Isoxazoles, isothiazoles and their benzoderivatives

What are isoxazoles, isothiazoles and their benzoderivatives?

Isoxazole and isothiazole are liquids of boiling point 95 and 113 ºC, respectively.


There are several natural isoxazoles with significant pharmacological activity, for example, muscimol, which is a fungus (Amanita muscaria) with psychotropic effects.

natural isoxazole pharmacological activity
Natural isoxazole with significant pharmacological activity.

Two types of isoxazoles and benzofused isothiazoles can occur.

benzofused isothiazole isoxazole benzisoxazole benzisothiazole
Benzofused isoxazole and isothiazole (benzisoxazole and benzisothiazole).

Thus, monocyclic systems and their benzoderivatives can be considered as aromatic, but they all have a weak N—X bond, which is a potential ring-opening center.

>Ring synthesis

Two main methods have been described to synthesize these rings:

  • Hydroxylamine reaction (NH2OH) with a 3-carbon atom compound, such as a 1,3-diketone or an α,β-unsaturated ketone.
isoxazole ring synthesis hydroxylamine diketone
Isoxazole ring synthesis from hydroxylamine and 1,3-diketone.

This method of synthesis is not used for isothiazoles as thiohydroxylamine (NH2SH) is not available. Thus, its closest equivalent is potassium thiohydroxylamine-5-sulphonate.

It reacts with the propargylic aldehyde at the carbonyl group to give a protected thioxime intermediate that can cyclize to isothiazole.

Isothiazole ring synthesis propargylic aldehyde
Isothiazole ring synthesis from propargylic aldehyde.
  • Reaction of a nitrile oxide with an alkene (C=C) or alkyne (C≡C), generally, nitrile oxide is produced in situ.

Those with aryl substituents are generally isolable.

Two routes have been described to prepare nitrile oxide in situ and capture it.

a) From aldoximes, they are chlorinated at the α-position and the α-chloro oxime obtained produces the nitrile oxides upon reaction with a base, which is usually trimethylamine.

nitrile oxide formation α-chloro oxime
Nitrile oxide formation from α-chloro oxime.

b) From nitroalkanes by treatment with phenyl isocyanate.

nitrile oxide formation nitroalkanes
Nitrile oxide formation from nitroalkanes.

Once the nitrile oxide is obtained, it is reacted with alkynes.

synthesis isoxazole nitrile oxide alkynes
Synthesis of isoxazoles from nitrile oxide and alkynes.

Another such reaction involving a Michael-type addition is described below.

reaction involving Michael-type addition
Reaction involving a Michael-type addition.

The 1,3-dipolar cycloaddition reactions of nitrile sulfides can be used for the synthesis of isothiazoles, but it is a more limited reaction.

The most important routes of isothiazoles synthesis are based on cyclization reactions in which the N1—C5 bond can be formed. Nucleophilic attack can occur on sulfur when it presents a good leaving group. Examples of this reaction are:

isothiazoles synthesis cyclization reactions
Isothiazoles synthesis from cyclization reactions.

Another example would be:

isothiazoles synthesis cyclization reactions
Isothiazoles synthesis from cyclization reactions.

Isothiazoles can also be prepared from isoxazole by reductive opening followed by conversion to thioamide and oxidative cyclization.

isothiazoles synthesis isoxazole reductive opening followed conversion thioamide oxidative cyclization
Isothiazoles synthesis from isoxazole by reductive opening followed by conversion to thioamide and oxidative cyclization.

Synthesis of benzofused systems

To prepare the benzofused systems of isoxazoles and isothiazoles, we start from ortho-substituted benzenes.

For isoxazoles it is done as follows:

synthesis benzisoxazoles ortho-substituted benzenes
Synthesis of benzisoxazoles from ortho-substituted benzenes.
synthesis benzisothiazoles ortho-substituted benzenes
Synthesis of benzisothiazoles from ortho-substituted benzenes.

and for isothiazoles:

Also, 1,2-benzisoxazoles can be synthesized by thermolysis of 2-azidoarylketones.

synthesis benzisoxazoles thermolysis azidoarylketones
Synthesis of 1,2-benzisoxazoles by thermolysis of 2-azidoarylketones.

This is a general example in which aryl azides with ortho-substituent are cyclized with loss of nitrogen.

Furthermore, this reaction is carried out with 2-azidothioketones and 1,2-benzisothiazoles are obtained.

synthesis benzisothiazoles azidothioketones
Synthesis of 1,2-benzisothiazoles from 2-azidothioketones.


A very characteristic reaction is the easy breaking of the N—O bond of isoxazoles. The general methods of cleavage are:

  • Catalytic reduction to give amino-butenones.
reduction isoxazoles yield amino-butanones
Reduction of isoxazoles to yield amino-butanones.
  • Reduction with metal and ammonia to give amino-butenones and enones.
reduction isoxazoles metal ammonia amino-butenones enones
Reduction of isoxazoles with metal and ammonia to give amino-butenones and enones.
  • Opening of 3-isoxazolyl anions to give α-cyanoketones.
opening isoxazolyl anions α-cyanoketones
Opening of 3-isoxazolyl anions to give α-cyanoketones.

Unsubstituted isoxazoles at C3 position are readily deprotonated at C3 with hydroxyl ions. Thus, isoxazole-3-carboxylic acids are opened by heating, through the same type of mechanism.

The opening of unsubstituted isoxazolium salts at C3 position is quite easy.

opening unsubstituted isoxazolium salts C3
Opening of unsubstituted isoxazolium salts at C3.

Isoxazolium salts have been used as reagents for peptide coupling.

Similar ring-opening reactions occur in benzisoxazoles to  yield a benzazetidinone.

ring-opening reaction benzisoxazoles
Ring-opening reaction in benzisoxazoles to yield benzazetidinone.

Isothiazoles, too, are deprotonated at C5. In addition, when the C5 position is blocked, the 3-isothiazole anion can be formed, which undergoes the same type of opening as the isoxazole.

The sulfur atom of isothiazoles can be reductively removed by hydrogenolysis using Raney nickel.

Electrophilic substitution reactions

Both isoxazoles and isothiazoles can undergo this reaction and are preferentially substituted at the C4 carbon.

substitution position C4 isoxazoles isothiazoles
Substitution position, at the C4, (orange arrow) in isoxazoles and isothiazoles.

The alkyl groups at the C3 and C5 positions are slightly activated and can be deprotonated with strong bases.