MXPA96001075A - Reagent and procedure useful for grafting a trifluorometry group substituted on a compound that has at least one functional group electrofil - Google Patents

Abstract

The invention relates to a nucleophilic reagent for inserting a substituted difluoromethyl group on a compound having at least one electrophilic functional group, characterized in that it comprises: a) a fluorocarboxylic atom of the formula Ea-CF2-COOH, where Ea represents a atom or a electrically entraining group, at least partially salified by an organic or mineral cation, and b) a polar aprotic solvent, and by the fact that the proportion of liberable protons possessed by their various components, including their impurities, is at most equal to half of the initial molar concentration of fluorocarboxylic acid. A synthesis process using this reagent is also described, by heating to graft a substituted difluoromethyl group onto various compounds.

Description

REAGENT AND PROCEDURE USEFUL FOR GRAFTING A TRIFLUOROMETRY GROUP SUBSTITUTED ON A COMPOUND THAT HAS AT LEAST ONE ELECTROPHILIC FUNCTIONAL GROUP FIELD OF THE INVENTION The present invention relates to a reagent and a process for grafting a substituted difluoromethyl group onto a compound having at least one electrophilic functional group. This relates more particularly to a technique for per f luoroalkylating different compounds by nucleophilic substitution or addition reactions, typically performed by organometallic derivatives.

BACKGROUND OF THE INVENTION The perfluoroalkylation techniques, or equivalent techniques, generally use derivatives of the perfluoroalkyl iodide type, in the presence of zinc. This technique is thus expensive, since it needs metal waste treatment facilities that should be treated, since zinc is a major pollutant of water currents. The other techniques, where the perfluoroalkyl radical does not form a stabilized reactive intermediate of the organometallic type, are generally difficult to implement by virtue of the very weak stability of the free perfluorinated anions in the reaction media. The latter generally lead to products of the carbene type, due to the loss of one of their substituents. This is why one of the objectives of the present invention is to provide a reagent that permits a perfluoroalkylation according to a mechanism of the type that involves a carbanion, without resorting to organometallic compounds of transition metals such as zinc. It has been frequently sought to use as the source of the perfluoroalkyl radicals, more generally the trifluoromethyl radicals, the perfluorocarboxylic acids, carrying out decomposition reactions with a view to eliminating the carboxylic fragment of the acids, liberating carbon dioxide. However, the successes that have been obtained have been very insignificant and use particularly complicated catalytic systems. The perfluoroalkyl radicals or their equivalents generated by the decomposition of the per-fluorocarboxylic acids are on the other hand unstable in the reaction medium and require the use of stabilizing agents. G. Stahly has also reported in Journal of Fluorine Chemistry, 45 (1989), 431-433 and in US Patent No. US-A-4 990 699 that the thermal decomposition of perfluoroalkanoic acid salts in the presence of aromatic compounds such as 1, 3, 5-trinitro-benzene, leads to the formation of trifluoromethyl-CF anions "evidenced by the formation of a Meisenheimer complex. The complex can then be converted by oxidation to give the perfluoroalkylated derivative on the corresponding aromatic nucleus. However, the need to proceed with this oxidation makes this route of perfluoroalkylation of the aromatic derivatives annoying.

BRIEF DESCRIPTION OF THE INVENTION The present invention is proposed to obviate the drawbacks of existing processes by providing a reagent that is not harmful to the environment, and • capable of conducting the desired products with satisfactory performance. In the course of the study which has led to the present invention, it has been shown that a fluoroalkylation reaction is possible with a fluorocarboxylic acid salt, without catalyst and without an agent capable of stabilizing the various intermediates considered, obtained after decomposition. of different perfluorocarboxylic acids. It is evident that in order to obtain a decomposition of fluorocarboxylic acids, two conditions are essential; one is the choice of the solvent, and the other the proportion of impurities in the mixture constituting the reagent according to the present invention. In this way, it has been possible to demonstrate the absolutely critical role of the proportion of labile hydrogens in the system, or more precisely of the releasable protons, which must be less than the proportion of fluorinated groups released by the decomposition of the salts of the Fluorocarboxylic acids. By labile hydrogen and releasable proton, is meant a hydrogen atom capable of being pulled out by a strong, low base • the proton shape. In practice, these are acid functional group protools having a pKa of less than about 20 (per "approximately", it is emphasized that the number 20 represents only a significant figure).

