Organic compounds -- part of the class 532-570 series – Organic compounds – Carboxylic acids and salts thereof
Reexamination Certificate
1999-09-02
2003-01-28
Killos, Paul J. (Department: 1623)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carboxylic acids and salts thereof
C562S606000, C562S608000, C564S301000, C564S300000
Reexamination Certificate
active
06512143
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to novel salts of N-tert-butylhydroxylamine and processes for their preparation. The salts are useful as intermediates in organic synthesis.
BACKGROUND OF THE INVENTION
N-Alkyl hydroxylamines, including N-tert-butylhydroxylamine, are important as intermediates in organic synthesis, particularly in the preparation of nitrones, hydroxamic acids and C-nitroso compounds (J. S. Roberts in D. H. R. Barton and W. D. Ollis,
Comprehensive Organic Chemistry
, Volume 2, pages 196-201, Pergamon Press, 1979).
Methods for the synthesis of N-alkyl hydroxylaimnes are well known in the art (J. S. Roberts in D. H. R. Barton and W. D. Ollis,
Comprehensive Organic Chemistry
, Volume 2, pages 185-194, Pergamon Press, 1979). The most common method for the synthesis of such compounds involves the reduction of a corresponding nitrogen-containing compound which is at a higher oxidation level than the hydroxylamine itself. Thus, reductions of nitro, nitroso and oxime derivatives have all been used.
W. D. Emmons (
J. Amer. Chem. Soc.,
1957, 79, 5739-5754) describes the preparation of various oxaziridines by oxidation of the corresponding imine derivative with peracetic acid. Further hydrolysis of these oxaziridines with aqueous acid provides a useful alternative route for the preparation of N-alkyl hydroxylamines.
In a related process, N-alkyl hydroxylamines such as N-tert-butylhydroxylamine may be prepared by oxidation of an imino ether with peracid and subsequent hydrolysis of the resultant alkoxyoxaziridine (D. Thomas and D. H. Aue,
Tetrahedron Letters,
1973, 1807-1810).
Hydroxylamines are basic compounds and form salts with mineral acids, for example, hydrogen chloride and hydrogen bromide. Salts with strong organic acids, for example, oxalic acid and trifluoromethanesulphonic acid, are also known.
As the free bases, N-alkyl hydroxylamines are not, in general, particularly stable, being prone, for example, to undergo aerial oxidation. For this reason, it is expedient to be able to prepare the generally more stable acid addition salts of such compounds. Such salts are particularly convenient as a means of storage of N-alkyl hydroxylamines.
Bayer (DE 35 35 451; EP 0 217 269) describe a process for the preparation of N-alkyl-substituted hydroxylammonium chlorides by the reaction of certain arylaldimines with perpropionic acid and subsequent hydrolysis of the oxaziridine formed thereby. Such hydrochloride salts are regarded as being particularly advantageous. Thus, it is stated that salts other than the hydrochlorides, for example, the corresponding sulphates or hydrogen sulphates, often crystallise only poorly or not at all, a factor which considerably complicates their preparation, isolation and handling.
It has now surprisingly been found that N-tert-butylhydroxylamine forms stable salts with lower carboxylic acids, for example, with acetic acid. Such salts display advantageous properties and are the subject of the present application.
DISCLOSURE OF THE INVENTION
According to the invention we provide a salt of formula (I)
(CH
3
)
3
CNHOH.RCO
2
H (I)
wherein:
R represents hydrogen or C 1 to 4 alkyl.
In particular, it is preferred that R represents methyl such that the compound of formula (I) is N-tert-butylhydroxylammonium acetate.
Unless otherwise indicated, the term “C 1 to 4 alkyl” referred to herein denotes a straight or branched chain alkyl group having from 1 to 4 carbon atoms. Examples of such groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl and t-butyl.
According to the invention, we further provide a process for the preparation of salts of formula (I) which comprises reaction of N-tert-butylhydroxylamine, (CH
3
)
3
CNHOH, with a lower carboxylic acid, RCO
2
H, wherein R is as defined above.
