EP1082284A1

EP1082284A1 - Condensation method for a carbonyl compound on an aromatic derivative in a basic medium

Info

Publication number: EP1082284A1
Application number: EP99920926A
Authority: EP
Inventors: Roland Jacquot; Michel Spagnol
Original assignee: Rhodia Chimie SAS
Current assignee: Rhodia Chimie SAS
Priority date: 1998-05-29
Filing date: 1999-05-26
Publication date: 2001-03-14
Also published as: US6541674B2; CN1305448A; AU3832399A; JP2002516890A; FR2779141B1; WO1999062853A1; US20030144524A1; US20010004670A1; FR2779141A1

Abstract

The invention concerns a condensation method for at least a carbonyl compound bearing at least an electroattractive group on an aromatic derivative bearing at least a hydroxyl function, characterised in that the electroattractive group present on the carbonyl compound is selected among fluoroalkyl derivatives, esters including orthoesters and nitriles and said condensation is carried out in a basic medium.

Description

Process for the condensation of a carbonyl compound on an aromatic derivative in a basic medium.

The present invention relates to a process for condensing, in basic medium, one or more carbonyl compounds on aromatic derivatives.

The object of the present invention is more specifically to propose a new synthetic route for functionalizing aromatic derivatives with one or more carbonyl derivatives and which advantageously does not require the formation of an intermediate.

Unexpectedly, the Applicant has demonstrated that it is possible to effectively condense in a single step a carbonyl derivative carrying at least one electron-withdrawing group, for example like fluorine, on an aromatic derivative.

This new access route to functionalized aromatic derivatives is all the more advantageous at the industrial level since these compounds are important synthesis intermediates for the preparation of compounds with pharmacological, phytosanitary activity or else of materials such as liquid crystals and / or pigments.

Consequently, the subject of the present invention is a process for condensing at least one carbonylated compound carrying at least one electron-withdrawing group on an aromatic derivative carrying at least one hydroxyl function, characterized in that the electron-withdrawing group present on the carbonylated compound is chosen from fluoroalkyl derivatives, esters including orthoesters and nitriles and said condensation is carried out in basic medium.

In the context of the present invention, a non-nitrogenous basic medium will be preferred.

As regards more particularly the carbonyl compound, the electron-withdrawing group is preferably positioned at the alpha of the carbonyl function. By electron-withdrawing group is meant a group as defined by HC BROWN in the work of Jerry March “Advanced Organic Chemistry”, 3 ^rd edition, chapter 9, pages 243 and 244.

Preferably, this electron-withdrawing group is characterized by a sigma p at least equal to 0.30 and advantageously greater than or equal to 0.40 and less than 0.75 and preferably less than 0.65.

According to a preferred embodiment of the invention, the electron-withdrawing group present on the carbonyl derivative is a fluoroalkyl derivative, advantageously polyfluoroalkyl.

As regards the corresponding alkyl group, it may in particular be a C, C ₁₅ , preferably C, C _{10 group} , linear or branched. This alkyl group can comprise, in addition to the fluorine atom (s) required, other substituents such as other halogen atoms such as chlorine for example. Of course, these other substituents must remain inert during the condensation reaction.

The number of fluorine atoms present on this alkyl group can vary significantly insofar as these fluorine atoms confer, if necessary in combination with the other substituents present on the alkyl group, a sigma p in accordance with the present invention .

According to a preferred embodiment of the invention, the electron-withdrawing group is a polyfluoroalkyl derivative corresponding to a radical of formula:

- (CX ₂ ) _P -GEA in which

- The X, identical or different, represent a hydrogen atom, halogen, preferably fluorine, or a radical of formula C _π X _{2n +} ι with n representing an integer at most equal to 5 preferably to 2;

- p represents an integer at most equal to 2; the symbol GEA represents an electron-withdrawing group the possible functions of which are inert under the conditions of the reaction, advantageously a fluorine atom or a perfluorinated residue of formula C _n X _{2n +} ι with n 'representing an integer at most equal to 8, advantageously to 5 provided that at least one of the X or GEA present on the carbon at α of the carbonyl function represents a fluorine atom, and with the total number of carbon atoms of the polyfluoroalkyl derivative between 1 and 15 , preferably between 1 and 10. As polyfluorinated derivative very particularly suitable are perfluorinated derivatives and in particular those defined by the preceding formula in which X represents a fluorine atom or a GEA group with GEA representing a fluorine atom or a perfluorinated residue of formula C _n X _2r y ₊₁

In addition to the electron-withdrawing group as defined above, the carbonyl compound to be condensed can carry, at the level of its carbonyl function, either a hydrogen atom or a group chosen from C ₅ to C ₁₈ aryls, linear or branched alkyls. C-, C ₁₃ or linear or branched C ₂ -C ₁₄ alkenyls, where appropriate substituted. The substituents can in particular be a hydroxyl group, a halogen atom, an alkyl group in O, -0 ^, and / or an amino group.