DETAILED DESCRIPTION OF THE INVENTION The aforementioned and other objects, which will appear below, are achieved by means of a nucleophilic reagent useful for grafting a substituted diforomethyl group onto a compound possessing at least one electrophilic functional group, characterized in that it comprises: a) a fluorocarboxylic acid of the formula Ea-CF "-C00H where Ea represents an atom or an electron withdrawing group, at least partially salified by an organic or mineral cation, and b) a polar aprotic solvent; and by the fact that their proportion of liberated protons possessed by their various components, including their impurities, is at most equal to half the initial molar concentration in said fluorocarboxylic acid. The electrophilic functional groups, capable of reacting with the reagent of the present invention, are the functional groups that usually react with the organometallic compounds, and will be detailed hereinafter. The smaller the proportion of releasable protons in the reagent, the lower the risk of parasitic reaction and the better performance.

Thus, it is preferable that, in the reactant, the proportion of labile hydrogen atoms be at most equal to 10%, preferably 1% (in moles), relative to the initial ratio in the fluoro-carboxylic acid . The main impurity, carrier of labile hydrogen atoms, is in general water that is capable of releasing up to two hydrogen atoms per molecule. In a general way, it is preferable to use carefully dehydrated reagents and solvents, so that the weight ratio of water of the reagent is at most equal to 1 per 1,000, relative to the total mass of the reagent. Depending on the set of reaction conditions, such water ratios may be satisfactory, but in certain cases, it may be interesting to operate at lower levels, for example of the order of 1 per 10,000. However, it is not necessarily essential to eliminate all water,? A molar ratio of water / fluorocarboxylic acid of less than 10% can be tolerated. On the other hand, it has been shown that other elements, namely transition elements that have two stable valence states, such as copper, may not be beneficial, they may even be harmful. Although this reagent according to the invention does not need a catalyst, such metal elements can be present as impurities provided mainly by the solvent. Thus, it is preferable that the molar ratio of these elements is less than 1,000, advantageously less than 100, preferably less than 10 ppm relative to the initial ratio in said fluorocarboxylic acid. Similarly, although it has been considered numerous times to use the elements of column VIII of the periodic classification of the elements with perfluoroacetic acid, to favor certain substrates and favor certain types of reaction, that which is revealed particularly harmful to the reaction considered above. This is why it is preferable to use reagents that do not contain metals from column VIII, mainly metals from the platinum mine which is the group consisting of platinum, osmium, iridium, palladium, rhodium and ruthenium. In the present description, reference is made to the supplement of the bulletin of the Chemical Society of France number 1, January 1996, where a periodic classification of the elements has been published. Thus, it is preferable that the proportion of metals of the platinum group, including the metals of column VIII, be less than 100 ppm, advantageously less than 10 ppm, preferably less than 1 ppm. These values are understood in relation to the initial f luorocarboxylic acid and are expressed in moles. In a more general and more empirical way, it can be indicated that these two categories of metals, namely the transition elements with two valence states, and the elements of column VIII, must be present in the reagent at a concentration level. globally at the most equal to 1000 ppm molar, preferably at 10 molar ppm. It will be noted that the different metals present at such a global concentration level are in extremely small amounts and, in this respect, they do not play any catalytic role. Their presence does not improve the kinetics of the reaction, even this is harmful when they are present in a very large amount. The use, in addition to the compounds of the aforementioned reactants, of alkali metal fluoride or of quaternary ammonium fluoride, usually present in the reactive systems using fluorinated carboxylates, has not been revealed as harmful, but has been little revealed. interest, by virtue of the fact that it produces saline effluents that are difficult to treat. It is noted, however, that the presence of fluorides in the medium has a tendency to limit the transformation of fluorocarboxylic acid rather than to reduce parasitic reactions. This effect tends to be all the more important when the opposite cation of the fluoride is bulky. The cations that can be considered are the cations of alkali metals of higher rank than that of sodium, in particular potassium or cesium, or the ions of the "onium" type, namely the cations formed by the elements of columns VB and VI B (as defined in the table of the periodic classification of the elements, published in the supplement of the Bulletin of the Chemical Society of France in January 1966), with 4 or 3 hydrocarbon chains. Among the oniums that are derived from elements of the V B column, the preferred reagents are tetra-alkyl- or tetraaryl-ammonium or -phosphochlo- nium. The hydrocarbon group advantageously has from 4 to 12 carbon atoms, preferably from 4 to 8 carbon atoms. The nons that are derived from column VI B are preferably derived from elements of atomic number greater than that of oxygen. Despite the drawbacks that have been mentioned above, the proportion of fluoride ions is a parameter that can be considered. However, it may be preferable to limit this proportion, in particular the initial proportion, in order to facilitate the final treatment of the reaction medium. In this way it is advantageous that the proportion of fluoride, which is qualified as ionic, ie suscep-tibie to be ionized in the polarizing medium of the reagent, is at most equal to the initial molar concentration in said salt of fluorocarboxylic acid, advantageously half, preferably a quarter. Thus, as mentioned above, the solvent plays an important role in the present invention and must be aprotic, and advantageously polar, and possess very few acid-carrying impurities. Thus it is preferable that the usable polar aprotic solvent has a significant dipole moment. In this way, its relative dielectric constant €. it is advantageously at least equal to about 5 (the position zeros are not considered as significant figures in the present description, unless otherwise specified). Preferably the value of £ is less than or equal to 50, and greater than or equal to 5, and is mainly comprised between 20 and 40. It is further preferred that the solvents of the invention are susceptible to solvate very well the cations, which can be coded by the donor index D of these solvents. It is thus preferable that the donor index D of these solvents be between 10 and 30. The donor index corresponds to? H (enthalpy variation), expressed in kilocalories per mole, of the association of polar aprotic solvent with antimony pentachloride. According to the present invention, it is preferable that the reagent does not present hydrogen hydrogen on the polar solvent (s) it uses. In particular, when the polar character of the solvent (s) is obtained by the presence of electro-attractant groups, it is desirable that it does not have hydrogen in the alpha position of the electro-attractant functional group. More generally, like all the compounds of the reactants, it is preferable that the pKa corresponding to the first acidity of the solvent is at least equal to about 20 ("approximately" means that only the first number is significant), advantageously at least equal to about 25, preferably between 25 and 35.

