from Chaetomium globosum16. Isatin has also been found to be a component of coal tar17.

SYNTHESIS OF ISATINS:

a) The Sandmeyer methodology:

The method developed by Sandmeyer is the oldest and the most frequently used for the synthesis of isatins. It consists in the 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 yield18. The method applies well to anilines with electron-withdrawing substituents, such as 2-fluoroaniline19, and to some heterocyclic amines, such as 2-aminophenoxathine20 (2) (Scheme-1).

Scheme-1

This method has some economic advantages, as the reagents are cheap and readily available, and the yields are usually high. Recently, the Sandmeyer methodology has been modified by the incorporation of ethanol as a co-solvent21. This modification proved to be particularly useful in cases where the aniline derivative was insoluble in the conventional reaction matrix. Application of the modified Sandmeyer methodology allowed the synthesis of 4,6-dibromoisatin, a key intermediate for the synthesis of the marine natural product convolutamydine A, in 85% yield, thus representing a greater than 70% improved in yield over the existing published procedure. The use of microwave irradiation during both stages of the Sandmeyer procedure has been investigated, and this modified procedure was also employed for the synthesis of convolutamydine A22.

In addition to the use of H2SO4 for the cyclization step, isonitrosoacetanilides can be heated in BF3.Et2O at 90oC. After cooling the reaction mixture, addition of water allows isolation of the respective isatins. This methodology has proved to be particularly effective for the preparation of benzo-oxygenated isatin derivatives23, 24. The Sandmeyer synthesis has been described as being inapplicable to ortho-hydroxy or ortho-alkoxyanilines. Therefore, an alternative procedure for the synthesis of isonitrosoacetanilides was reported25, 26 (3) (Scheme-2).

Scheme-2

 

On the other hand, there are some disadvantages, for instance those listed below.

• The use of N-alkylanilines furnishes the corresponding N-alkylisatins in low yield. For example, N-methylisatin is obtained in 22% overall yield27.

• Metasubstituted anilines lead to two isomers (4- and 6-substituted isatins), e.g., 3-bromo-4-methoxyaniline yields 4-bormo-5-methoxyisatin (27%) and 6-bromo-5-methoxyisatin (63%). These isomers can be separated by conversion to the corresponding sodium isatinates using 0.5 mol/l NaOH. Subsequent controlled acidification of the reaction medium leads to cyclisation of the two isomers at different pH values, regenerating the corresponding isatins (4, 5), which precipitate from the reaction medium28

 

Other method 29-31 of Sandmeyer’s procedure starts with thiocarbanilide and is carried out according to the following Scheme-4.

Scheme-4

b) The Stolle Procedure:

The most important alternative to Sandmeyer’s procedure is the method of Stolle32. In this method anilines are allowed to 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 TiCl433 has also been used to give the corresponding isatin. This method has been used for the synthesis of 1-aryl34, 35 and polycyclic isatins derived from phenoxazine, phenothiazine and dibenzoazepine36 as well as indoline37. 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 (7), albeit in very low yield (Scheme-5).

Scheme-5

 

Methoxyisatins can be converted to the corresponding phenolic compounds by the action of pyridinium hydrobromide perbromide. This seems to be the best method for obtaining these derivatives, as aminophenols are not useful substrates for the synthesis of isatins38.

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 (8). This method was applied with success for the synthesis of 5, 6-dimethoxyisatin from 4-aminoveratrole whereas the use of 2, 4-dimethoxyaniline was less successful 39 (Scheme-6).

 

Scheme-6

The Martinet procedure is readily applied to naphthylamines, thus yielding benzoisatin derivatives40.

 

d) The Gassman Procedure:

A fundamentally different and general procedure developed by Gassman is another option for the synthesis of isatins41, 42. This methodology consists in the formation and subsequent oxidation of an intermediate 3-methylthio-2-oxindole43-45 to give the corresponding substituted isatins (9) 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 an N-chloroaniline intermediate, which further reacts with a methyl thioacetate ester to furnish an azasulfonium salt (Method 1, Scheme-7). In the case of electron-donating groups that destabilize the N-chloro intermediate, and

Impressum

Verlag: BookRix GmbH & Co. KG

Texte: Dr Konda Swathi
Bildmaterialien: Dr Konda Swathi
Lektorat: Editor
Tag der Veröffentlichung: 22.04.2015
ISBN: 978-3-7368-9107-4

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