Process for the preparation of N-aryl-N-hydroxamides

Details Process for the preparation of N-aryl-N-hydroxamides Process for the preparation of N-aryl-N-hydroxamides

1999-08-25

2001-05-15

Kumar, Shailendra (Department: 1621)

Organic compounds -- part of the class 532-570 series

Organic compounds

Hydroxamate esters or chalcogen analogues thereof

C560S129000, C564S161000, C564S201000

Reexamination Certificate

active

06232492

ABSTRACT:

TECHNICAL FIELD
The invention relates to a process for the preparation of N-aryl-N-hydroxamides.
DESCRIPTION OF THE RELATED ART
Processes for the preparation of N-aryl-N-hydroxamides from the corresponding N-arylhydroxylamines are known. In the synthesis described by Matlin, Stephen A.; Sammes, Peter G.; Upton, Roger M. in J. Chem. Soc., Perkin Trans. 1 (1979), (10), 2481-7, N-arylamides are reacted with suitable silylation agents, such as, for example, hexamethyldisilazane, to give N-trimethylsilyl-N-arylamides, which are then oxidized using peroxovanadate complexes. The desired products are then released from the resulting vanadium complexes of the N-aryl-N-hydroxamides by leaching with EDTA. Because of the necessary protective groups and the lengthy workup, this process is not cost-effective.
I.C. Calder, P. J. Williams, J. Chem. Soc. Chem. Comm. 1972, 891-892 describe the reaction of aryl-hydroxylamines with ketene in diethyl ether or chloroform. However, the product is isolated only in a very low yield (46%) and is contaminated as a result of a lengthy basic extraction process. If ketene is used in excess, two other products are produced (N,O-diacetylarylhydroxylamine and 1-acetyloxindole). Formation of the second byproduct can only be suppressed by carrying out the reaction at −70° C.
In industrial processes, it is difficult to meter ketene exactly stoichiometrically, which means that the known process for the preparation of N-aryl-N-hydrox-amides inevitably always gives at least two byproducts, which reduce the yield and make product isolation difficult. In addition, N-arylhydroxylamines, which have withdrawing substituents, such as, for example, the nitro, cyano or halogen group, can be reacted with ketenes even when they are used stoichiometrically in a non-selective manner to give N-arylhydroxyamides.
The number of byproducts in the processes described can be reduced only by using extremely low and thus uneconomical temperatures.
Moreover, if it is desired to synthesize N,O-diacylarylhydroxylamines, the known processes always produce byproducts which can only be avoided by working at extremely low and thus uneconomical temperatures.
SUMMARY OF THE INVENTION
The object of the invention was, therefore, to overcome the disadvantages of the prior art and to develop a cost-effective process for the preparation of N-aryl-N-hydroxamides which is characterized by high conversion, high yield and simple product isolation, and which produces as few undesired byproducts as possible.
It was a further object of this invention to develop a cost-effective process for the preparation of N,O-diacylarylhydroxylamines which is characterized by high yields and simple product isolation.
This object is achieved by the process according to the invention.
DETAILED DESCRIPTION OF THE INVENTION
The invention provides a process for the preparation of N-aryl-N-hydroxamides in which arylhydroxylamines (I) are reacted with ketenes (II) to give N-aryl-N-hydroxamides (III), where no solvents which form acyloxindoles are used.
Arylhydroxylamines are prepared, for example, by reducing nitrobenzene using zinc, catalytically using hydrogen or hydrazine or electrochemically (see Houben-Weyl, Volume 10/1, pp. 1091 et seq.).
Preferred arylhydroxylamines are those of the formula I
where Ar is an aryl radical selected from the group consisting of phenyl, biphenyl, naphthyl, pyridyl, pyrimidyl, pyridazinyl, triazinyl, furanyl, thiophenyl, pyrrolyl and thiazolinyl and where this aryl radical may be substituted by one or more, identical or different R
3
radicals selected from the group consisting of halogen, hydroxyl, formyl, cyano, carbamoyl, carboxyl, ester or salt of the carboxyl radical, sulfono radical, ester or salt of the sulfono radical, sulfamoyl, nitro, nitroso, amino, phenyl, aryl-C