The acidic character can also be expressed by the acceptor index A of the solvent, such as that defined by Reichardt, "Solvents and solvent effects in Organic Chemistry", 2nd edition, VCH (RFA), 1990, pages 23-24. Advantageously, this acceptor index A is less than 20, in particular less than 18. It is preferable that the acid or the fluorocarboxylic acid salt is at least partially (at least 10 mol%), preferably completely, soluble in the medium that constitutes the reagent. The solvents that give good results, can be mainly the solvents of the amide type. Amides also include amides of a particular nature such as tetrasubstituted ureas, including cyclic tetrasubstituted ureas, mainly 5-membered or 6-membered ureas, for example DMPU (dimethylpropyleneurea or 1,3-dimethyl-3, 4, 5, 6-tetrahydro-2 (lH) pyrimidinone) and DMEU (dimethylethylene urea), or 1,3-dimethyl-2-imldazolidinone, and mono-substituted lactams. The amides are preferably substituted (disubstituted for the ordinary amides). Mention may be made, for example, of pyrrolidone derivatives, such as N-methylpyrrolidone, or even N, N-dimethylformamide, or N, N-dimethyl acetamide. Solvents such as 1,3-dimethyl-3,4,5,6-tetrahydro-2 (1H) pyrimidinone (DMPU) or benzonitrile are also advantageous. Another particularly interesting category of solvents is constituted by the ethers, which are either symmetrical or non-symmetrical, which are open or not. In the ether category, the different derivatives of glycol ethers such as the different gels (ethylene glycol dimethyl ether), for example diglyme (diethylene glycol diraethyl ether), must be incorporated. In the fluorocarboxylic acid of constituent a) of the reagent of the invention, the entity Ea which exerts an electrowinning effect on the difluorinated carbon atom, is preferably chosen from among the functional groups where the Hammett sp constant is at least equal to 0.1 It is, on the other hand, preferable to the inductive component of s, s. , is at least equal to 0.2, advantageously to 0.3. In this regard, reference will be made to March's work, "Advanced Organic Chemistry", third edition, John Wiley and Son, pages 242 to 250, and mainly in table 4 of this section. More particularly, the electrically entraining entity can be chosen from halogen atoms, preferably light, mainly chlorine and fluorine atoms. The corresponding fluorocarboxylic acid is a halogenofluoroacetic acid of formula (1) X-CF-C00H wherein X is a halogen atom, advantageously light (chlorine or fluorine). Ea can also be advantageously chosen from the nitrile groups (with the risk, as a parasitic reaction, of an alpha-elimination), carbo-nyls, sulfones and perfluoroalkyls. Fluorocarboxylic acids of this type which can be used correspond to the formula (2) RG-CF2-COOH where RG represents a nitrile group, or G represents C = 0, ^^ - S = 0, or - (CF ") -, where n is greater than or equal to 1, and R represents an organic, even mineral, indifferent residue, preferably an organic radical such as aryl, alkyl, or aralkyl, optionally substituted. R may also represent an organic solid support, such as a resin, or mineral. In the case where G represents a per-fluoroalkylene group - (CF2) -, n is advantageously comprised between 1 and 10, preferably between 1 and 5. Even in this case, R can also represent a halogen atom, mainly fluorine. Generally, except in the case where the fluorocarboxylic acid is a polymer, the total number of carbon atoms of the fluorocarboxylic acid does not advantageously exceed 50.

