Method for grafting a substituted difluoromethyl group

Chemistry: electrical and wave energy – Processes and products – Processes of treating materials by wave energy

Reexamination Certificate

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C204S157430, C204S157790, C204S157800, C204S157940

Reexamination Certificate

active

06203670

ABSTRACT:

The present invention relates to a process for grafting a substituted difluoromethyl group onto a compound containing at least one electrophilic function, and which is useful in particular for preparing difluoro- or trifluoromethanesulphinic and -sulphonic acids and their salts.
The invention relates more particularly to a technique for perfluoroalkylating different compounds by nucleophilic substitution reactions or addition reactions typically carried out by organometallic derivatives.
Perfluoroalkylation techniques, or equivalent techniques, generally use derivatives of the perfluoroalkyl iodide type, in the presence of zinc. This technique is thus expensive, while at the same time requiring plants for processing the metal rejects, which need to be processed since zinc is a serious pollutant of water courses.
The other techniques, in which the perfluoroalkyl radial does not form an organometallic-type stabilized reactive intermediate, are generally difficult to carry out on account of the very poor stability of the free perfluoro anions in the reaction media. These anions generally lead to carbene-type products which, when they react, have lost one of their substituents.
In the specific case of perhaloalkanesulphonic acids and more particularly of trifluoromethanesulphonic acid, used as catalysts or as intermediates in organic synthesis, the process first known for preparing trifluoromethanesulphonic acid was electrochemical fluorination, as described in particular by R. D. Howels and J. D. McCown in Chemical Reviews, 1977, 77, 69.
At the present time, the process for preparing trifluoromethanesulphinic acid described in the European patent published under No. EP-165,136 is also known. This consists in placing a metal selected from zinc, aluminum, manganese, cadmium, magnesium, tin and iron, or even nickel and cobalt, in the presence of sulphur dioxide in a polar aprotic solvent and then in adding a trifluoromethyl halide at a pressure of more than 10
8
Pa. This process gives a product in trifluoromethanesulphinate form in good yield. However, the sulphinate obtained is in a medium containing a large amount of zinc salt. The separation of the sulphinate and of the other salts of zinc poses a problem to be solved at the industrial level. Moreover, this technique, as well as the one described in the French patent application published under No. 2,593,808, required the use of perfluoroalkyl bromides which are reputed to be particularly harmful to the atmospheric layers, in particular on account of their strong greenhouse effect and their reputed harmful effect on ozone.
Accordingly, one of the aims of the present invention is to provide a reagent which allows a perfluoroalkylation according to a mechanism of the type involving a carbanion, without using organometallic reagents of transition metals such as zinc, and which uses products that are less harmful to the environment than, for example, trifluoromethyl bromide, while at the same time remaining low in cost.
It has often been sought to use perfluorocarboxylic acids as a source of perfluoroalkyl radials, ore generally of trifluoromethyl radicals, by carrying out decomposition reactions aimed at eliminating the carboxylic fragment from the said acids, thus releasing carbon dioxide. However, the successes which were obtained were very mixed and used particularly complicated catalytic systems. The perfluoroalkyl radicals or their equivalents generated by the decomposition of the said perfluorocarboxylic acids were moreover unstable in the reaction medium and required the use of stabilizers.
The present invention proposes to circumvent the drawbacks of the existing processes by providing a reagent which is not harmful to the environment and which is capable of giving the desired products in satisfactory yield.
In the course of the study which has led to the present invention, it has been demonstrated that a fluoroalkylation reaction is possible with a fluorocarboxylic acid salt, without a catalyst and without an agent capable of stabilizing the various intermediates envisaged obtained during the decomposition of the various perfluorocarboxylic acids, by working in a polar aprotic solvent and under the action of microwaves.
The abovementioned aims and others, which will become apparent hereinbelow, are thus achieved according to the invention by a process for grafting a substituted difluoromethyl group onto a compound containing at least one electrophilic function, which comprises the steps consisting in:
i) placing the said compound containing at least one electrophilic function in the presence of a nucleophilic reagent comprising:
a) a fluorocarboxylic acid of formula Ea—CF
2
—COOH in which Ea represents an electron-withdrawing atom or group, which is at least partially salified with an organic or inorganic cation, and
b) a polar aprotic solvent; and then
ii) exposing the reaction medium to the action of microwaves.
The electrophilic functions capable of reacting with the reagent of the present invention are the functions which usually react with organometallic reagents, and will be described in detail hereinbelow.
The first essential feature of the invention relates to the reagent.
As has been mentioned above, the solvent plays an important role in the present invention and must be aprotic, and advantageously polar and preferably contains very few impurities bearing an acidic hydrogen, as will be seen hereinbelow.
It is thus preferable for the polar aprotic solvent which can be used to have a significant dipolar moment. Thus, its relative dielectric constant e is advantageously at least equal to about 5 (the positional zeros are not considered as significant figures in the present description unless otherwise specified). Preferably, e is less than or equal to 50 and greater than or equal to 5.
It is also preferred for the solvents of the invention to be capable of solvating the cations well, which can be codified by the donor index D of these solvents. It is thus preferable for the donor index D of these solvents to be between 10 and 30. The said donor index corresponds to the DH (heat difference), expressed in kilocalories, for the combination of the said polar aprotic solvent with antimony pentachloride.
According to the present invention, it is preferable for the reagent not to have any acidic hydrogens on the polar solvent(s) it uses. In particular, when the polar nature of the solvent(s) is obtained by the presence of electron-withdrawing groups, it is desirable for there to be no hydrogen alpha to the electron-withdrawing function.
More generally, it is preferable for the pKa corresponding to the first acidity of the solvent to be at least equal to about 20 (“about” emphasizing that only the first figure is significant), advantageously at least equal to about 25, preferably between 25 and 35.
It is preferable for the said fluorocarboxylic acid or acid salt to be at least partially, preferably completely, soluble in the medium constituting the reagent.
Solvent which give good results can be, in particular, amide-type solvents. Among the amides which are also included are amides with a specific nature, for instance tetrasubstituted ureas and monosubstituted lactams. The amides are preferably substituted (disubstituted in the case of the ordinary amides). Mention may be made, for example, of pyrrolidone derivatives, such as N-methylpyrrolidone, or alternatively N,N-dimethylformamide or N,N-dimethylacetamide.
Another particularly advantageous category of solvents consists of the ethers, which may be either symmetrical or unsymmetrical and may be either open or closed. The category of ethers should include the various derivatives of glycol ethers, such as the various glymes, for example diglyme.
It was also found that the decomposition of fluorocarboxylic acids can be obtained in a particularly effective manner when the content of labile hydrogens in the system, or more exactly of releasable protons, is less than the content of fluoro groups released by the decomposition of the fluorocarboxylic acid salts. The terms “labi

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