It is also possible that the two substituents of the carbonyl function are linked together to form a C ₄ to C ₈ ring. As carbonyl derivatives which are very particularly suitable for the invention, mention may in particular be made of fluorinated aldehyde derivatives of the perfluoroacetaldehyde, perfluoropropionaldehyde, perfluorobutyialdehyde, perfluorooctylaldehyde, perfluorobenzaldehyde derivative as well as any partially or completely fluorinated alkyl aldehyde derivative having a linear or branched chain 13 carbon atoms as well as any partially or fully fluorinated aryl aldehyde derivative having from 7 to about 18 carbon atoms. They can also be fluorinated ketone derivatives such as hexafluoroacetone, 1, 2-dichlorotetrafluoroacetone, 1, 1, 1 -trifluoroacetone as well as any ketone derivative partially or totally fluorinated with a straight or branched chain having from 3 to about 13 atoms of carbon as well as partially or fully fluorinated ketone aryl derivatives having about 8 to 18 carbon atoms in the aryl group or in the group constituting acetone.

According to a preferred embodiment of the invention, the carbonyl derivative used is trifluoroacetaldehyde, also called fluorine, in its hydrated form or not.

Preferably, it is used in its hydrated form.

As mentioned above, the compound which it is sought to functionalize according to the invention is an aromatic derivative. In the following description of the present invention, the term "aromatic" means the classic concept of aromaticity as defined in the literature, in particular by Jerry MARCH, Advanced Organic Chemistry, 4 ^th edition, John Wiley and Sons, 1992, pp. 40 and following.

In the context of the present invention, the aromatic derivative can be monocyclic or polycyclic.

In the case of a monocyclic derivative, it can comprise, at the level of its cycle, one or more heteroatoms chosen from nitrogen, phosphorus, sulfur and oxygen atoms.

According to a preferred mode, they are nitrogen atoms. By way of illustration of the monocyclic heteroaromatic derivatives capable of being condensed according to the invention, mention may in particular be made of pyridine derivatives as well as pyrimidine, pyridine and pyrazine derivatives.

The process claimed is more particularly effective for condensing heteroaromatic derivatives of the pyridine type with the nitrogen atom present in position 3 with respect to the hydroxyl function.

The carbon atoms of the aromatic derivative may optionally be substituted provided that the carbon or carbons capable of being involved in the condensation reaction remain reactive.

Two vicinal substituents present on the aromatic ring can also form together with the carbon atoms which carry them a hydrocarbon ring, preferably aromatic and comprising, where appropriate, at least one heteroatom. The aromatic derivative is then a polycyclic derivative.

As an illustration of this type of compound, mention may in particular be made of derivatives of naphthalene and quinoline and isoquinoline.

As representative of the aromatic compounds which are suitable for the present invention, mention may in particular be made of those corresponding to the general form I

in which : - X _{1 τ} X ₂ and X ₃ represent independently of each other:

• a heteroatom and preferably a nitrogen atom, or

• C (R ^" ) = with R ^" being as defined below and

- R ', R "and R'" independently of one another represent a hydrogen atom or an electron donating substituent or R 'and R "form together with the carbon atoms which carry them a hydrocarbon ring preferably aromatic at C ₆ and comprise, where appropriate, one or more heteroatoms with at least one of R ', R "and R'" representing a hydrogen atom. The electron-donor nature of the substituents present on the aromatic derivative appreciated in the context of the present invention according to the scale (for negative values) defined in the book by Jerry March "Advanced Organic Chemistry," ^3rd edition, chapter 9, pages 243 and 244.

Examples of preferred electron-groups there may be mentioned alkyl, C ^ -C _10l linear or branched alkoxy, C _λ -C ₁₀ ethers, C ^ -C _10, amino, mono- or di-alkylamino, cycloalkyl or heterocycloalkyl C ₃ to C ₉ optionally themselves substituted by a halogen atom or a hydroxy, amino or mono- or di-alkylamino group. Preferably, the compound of general formula I comprises a single heteroatom, preferably a nitrogen atom which is located in position 3 with respect to the hydroxyl function present on the ring. They may especially be 3-hydroxypyridine derivatives.