Opposing cations capable of forming a salt with fluorocarboxylic acid are advantageously bulky. Thus, alkali salts are preferred, advantageously those where the alkali metal is chosen from sodium, potassium, ruby-dio, cesium and francium. Preferably, the metal is from a period where the range is at least equal to that of sodium, advantageously that of potassium. Quaternary ammonium salts are also preferred. It is also possible to improve the reaction using cations which are either naturally bulky such as quaternary ammonium cations or quaternary phosphonium cations, or bulky events by the addition of chelating agents, or preferably cryptants, such as for example crown ethers or derivatives that are both amined and oxygenated. The chelating or sequestering agents when used are advantageously chosen from a part of the amines, and on the other hand from the ethers whose molecules have at least one other ether functional group. In this way, the usable sequestering agents are advantageously chosen so that they possess, or at least one amine functional group; or an ether functional group and at least one functional group amine and / or ether, to form a complexing agent advantageously at least bidentate, preferably tridated, the ether and / or amine functional groups that are separated by at least one 1, advantageously 2 atoms and at most 4, advantageously at most 3 atoms, generally carbon. When the atoms that are said to ensure coordination are joined together by 2 arms that thus form a cycle, it is preferable that one arm has at least 3 members, advantageously 4 members and the other at least 2, advantageously 3 members. Obstruction and mobility must be such that bi-, tri- or polydentates are complex agents before. Such is not the case of 1,4-diaza- (2, 2, 2) -bicyclo-octane. In a general way, this coercion can be quantified, indicating that the bicyclic systems obtained through the bridge formation of a cycle (which are in fact tricyclic), and that have a number of members at least equal to 8, should be avoided. all when the bridge heads are the atoms that assure the coordination, of the diaza-bicyclo-octane type, heptane and lower, and to a lesser extent nonane. In a more general way, it is advantageous to avoid any bicyclic system: - whose bridge heads are atoms intended to ensure coordination and where 2 of their arms have, taking into account the bridge heads, a length of members at least equal to 2, preferably at least equal to 3, when the third arm has a length, expressed in members, of less than 7. The bidentate character with at least one, preferably an amine function, is necessary for the phosgene and derivatives, but not for the oxalyl halide and equivalents. Particularly interesting are at least 3 classes of complexing agents comprising the oxygenated tertiary amines; oxygenated or sulfuric, cyclic or macrocyclic polyethers; the cryptants. The first class consists of sequestering agents of the general formula: ert which n is an integer greater than or equal to 0 and less than or equal to about 10 (or < n < 10), Rn, R 2, R 3, and R identical or different represent a hydrogen atom or an alkyl radical which has from 1 to 4 carbon atoms, and R .. represents an alkyl or cycloalkyl radical having from 1 to 12 carbon atoms, a phenyl radical or a radical of formula -CmH "uiCo, Ho_, or CmH¿m + .. 1.-Co,! 5-., M being between 1 and approximately 12. The second class of complexing agents consists of cyclic polyethers, preferably macro-cyclic , which have from 6 to 30 atoms in the cycle, and preferably from 15 to 30 atoms in the cycle and constituted from 2 to 10, preferably from 4 to 10 units -0-X in which X is either -CHR, -CHR7-, or -CHR6-CHRg-CRgR7, where R & R ?, Rg and Rg identical or different are a hydrogen atom or an alkyl radical having 1 to 4 carbon atoms, X can be when the -0-X- comp units come to the group -0-CHRg-CHR-,. The third class of complexing agents consists of the compounds described in European patent application EP 0423008 page 3 line 29 to page 6 line 45. The salts of perfluorocarboxylic acids * can be advantageously used, such as trifluoroacetate, perfluoropropionate and perfluorobutyrate of alkali metal, mainly potassium. It is noted that the use of sequestering agents of the crown ether type, in solvents that are relatively slightly polar (less polar than dimethylformamide), markedly accelerates the transformation of the starting fluorocarboxylic acid. Such sequestering agents may advantageously be used in a proportion of 5 to 100 mol%, in particular 5 to 25 mol%, based on the initial proportion of luorocarboxylic acid. However, certain associations with the other members of the reaction medium, mainly certain solvents, may have a less favorable effect as regards the stability of the final product, and will therefore not be considered as advantageous. Yet another object of the present invention is to provide a method of synthesizing an organic derivative possessing a difuoromethylene group, which utilizes the reagent according to the present invention. This objective is achieved: a) by contacting the reagent with a compound having at least one electro-philic functional group, and b) by heating the resulting mixture at a temperature comprised between 100 ° C and 200 °. C, preferably between 110 and 150 ° C, and for a duration of at least half an hour, advantageously of at least one hour, and at most one day, advantageously less than 20 hours. The presence or contact of the reagent with the substrate can be progressive or not. In particular, it can be done that one of the two is at a good temperature to introduce the other. This introduction can be progressive or not. The reagent can be emptied into the substrate or reciprocally. The fluorocarboxylate and the substrate can be introduced simultaneously, and progressively into the solvent. The reagent of the invention reacts according to the invention with an electrophilic compound, which has an electrophilic atom, this atom can be a carbon atom or a heteroatom, for example sulfur, selenium or tellurium. This reacts advantageously with the hydrocarbon compounds on an electrophilic carbon atom that does not belong to an aromatic system. According to a first aspect of the invention, the reagent preferably reacts with compounds possessing an electrophilic atom, advantageously an electrophilic heteroatom, attached to a halogen atom or a pseudohalogen group, to perform the substitution of the halogen or the pseudohalogen in one stage.