1
-C
5
-alkyl, C
1
-C
12
-alkyl, C
1
-C
5
-alkoxy, C
1
-C
10
-carbonyl, carbonyl-C
1
-C
6
-alkyl, phospho, phosphono, phosphonooxy, ester or salt of the phosphonooxy radical and where carbamoyl, sulfamoyl, amino and phenyl radicals can be unsubstituted or mono- or polysubstituted by an R
2
radical, and the aryl-C
1
-C
5
-alkyl, C
1
-C
12
-alkyl, C
1
-C
5
-alkoxy, C
1
-C
10
-carbonyl and carbonyl-C
1
-C
6
-alkyl radicals can be saturated or unsaturated, branched or unbranched and can be mono- or polysubstituted with an R
4
radical, where
the R
4
radicals are identical or different and are hydroxyl, formyl, cyano, carboxyl, ester or salt of the carboxyl radical, carbamoyl, sulfono, sulfamoyl, nitro, nitroso, amino, phenyl, C
1
-C
5
-alkyl, C
1
-C
5
-alkoxy or C
1
-C
5
-alkylcarbonyl or
two of each of the R
3
or R
4
radicals can be linked in pairs via a [—CR
5
R
6
—]
m
bridge, where m is 0, 1, 2, 3 or 4, and
R
5
and R
6
are identical or different and are as defined for R
3
, and one or more non-adjacent [—CR
2
R
3
—] groups can be replaced by oxygen, sulphur or an unsubstituted or monosubstituted imino radical, and two adjacent [—CR
5
R
6
—] groups can be replaced by a [—CR
5
═CR
6
—] group, and
R
5
and R
2
are identical or different and are hydrogen or a C
1
-C
12
-alkyl radical.
The ketene used is preferably a ketene of the formula (II)
where R
1
and R
2
are as defined above. The N-aryl-N-hydroxamides (III) have the following formula
where Ar, R
1
and R
2
are as defined above.
The process according to the invention is preferably carried out in the presence of solvents or solvent mixtures.
The word solvent does not mean that all reaction components have to be soluble in it. The reaction can also be carried out in a suspension or emulsion of one or more co-reactants.
Examples of suitable solvents in which no acyloxindoles are formed are water, alcohols, such as methanol, ethanol, isopropanol, propanol, butanol, isobutanol, tertiary butanol, hexanol, cyclohexanol, glycol, methoxyethanol, esters, such as methyl acetate, ethyl acetate, butyl acetate, cyclohexyl acetate, ethyl formiate, ethyl butyrate, dimethyl carbonate, acids, such as acetic acid, nitriles, such as acetonitrile, benzonitrile, cyclic ethers, such as tetrahydrofuran, dioxane, amides, such as dimethylformamide, dimethylacetamide, sulphoxides, such as dimethyl sulphoxide, aromatic solvents, such as benzene, toluene, xylene, chlorobenzene, anisole, N,N-dimethylaniline, nitrobenzene, and heteroaromatic compounds, such as pyridine, pyrimidine and mixtures of these solvents. Preferred solvents are water, alcohols, such as methanol, ethanol, isopropanol, propanol, butanol, isobutanol and esters, methanol, ethanol, water and ethyl acetate being particularly preferred.
In ethers, such as diethyl ether and in halogenated hydrocarbons, such as chloroform, acyloxindoles are formed, so these are not used in the process according to the invention.
The process according to the invention is preferably carried out at the pressure of the ambient atmosphere, i.e. about 0.1 MPa (abs.), although it can also be carried out at higher or lower pressures. The process according to the invention is preferably carried out with the exclusion of oxygen.
The process according to the invention is preferably carried out at temperatures of from −30° C. to +100° C., particularly preferably between −10° C. and +50° C.
For the preparation of N-aryl-N-hydroxamides (III), preferably 0.5 to 2.5 mol, particularly preferably 1.0 to 2.2 mol, of ketene of the formula (II) are used per mole of arylhydroxylamine of the formula (I).
For the preparation of N,O-diacylarylhydroxyl-amines (IV), preferably 2.0 to 3.0 mol of ketene of the formula (II) are used per mole of arylhydroxylamine of the formula (I), the N,O-diacylarylhydroxylamines (IV) having the formula (IV)
where Ar, R
1
and R
2
are as defined above.
In the process according to the invention it is possible, even when only N-aryl-N-hydroxamides (III) are to be prepared, that N,O-diacylarylhydroxylamines (IV) are produced as by-product, meaning that to obtain a high yield of N-aryl-N-hydroxamide, N,O-diacylarylhydroxyl-amine (IV) must be converted into the N-a

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