Isatin

Isatin, also known as tribulin, is an organic compound derived from indole with formula C₈H₅NO₂. The compound was first obtained by Otto Linné Erdman and Auguste Laurent in 1840 as a product from the oxidation of indigo dye by nitric acid and chromic acids.

Isatin is a well-known natural product which can be found in plants of the genus '' Isatis'', in ''Couroupita guianensis'', and also in humans, as a metabolic derivative of adrenaline.

It looks like a red-orange powder, and it is usually employed as building block for the synthesis of a wide variety of biologically active compounds including antitumorals, antivirals, anti-HIVs, and antituberculars.

The isatin core is also responsible for the color of “Maya blue” and “Maya yellow” dyes.

It is rumored that isatin is a MAOI with dopaminergic properties.

Synthesis

Sandmeyer methodology

The Sandmeyer methodology is the oldest and straightforward way for the synthesis of isatin. The method involves the condensation between chloral hydrate and a primary arylamine (e.g. aniline), in the presence of hydroxylamine hydrochloride, in aqueous sodium sulfate to form an α‐isonitrosoacetanilide. Isolation of this intermediate and subsequent electrophilic cyclization promoted by strong acids (e.g. sulfuric acid) furnishes isatin in >75% yield.

Stolle methodology

The Stolle procedure is considered the best alternative to Sandmeyer methodology for the synthesis of both substituted and unsubstituted isatins. In this case primary or secondary arylamines are condensed with oxalyl chloride to form a chlorooxalylanilide intermediate which can then cyclize in the presence of a Lewis acid (e.g. aluminium trichloride, titanium tetrachloride, boron trifluoride, ''etc''.).

Other procedures

More recent approaches to the synthesis of N-substituted isatins involves the direct oxidation of commercially available, substituted indoles or oxindoles with different oxidizing agents such as TBHP, IBX-SO3K, tBuONO ''etc''.

Reactivity

The presence of an aromatic ring, a ketone and a γ-lactam moiety, gives to isatin the rare potential to be used as both an electrophile and a nucleophile: indeed, it undergoes an enormous number of reactions, such as N-substitutions, electrophilic aromatic substitution at positions C-5 and C-7 of the phenyl ring, nucleophilic additions onto the C-3 carbonyl group, chemoselective reductions, oxidations, ring-expansions and spiro-annulations. Because of this unique reactivity, isatin is considered one of the most valuable building blocks in organic synthesis.

''N''-Substitution

The ''N''-functionalization of the isatin core can be readily obtained by the deprotonation of the amino moiety, forming the corresponding sodium or potassium salt, and subsequent addition of an electrophile (e.g. alkyl or acyl halides).

On the other hand, ''N''-arylation is usually achieved by cross-coupling reactions with aryl halides using copper or palladium catalysts.

Ring expansion

In the field of organic synthesis, ring expansions are considered valuable reactions since they allow the obtainment medium-size ring (7-9 atoms) which are difficult to synthesize through "classical" methods.

To date, only few articles concerning the ring expansion of isatin derivatives has been reported.
The first one is an acid-catalyzed one-pot multicomponent reaction involving isatins, aminouracils, and isooxazolones to form isoxazoquinolines, important scaffolds in medicinal chemistry.

In another one-pot multicomponent reaction, a unique two-carbon expansion has been achieved by reacting isatin with indene-1,3-dione and N-substituted pyridinium bromide to form dibenzo ,dzepin-6-ones.

''C-2''/''C-3'' nucleophilic addition

Isatin suffers nucleophilic addition on carbonyls at ''C-2'' and ''C-3'' positions. The regioselectivity of the process strongly depends both on the substrate (properties of the substituents on the isatin core, especially those bonded to the nitrogen atom) and the reaction conditions (solvent, temperature etc.). In some cases the nucleophilic addition could be followed by secondary reactions (''e.g.'' cyclization, ring expansion, ring opening ''etc.'')

Oxidation

The oxidation of isatin using hydrogen peroxide (Baeyer–Villiger oxidation) or chromic anhydride yields isatoic anhydride, a compound widely used either in herbicide products and in medicinal chemistry. The use of peroxydisulfuric acid gives rise to 1,4‑benzoxazine compounds.

Dimerization

Dimerization of isatin with KBH₄ in methanol yields Indirubin. This represents the indigo pigment's red component and a highly effective cytotoxic compound.

Reduction

Reduction of the non-amide carbonyl group obviously occurs to give oxindole, respectively.

See also

* Pfitzinger reaction

References

Reviews

*

*

*

*

External links

*{{cite EB1911 , wstitle=Isatin , volume=14 , pages=865–866 , short=1

Lactams
Oxindoles