The reaction proceeds so much better if, in opposition to a SN2, it is passed through a reaction intermediate that comes from an addition over a multiple bond or over a doublet. When the electrophysic atom is a sulfur atom, the reaction can be mentioned with: the halogenated or pseudohalogenated derivatives of organic sulfur compounds, mainly the sulfenyl, sulfinyl or sulfonyl halogenides, where the halogen atom or the group pseudohalogen is replaced in the course of the reaction by a substituted difluoromethyl group; the disulfides, for example the aryl-sulfides optionally substituted, where the S-S bond is broken and replaced by a substituted difluoromethyl group; the appropriate disulfides can be, in particular, aryl disulfides having 5 to 10 carbon atoms, optionally substituted by an alkyl group of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, nitro or by one or more (less than or equal to 3) ) halogen atom (s); - the compounds of the thiocyanate type wherein the cyano group is substituted in the course of the reaction by a substituted difluoromethyl group; the preferred thiocyanates are aryl thiocyanates of 5 to 10 carbon atoms, including alkylaryl, and alkyl thiocyanates of 1 to 10 carbon atoms, including aralkyl. In the aforementioned compounds, the halogen atom can be chosen from the atoms of iodine, bromine, chlorine and fluorine. A "pseudohalogen" group is a group which, starting from the anionic form, has an associated acid whose pKa is less than 4, preferably 3, in particular 0. The groups whose associated acid has an acidity are preferred. measured by the Hammett constant) at least equal to that of acetic acid, advantageously that of sulphonic acids, or trihalogenated acids. One of the typical pseudohalogens is a perfluoroalkanesulfonyloxy group that releases a perfluoroalkanesulfonate. Preferred pseudohalogen groups can be chosen from the tosylate (p-toluenesulfonyloxy), mesylate (methylsulfonyloxy), trifluoromethylsulphonyloxy or trifluoroacetoxy groups. The acetate group can also be considered as such a starting group. According to a second aspect, the reagent also reacts advantageously on a compound selected from the carbonyl compounds of the ketone, aldehyde, acid halide or activated ester, anhydride type, by adding to the carbonyl functional group. Mention may be made, by way of preferred and non-limiting examples, of the aromatic aldehydes, preferably of 5 to 10 carbon atoms, where the aromatic nucleus may optionally be substituted by an alkyl group of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, nitro or a halogen atom; cyclic ketones such as cyclohexanone; non-enolizable ketones, activated by a donor group, such as trifluoromethylacetophenone; the aromatic anhydrides, such as benzoic anhydride. When there is a risk of reaction between the substrate and the fluorocarboxylate, then it may be preferable not to introduce the substrate or the fluoro-carboxylate more than under the conditions of carboxylate decarboxylation (see the conditions of start-up above). In this case, the product of the reaction is generally an alcohol (for example in the form of an alcoholate) whose carbon atom carrying the hydroxyl functional group is replaced by a substituted di-fluoromethyl group. This product can eventually react immediately with the reagent or with the starting product, following the reaction conditions.