More preferably, the aromatic compound to be functionalized according to the invention, corresponds to the general formula IA

in which :

- X ₄ represents a nitrogen atom or -C (R ₂ ) = and

- R _{1 f} R ₂ , R ₃ , R and R ₅ , identical or different, represent a hydrogen atom, a halogen atom or a group chosen from: C alkyl, C _10, linear or branched alkoxy, C ₁ -C ₁₀ alkyl ethers, C, to C ₁₀ amino, mono- or di-alkylamino, cycloalkyl or heterocycloalkyl, C ₃ -C ₉ optionally themselves substituted by one atom halogen or a hydroxy, amino or mono-or di-alkylamino group, or either R _{1 t} and R ₂ or R ₂ and R ₃ constitute, with the bond established between them, an aromatic or heteroaromatic ring and with at least one substituents R _{1 (} R ₂ , R ₃ , R ₄ and R ₅ representing a hydrogen atom.

In addition to the required hydroxyl function, this aromatic derivative can comprise one or more additional substituents. As mentioned above, these are preferably electron donating substituents which make it possible to favor the generation of the anionic form of the aromatic derivative in the presence of a base.

As a representative of the aromatic derivatives which can be effectively functionalized according to the invention, mention may in particular be made of cresol derivatives, naphthol 3-hydroxypyridine, gaiacol, halophenols, phenolic derivatives carrying one or more additional hydroxyl functions and more preferably derivatives of phenol, 3-hydroxypyridine, napthol, hydroxyquinoline or hydroxyisoquinoline type.

According to a particular embodiment of the invention, the condensation is carried out in the presence of a defect in the carbonyl compound. To this end, it is preferably carried out using the carbonyl derivative in a ratio of at most 1 to 2 and preferably of at most 1 to 4 equivalents of aromatic derivative. The latter value constituting an excellent compromise for obtaining the condensation of a single carbonyl compound on the aromatic derivative.

The condensation of carbonyl compound (s) on the aromatic derivative can be carried out in accordance with the present invention according to two variants.

According to the first variant, this condensation is carried out in the presence of a water-soluble mineral base. More preferably, it is a non-nitrogenous mineral base. Mineral bases other than nitrogenous bases have the advantage of being more moderate in cost and of being less harmful from an environmental point of view. Finally, any side reaction liable to be observed with primary or secondary amines for example is avoided.

The contacting of this base with the aromatic derivative must lead to the transformation of said compound into its anionic derivative.

For this purpose, a base is preferably chosen having at least one pKa unit and preferably two pKa units which are different from the anionic form of the aromatic derivative.

The water-soluble alkali salts of the hydroxide and carbonate type are more particularly suitable for the invention.

By way of illustration of these bases, mention may in particular be made of hydroxides such as NaOH, KOH, LiOH and salts of strong bases with a weak acid such as K ₂ CO ₃ and Na ₂ CO ₃ .

Generally, the base chosen is used in an amount of at least one equivalent with respect to the aromatic derivative and preferably in slight excess.

Of course, this quantity is to be adjusted according to the degree of condensation sought.

Likewise, the choice of the water-soluble base can be made by taking into account the presence or not of electron donor substituents at the level of the aromatic derivative to be functionalized. For example, in the particular case where the compound of general formula I carries one or more electron-withdrawing groups, a weak base may be sufficient to lead to its anionic form.

Advantageously, it is possible according to this variant to stereoselectively orient the condensation of the carbonyl compound at the aromatic cycle through the choice of the generally metallic cation associated with the base.

Certain cations such as sodium and lanthanum favor condensation in the ortho position. Conversely, other cations such as potassium orient it more particularly in para.

According to this variant of the claimed process, the condensation is preferably carried out by progressive introduction of the carbonyl compound into the mixture composed of the aromatic derivative and the water-soluble base. In this way, we favor monocondensation.

With regard more particularly to the other parameters of the reaction, namely time or temperature, their adjustment is generally a function of the electronic density of the aromatic derivative to be functionalized and of the pKa of the base used.

Generally, the condensation reaction is preferably carried out under heating. To this end, the reaction medium can be brought to a temperature of between approximately 40 and 100 ° C. and preferably of the order of 50 ° C. This heating is carried out sufficiently over time to obtain an optimal conversion rate, TT, of the aromatic derivative.