In one aspect of this process, a solution of N-tert-butylhydroxylamine, either formed by liberation of the free base from a salt such as the hydrochloride, or generated directly by synthesis, in a suitable solvent such as ethyl acetate, isopropyl acetate, n-butyl acetate, diisopropyl ether, or methyl t-butyl ether is treated at a suitable temperature with an appropriate amount of a lower carboxylic acid such as acetic acid.
In a preferred aspect, ethyl acetate and sodium acetate, are added to a solution of N-tert-butylhydroxylammonium chloride in water.
In another preferred aspect, ethyl acetate, acetic acid and sodium hydroxide, are added to a solution of N-tert-butylhydroxylamine hydrochloride in water.
In either way, N-tert-butylhydroxylammonium acetate is generated in situ, and may be isolated by separation of the organic (ethyl acetate) layer, followed by evaporation.
It is particularly surprising and advantageous that the novel salt, N-tert-butylhydroxylammonium acetate, can be partitioned from an aqueous phase into an organic phase.
The novel salts of formula (I) may, if necessary, be purified using techniques that are well known in the art. Thus, they may be recrystallised from a suitable solvent such as toluene or ethyl acetate, or from a suitable solvent mixture.
However, most surprisingly and advantageously, the novel salt, N-tert-butylhydroxylammonium acetate, may also be purified by distillation under reduced pressure.
N-tert-butylhydroxylamine, (CH
3
)
3
CNHOH, is well known in the literature and may be prepared by methods that are known per se.
Thus, N-tert-butylhydroxylamine may be produced by reduction of 2-methyl-2-nitropropane, (CH
3
)
3
CNO
2
, with, for example, zinc or aluminium amalgam (J. March,
Advanced Organic Chemistry,
1985 (3
rd
edition), pages 1103-1104;
Organic Syntheses
, vol. 52, 77-82). For process scale work, such methods suffer from the disadvantages that the 2-methyl-2-nitropropane required as a starting material is itself relatively expensive to prepare, and the reduction process requires careful control not least because of its potentially very exothermic nature.
N-tert-Butylhydroxylamine may also conveniently be prepared using the general methodology described by Emmons (vide infra) as summarised in Scheme 1
−
. R
1
therein may conveniently represent hydrogen, but may also represent one or more other suitable substituents. According to the Scheme, N-tert-butylamine (2) is reacted with a benzaldehyde (3) to give the imine (4) which in turn is oxidised with a peracid to afford the oxaziridine (5). The oxaziridine (5) may then either be hydrolysed directly using aqueous acid or alternatively may be first rearranged to the nitrone (6) which is then itself hydrolysed. In either case the hydrolysis yields a mixture of N-tert-butylhydroxylamine (7), as a salt, and the benzaldehyde (3) which may be readily separated. Advantages of this process are that both of the starting materials (2) and (3) are relatively inexpensive. Furthermore, the benzaldehyde (3) is regenerated in the course of the final hydrolysis and may conveniently be separated and recycled. In addition, if a peracid such as meta-chloroperbenzoic acid is used for oxidation of the imine, the meta-chlorobenzoic acid generated therefrom may also be recovered and subsequently re-oxidised.
The novel salts of formula (I) are, in general, crystalline compounds which, unlike the corresponding free base, N-tert-butylhydroxylamine, exhibit good stability upon storage, particularly towards aerial oxidation.
If required, N-tert-butylhydroxylamine may be liberated from the salts of formula (I) simply by treatment with base.
When compared to N-tert-butylhydroxylammonium chloride, the novel salts of formula (1) have the particular advantage that they possess a surprisingly greater stability towards heat. Thus, investigation of N-tert-butylhydroxylammonium chloride using differential scanning calorimetry showed that this salt undergoes an extremely exothermic process (&Dgr;H=−1312 J/g) at an onset temperature of +136° C. In contrast, N-tert-butylhydroxylammonium acetate undergoes no significantly exothermic processes when treated under the same conditions.
In addition, N-tert-butylhydroxylammonium chloride is rather hy
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Chaudhry Mahreen
Killos Paul J.
White & Case LLP
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