In general, the amount of reagent involved in the process of the invention will be fixed in a manner known per se according to the functionality of the electrophilic compound. It should be noted that the product produced by the decomposition of fluorocarboxylic acid can react on itself if it possesses one of the functional groups capable of reacting, such as those mentioned above. It will be noted that the compounds with an electrophilic functional group that are present in the liquid form are susceptible to being used as the solvent according to the present invention, insofar as they are aprotic. In this way, the reaction of the present invention can advantageously be carried out by: a) a salt of fluorocarboxylic acid as defined above; and b) a compound having at least one electrophilic functional group which acts both as a solvent and as a solvent. substrate of the reaction. When the reagent according to the invention is put into operation, with a substrate having at least one electrophilic functional group, it is important that the latter interfere as little as possible with the conditions described above. Thus, it is preferable to use a sufficiently dehydrated substrate, or one that does not possess acid hydrogen which can be pulled off by the strong bases, nor harmful impurities, that is, in a general manner, satisfying the same constraints as those exposed for the reagent. It has been found that, all things being equal, the yield in the organic derivative considered depends on the degree of progress of the reaction, and that a very small final yield can be obtained despite a significant conversion of the reactants . Without pretending to be linked to any scientific theory, it seems that this step had a kinetic of formation and a kinetic of degradation of the obtained products. In order to avoid a fairly significant degradation of the final product, and thus ensure a good selectivity of the reaction, it is preferable not to seek to completely convert the starting fluorocarboxylic acid. The progress of the reaction can be controlled by the rate of transformation (TT) of the acid, which is the molar ratio of the amount of acid disappeared over the initial acid amount in the reaction medium, this rate being easily calculated after the dosage of the remaining acid in the medium. Advantageously, the reaction will not be conducted other than to obtain a transformation rate of 40 to 80%, preferably 50 to 70%, after the reaction products are separated. It is possible to achieve in this way a selectivity of the order of 80%, expressed by the molar ratio of the desired product / transformed fluorocarboxylic acid. To be placed in these optimal reaction conditions, it is possible to limit the transformation rate by acting both on the duration of the reaction, the nature of the solvent and the presence of additives that tend to limit this transformation, such as fluoride ions. example. The reaction kinetics, on the other hand, depends on reaction partners (luorocarboxylic acid and electrophilic reagent) and the appropriate reaction time can easily be adapted on a case-by-case basis depending on this kinetics. Once the desired transformation rate is achieved, the reaction mixture can be treated in a manner known per se to separate the product obtained, the starting products can be recycled to produce a supplemental amount of the organic derivative considered. If necessary, an additional chemical reaction allowing the conversion of the desired product into a more volatile and easily distillable derivative may be put into operation for the separation.

The following examples illustrate the invention.

Example 1: Synthesis of 1-trifluoromethylbenzyl alcohol.

Under atmos >Nitrogen, 26 g of anhydrous dimethylformamide, 4.98 g (32.7 mmol) of potassium trifluoroacetate and 2 g (18.8 mmol) of benzaldehyde are added. The molar ratio of trifluoroacetate to benzaldehyde is 1.7. The obtained mixture is transferred to a 50 ml Hastelloy reactor. The reactor is closed, the mixture is heated at 104 ° C for 3 hours 30 minutes. After cooling to 5 ° C, the crude reagent is transferred, diluted in methylene chloride and washed with water. The organic phase is dried and then dosed by gas phase chromatography. The conversion rate (TT) of the benzaldehyde is 50% (in the number of moles of benzaldehyde transformed relative to the number of moles of initial benzaldehyde) and the actual yield (RR) of the 1-trif luoromethylbenzyl alcohol is 20%.

Example 2 The reaction between potassium trifluoroacetate and benzaldehyde is carried out as in Example 1, replacing dimethylformamide with NMP (N-methylpyrrolidone). 7.6 grams of CF ,, C07 K (50 mmol) and 3.2 g of benzaldehyde (30 mmol) are dissolved in 40 g of N-methylpyrrolidone. The water content of the medium is less than 4 mol% in relation to trifluoroacetate. The mixture is heated at 140 ° C for 3 hours 30 minutes. The treatment and the dosage of the crude reaction is carried out as in the example 1 given above. The conversion rate of benzaldehyde is equal to 55%. The yield of the 1-trif luoromethylbenzyl alcohol is equal to 15%.

Example 3 The reaction between potassium trifluoroacetate and benzaldehyde is conducted as in example 1, except that the dimethylformamide is replaced by acetonitrile. Dissolve 2 g of benzaldehyde and 4.75 g of potassium trifluoroacetate in 25 ml of CH CN. The mixture is heated at 140 ° C for 3 hours 30 minutes. After treatment and dosing of the crude reaction mixture, the following are obtained: Benzaldehyde conversion rate equal to 53%. Yield of 1-trifluoromethylbenzyl alcohol equal 2.5%. The main product formed in this reaction is cinnamonitrile (Z and E isomers). The cinnamonitrile is formed by condensation of the acetonitrile anion on the benzaldehyde, followed by dehydration. This example shows that the solvent to be used must not have too acidic protons.

