Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Patent
1986-07-24
1988-09-20
Daus, Donald G.
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
548125, 548248, C07D26110
Patent
active
047727195
DESCRIPTION:
BRIEF SUMMARY
This invention relates to a process for the preparation of 3,5-disubstituted isoxazoles and more specifically of 5-substituted 3-haloisoxazoles.
The process of this invention comprises the reaction of a dihaloformaldoxime with an excess of an 1-alkyne derivative in the presence of an alkaline base in an inert solvent.
The cycloaddition of a dihaloformaldoxime with an alkyne has precedents in the literature (Gazz. Chim. Ital. 91, 47 (1967) and 99, 1107 (1969)). In accordance with this procedure the alkyne is used as organomagnesium derivative.
This fact does limit its applicability only to the alkynes which do not contain functional groups reactive to Grignard compounds.
This procedure cannot be used on industrial scale because of the well-known difficulties in processing and handling the Grignard compounds.
3,5-Disubstituted-isoxazoles, but not 3-halo, 3-hydroxy or 3-alkoxy-5-substituted isoxazoles, may be prepared by cycloaddition according to C. Grundmann, P. Grunanger "The nitrile-oxides" Springer-Verlag, Berlin (1971).
Cycloadditions of dihaloformaldoximes with alkenes to obtain the corresponding 5-substituted 3-halo-isoxazolines are known (Tetrahedron Letters, 21, 229, (1980); 23, 4563, (1982) and 25, 478 (1984)). However, this reaction was specifically studied for the preparation of alpha-amino-3-chloro-4,5-dihydro-5-isoxazolylacetic acid and its 3-bromo analog, these compounds being antitumor agents known as Acivicin and Bromo-acivicin, respectively.
This cycloaddition is carried out by reaction of an excess of dihaloformaldoxime (3-5 times) with the alkene in the presence of a base or of silver nitrate.
Disappointing results were obtained when the procedure was used to condensate a dihaloformaldoxime with an 1-alkyne derivative. The main reaction product was a dihalofuroxan resulting from the reaction between two molecules of dihaloformaldoxime.
The presence of relevant amounts of furoxan is a serious drawback and must be avoided as much as possible because of its dangerousness (J. Chem. Soc. Perkin Trans. I; 294 (1983)) and of problems connected with the isolation of the desired isoxazole derivative.
We have now surprisingly found that 3-halo-isoxazoles having a wide range of substituents at 5-position can be easily prepared with high selectivity and with high yields by reacting a dihaloformaldoxime with an excess (from 2 to 5 times) of an 1-alkyne derivative in the presence of an alkaline base in an inert solvent at room temperature. The formation of furoxans is minimized (see Example 6).
The dihaloformaldoximes which are useful in the process of the present invention are dichloroformaldoxime and dibromoformaldoxime.
The high versatility of the process of this invention is due to the fact that a variety of 1-alkyne derivatives can be successfully used to afford 3-chloro or 3-bromoisoxazoles having at 5-position various different groups.
Suitable 1-alkyne derivative comprise hydrocarbons such as propyne, 1-butyne, 1-pentyne, 1-hexyne, 3-methyl-1-butyne and acetylene; aryl-derivatives optionally substituted at the aromatic ring such as phenylacetylene, 4-chloro phenylacetylene, 4-methylphenylacetylene, 2,4-dimethylphenylacetylene, and the like; compounds containing a hydroxy group such as 3-butyn-2-ol, 3-butyn-1-ol, propargyl alcohol, 1,1-dimethylpropargyl alcohol, 1-pentyn-3-ol, 1-hexyn-3-ol, 1-phenylpropargyl alcohol and the corresponding derivatives in which the hydroxy group is protected such as in the form of tetrahydropyranyl or acyl derivatives; compounds containing an optionally protected carbonyl group like acetal or thioacetal, such as for example propargyl aldehyde, methyl ethynyl ketone, methyl propargyl ketone, ethyl ethynyl ketone, propyl ethynyl ketone, phenyl ethynyl ketone; esters like ethyl propiolate or amides of propiolic and 3-butynoic acid; compounds containing a protected amino group such as for example amides of propargylamine, alpha-methyl-propargylamine, alpha,alpha-dimethylpropargylamine, alpha,alpha-diethylpropargylamine, and N-tert.butylpropargylamine; halogenated compo
REFERENCES:
Christoph Grundmann et al., J. Org. Chem., 30(8); pp. 2809-2812 (1965).
Chemical Abstracts, 56, 12869e (1962).
Chiarino Dario
Napoletano Mauro
Sala Alberto
Bernhardt E.
Daus Donald G.
Zambon S.p.A.
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