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The Martinet dioxindole synthesis was first reported in 1913 by J. Martinet. It is a chemical reaction in which a primary or secondary 
In the first step, the amino group on the aniline (1) attacks the carbonyl of the ethyl oxomalonate (2). A proton from the nitrogen is extracted by the oxygen and an alcohol group forms (3). The carbonyl re-forms to make a keto group and an ethanol molecule leaves (4). Next, a ring closing reaction occurs by the bond from the aromatic benzene ring attacking the partially positive carbonyl to form a five-member ring (5). After a proton transfer (6), an isomerization or a ,3 hydride shift occurs and aromaticity is restored to the six-membered ring (7). In the presence of base, the ester is 
aniline
Aniline is an organic compound with the formula C6 H5 NH2. Consisting of a phenyl group attached to an amino group, aniline is the simplest aromatic amine
In organic chemistry, an aromatic amine is an organic compound consisting of an aroma ...
or substituted aromatic amine
In chemistry, amines (, ) are compounds and functional groups that contain a basic nitrogen atom with a lone pair. Amines are formally derivatives of ammonia (), wherein one or more hydrogen atoms have been replaced by a substituen ...
is condensed with ethyl or methyl ester of mesoxalic acid
Mesoxalic acid, also called oxomalonic acid or ketomalonic acid, is an organic compound with formula C3H2O5 or HO−(C=O)3−OH.
Mesoxalic acid is both a dicarboxylic acid and a ketonic acid. It readily loses two protons to yield the divalent a ...
to make a dioxindole in the absence of oxygen.
Proposed mechanism
In the first step, the amino group on the aniline (1) attacks the carbonyl of the ethyl oxomalonate (2). A proton from the nitrogen is extracted by the oxygen and an alcohol group forms (3). The carbonyl re-forms to make a keto group and an ethanol molecule leaves (4). Next, a ring closing reaction occurs by the bond from the aromatic benzene ring attacking the partially positive carbonyl to form a five-member ring (5). After a proton transfer (6), an isomerization or a ,3 hydride shift occurs and aromaticity is restored to the six-membered ring (7). In the presence of base, the ester is hydrolyzed
Hydrolysis (; ) is any chemical reaction in which a molecule of water breaks one or more chemical bonds. The term is used broadly for substitution, elimination, and solvation reactions in which water is the nucleophile.
Biological hydrolysis ...
, ethanol is lost (8) and a decarboxylation
Decarboxylation is a chemical reaction that removes a carboxyl group and releases carbon dioxide (CO2). Usually, decarboxylation refers to a reaction of carboxylic acids, removing a carbon atom from a carbon chain. The reverse process, which is t ...
occurs (9). The resulting product is the desired dioxindole (10).
In the presence of oxygen, dioxindole converts to isatin through oxidation
Redox (reduction–oxidation, , ) is a type of chemical reaction in which the oxidation states of substrate change. Oxidation is the loss of electrons or an increase in the oxidation state, while reduction is the gain of electrons or a d ...
.
Applications
The Martinet dioxindole synthesis is utilized in the preparation of oxindole derivatives. Oxindole derivatives found in natural products are gaining popularity in research because of their structural diversity. 3-substituted-3-hydroxy-2-oxindole is the central structure of a wide variety of biologically important compounds found in natural products. The 3-substituted-3-hydroxy-2-oxindole structure holds anti-oxidant, anti-cancer, anti-HIV, and neuroprotective properties. The utilization of this core structure for drug synthesis and the relevant cellular pathways involved are being extensively studied. The enantio-selective addition of 3-substituted oxindole derivatives to different electrophiles gives access to chiral 3,3-disubstituted oxindole derivatives. The dioxindole is a strong nucleophile for the Michael addition of dioxindoles to nitroalkenes in order to obtain 3,3-disubstituted oxindole derivatives.Experimental examples
The Martinet dioxindole synthesis proceeds with an alkoxyaniline, 3,4,5-trimethoxyaniline, which reacts with an oxomalonic ester in glacial acetic acid to synthesize 2-carbethoxy-4,5,6-trimethoxyindoxyl, 2-carbethoxy-3,4,5,6-tetramethoxyindole and 4,5,6-trimethoxy-3-hydroxy-3-carbethoxyindole.
Dioxindole
Dioxindole is a non-aromatic heterocyclic organic compound. It has a bicyclic structure consisting of a six-memberedaromatic
In chemistry, aromaticity is a chemical property of cyclic ( ring-shaped), ''typically'' planar (flat) molecular structures with pi bonds in resonance (those containing delocalized electrons) that gives increased stability compared to satur ...
ring fused to a five-membered nitrogen containing ring. It is a hydroxy derivative of oxindole first prepared by reducing isatin with sodium amalgam in an alkaline solution.
See also
* Indole * OxindoleReferences
{{Reflist Indole forming reactions Name reactions