Example 4 In the conditions of example 1, the reaction between potassium trifluoroacetate (5.05 g, 32.7 mmol) and parafluorobenzaldehyde (2.5 g, 20.2 mmol) in 25 ml of dimethylformamide is carried out. The mixture is heated at 140 ° C for 4 hours. After treatment and dosing by gas chromatography (GFC), the following is obtained: TT of p-fluorobenzaldehyde equal to 75%. RR of 1-trifluoromethyl- (p-fluorobenzyl) alcohol less than or equal to 2%. The main product corresponds to the addition of trifluoromethyl carbinolate intermediately formed on parafluorobenzaldehyde: This reaction shows that when the used electrophile has several reactive functional groups, side reactions can occur.

Example 5 A mixture consisting of 1.43 g of CF "C02 K (9.44 mmol) and 0.55 g of cyclohexanone (5.6 mmol) diluted in 6.4 g of dimethylformate is heated at 140 ° for 5 hours 30 minutes. Analysis by gas chromatography of the crude reaction mixture after hydrolysis gives The main products formed correspond to the condensation products of cyclohexanone on it, followed by a de-slurry: RR = 40% This reaction shows that when the electrophile has an enolizable functional group, secondary reactions can take place.

Example 6: Reaction of trifluoromethylacetophenone with CF3C02K.

A mixture of CF3C02 (0.87 g-, 5.7 mmol) and 0.62 g (3.56 mmol) of trifluoromethylacetophenone dissolved in 6.5 g of dimethylformamide was heated at 140 ° C for 5 hours 30 minutes. After cooling and hydrolysis the analysis by gas phase chromatography of the reaction medium gives: TT (or -) - 50% «" (d *) - 25% The same reaction can be carried out in N-methylpyrrolidone instead of dimethylformamide.

Example 7: Reaction between benzoic anhydride and potassium trifluoroacetate A mixture of 0.81 g (5.32 mmol) of CF3C02 K + and 0.7 g (3.1 mmol) of benzoic anhydride in 6.15 g of N-methylpyrrolidone is heated at 140 ° C for 5 hours 30 minutes. After hydrolysis the analysis by gas chromatography of the reaction medium gives TT ((FCO) 2O) * = 100% OR RR (F ~ li-NMe2) = 30% Bis-trifluoromethylcarbinol comes from the trifluoromethylation of the trifluoromethyl-acetophenone formed intermediately: N, N-dimethylbenzamide comes from a degradation reaction of dimethylformamide, which is produced from N, N-dimethylamine, reacting it with benzoic anhydride: (FCO) 20 -K-N ßg + FCOgH The reaction between the benzoic anhydride and CF.CO.sub.1 K may also be conducted in dimethylformamide.

Example 8 Reaction between diphenyl disulfide -, + C6H5SSC6H5 and CF3C02 A mixture of 0.83 g (5.46 mmol) of CFCO ~ K, 0. 6 g (2.75 mmol) of diphenyldisulfide in 6.2 g of dimethylformamide is heated at 140 ° C for 6 hours. The analysis of the reaction medium (after hydrolysis) by means of gas chromatography and nuclear magnetic resonance of 19F (RM'N19F), gives: TT (C6H5SSC6H5) = 675 RR (C6H5SCF3) = 84% The reaction can be conducted in the same manner in N-methylpyrrolidone.

Opposite example.

The procedure is as in Example 8 but with a supplementary addition of 20 mol% of Cul with respect to the initial CF "C0" K (5.46 mmol), and a total inhibition of the trifluoromethylation reaction of the diphenyldisulfide is obtained.

Example 9: Reaction between di (4-nitrophenyl) disul-furo and CF3C02 ~ K +.

Reproducing the protocol of Example 8 with a mixture of 0.82 g (5.39 mmol) and CF3C02 ~ K +, 0.83 g (2.7 mmol) of di (4-nitrophenyl) disulfide in 7 g of dimethylformamide gives a crude reaction mixture contains, in addition to the starting di (4-nitrophenyl) diflufide, also 4-nitro-trifluoromethyl-benzene Example 10. Reaction of benzyl thiocyanate C6, H5, -CH, 2, SCN with CF "3C02 K +, The mixture of 0.67 g (4.45 mmol of CF., C02_K and 0.42 g (2.8 mmol) of benzyl thiocyanate in 5 g of dimethylformamide is heated at 140 ° C for 3 hours after the hydrolysis the chromatography analysis in gaseous phase of the crude reaction mixture gives: TT (C6H5-CH2SCN) = 100% RR (C6H5-CH2SCF3) = 36% The reaction can be conducted in N-methyl pyrrolidone, similarly.

It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention is that which is clear from the present description of the invention. Having described the invention as above, the content of the following is claimed as property:

Claims (20)

1. A nucleophilic reagent useful for grafting a substituted difluoromethyl group, on a compound having at least one electrophilic functional group, characterized in that it comprises: a) a fluorocarboxylic acid of the formula Ea-CF ~ -C00H, where Ea represents an atom or an electrically entraining group, at least partially salified by an organic or mineral cation, and b) a polar aprotic solvent; and because the proportion of the liberable protons possessed by their various components, and including their impurities, is at most equal to half the initial molar concentration of the fluorocarboxylic acid.

2. The reagent according to claim 1, characterized in that the polar aprotic solvent is the compound possessing at least one electrophilic functional group. *

3. The reagent according to claim 1 or 2, characterized in that the proportion of protons is at most equal to 10% of the initial molar concentration in the salt of fluorocarboxylic acid.

4. The reagent according to any of the preceding claims, characterized in that its water content is less than 10% of the molar concentration in the fluorocarboxylic acid co.

5. The reagent according to any of the preceding claims, characterized in that its proportion of transition elements having at least two stable valence states is less than 1000 molar ppm, relative to the fluorocarboxylic acid salt.

6. The reagent according to any of the preceding claims, characterized in that its proportion of elements of column VIII of the periodic classification of the elements, is less than 100 ppm molar, relative to the salt of fluorocarboxylic acid.

7. The reagent according to any of the preceding claims, characterized in that its proportion, expressed in equivalents, of ionic fluoride, is at most equal to the initial molar concentration of the fluorocarboxylic acid salt.

8. The reagent according to any of the preceding claims, characterized in that the donor index of the polar aprotic solvent is between 10 and 30.

9. The reagent according to any of the preceding claims, characterized in that the acceptor index of the solvent is less than 20.

10. The reagent according to any of the preceding claims, characterized in that the pKa corresponds to the first acidity of the solvent and is at least equal to 20.

11. The reagent according to any of the preceding claims, characterized in that it comprises a crown sequestering ether.

12. The reagent according to any of the preceding claims, characterized in that the electrically entraining atom or group is chosen from the electro-attractant groups, where the Hammet s constant is at least equal to 1 P

13. The reagent according to any of the preceding claims, characterized in that the acid is chosen from the compounds of the formula (1) X-CF "-C00H, wherein X represents a halogen atom, and the compounds of the formula 2) RG-CF ~ -C00H, where RG represents a nitrile group or G represents __ C = 0,: s = o (CF2) n-, with n that is greater than or equal to 1, and R represents an organic residue or indifferent mineral.

14. The reagent according to any of the preceding claims, characterized in that the acid or the fluorocarboxylic acid salt is completely soluble in the reaction medium.

15. The reagent according to any of the preceding claims, characterized in that the salt of the acid is an alkali metal salt chosen from sodium, potassium, rubidium, cesium and francium, or a quaternary ammonium salt.

16. The reagent according to any of the preceding claims, characterized in that the solvents are chosen from among the N-disubstituted amides, including tetrasubstituted ureas and monosubstituted lactams, and cyclic ethers, and benzonitrile.

17. The process for the synthesis of a derivative having a difluoromethylene group, characterized in that it has the step of: a) introducing a reagent according to any of claims 1 to 14, with a compound having at least one functional group electrophilic, and b) the heating of the resulting mixture at a temperature comprised between 100 and 200 ° C, for a duration comprised between half an hour and a day.

18. The process for the synthesis of a derivative having a difluoromethylene group, characterized in that it comprises the step of heating a reagent according to claim 2, at a temperature comprised between 100 and 200 ° C, for a duration comprised between half an hour and one hour. day.

19. The process according to claim 17 or 18, characterized in that the compound with electrophilic functional group is selected from the halogenated or pseudohalogenated derivatives of organic sulfur compounds, mainly the sulfenyl, sulfinyl or sulfonyl halides; the disulfides; the thiocyanates; and carbonylated compounds, mainly ketones, aldehydes, acid halides, active esters and anhydrides.

20. The process according to any of claims 17 to 19, characterized in that the compound has at least one electrophilic functional group that does not possess hydrogen that can be boosted by a strong base.