For a temperature above 50 ° C, it is possible to observe the condensation of several carbonyl compounds on the aromatic derivative.

However, it is clear that for certain aromatics, there is no such risk of multi-condensation. It is then possible to increase the reaction temperature beyond 50 ° C for the sole purpose of reducing the time required for condensation.

According to a second variant of the invention, the condensation is carried out in the presence of a heterogeneous basic catalyst.

In this particular case, the base used is a heterogeneous catalyst based on hydroxides and / or metal salt oxides. It can in particular be magnesia.

More preferably, it is a catalyst chosen from oxides, hydroxides and basic salts of alkaline earths and / or rare earths not having a degree of valency IV and from the minerals containing them. Particularly suitable for the invention are natural minerals or synthetic analogues which consist of interleaved layers based on metal oxides or hydroxides, such as hydrotalcite. More preferably, it is a natural hydrotalcite or a synthetic analog. These basic salts contain various combinations of metal cations M ²⁺ such as Mg ²⁺ , Zn ²⁺ , Cu ² \ Ni ²⁺ , Te ²⁺ , Co ²⁺ and divalent cations of type M ³⁺ such as Al ³⁺ , Cr ³⁺ , Fe ³⁺ . The anions associated with these metal cations can be halogens, organic anions or even oxanions.

As a representative of these hydrotalcites, mention may in particular be made of that corresponding to the formula [Mg ₆ AI ₂ (O ₄ ) ₁₆ ] CO ₃ .4H ₂ O.

Likewise, the basic catalytic condensation process can be carried out using, as catalysts, the rare earth oxides and carbonates such as Ytterbium and Lanthanum.

The catalyst can generally be introduced at a rate of 5 to

90% preferably from 10 to 50% by weight relative to the substrate.

According to this second variant of the claimed process, the condensation is preferably carried out by introducing the heterogeneous basic catalyst into a mixture of the aromatic derivative and the carbonyl compound. Generally, the condensation is carried out under heating of the reaction medium at a temperature equal to or greater than 50 ° C., preferably between approximately 80 and 120 ° C., and more preferably of the order of 100 to 110 ° C.

It also appears possible, according to this variant, to favor condensation towards one of the para or ortho positions through the choice of catalyst.

This is how hydrotalcite or rare earth oxide type catalysts rather orient the condensation of the carbonyl compound in the ortho position.

At the end of the condensation of the carbonyl compound on the aromatic derivative, carried out according to one or the other of the two variants of the invention, the expected product or products is recovered.

To this end, in the case of a reaction according to the first variant, the reaction is carried out at the end of the reaction, neutralization of the reaction medium and extraction of the expected compound according to conventional methods and therefore familiar to those skilled in the art. job. When the condensation reaction is carried out in the presence of a heterogeneous basic catalyst, it suffices to carry out filtration of the reaction medium to isolate the condensed product. Generally, it is necessary to purify the condensed product so as to separate it either from the initial unreacted aromatic derivative or from other compounds which may also have formed during the reaction, such as other aromatic derivatives. mono- or pluri- condensed.

These separation and / or purification operations also fall within the competence of a person skilled in the art. They may in particular be chromatographic operations.

The present invention also extends to the compounds obtained according to the claimed process.

More particularly, it also relates to the compounds chosen from:

- 2,2,2 trifluoro-1 (2-hydroxyphenyl) ethanol, - 2,2,2 thfluoro-1 (2-hydroxy 5-methylphenyl) ethanol,

- 2,2,2 trifluoro-1 (2-chlorophenyl) ethanol,

- 2,2 difluoro-1 (2-hydroxyphenyl) ethanol,

- 2.2 difluoro-1 (4-hydroxyphenyl) ethanol,

- 2,2,2 thfluoro-4 (3-hydroxypyridinyl) ethanol, and - 2,2,2 trifluoro-2 (3-hydroxypyridinyl) ethanol.

The examples given below are presented below by way of illustration and without limitation of the invention.

EXAMPLE 1

2,2,2 trifluoro-1 (2-hydroxyphenyl) ethanol.

15 g (161 mmol) of phenol, 6.4 g of NaOH in pellets are introduced into a 100 ml three-necked flask. Stir and add 22.5 g (145 moles) of fluoride hydrated at 75% w / w in water. It is heated to 50 ° C. and maintained for 12 hours under these conditions. The reaction medium is cooled. 50 ml of toluene and 50 ml of water are added. Neutralized with a 3N HCl solution.

Decanted and then extracted the aqueous phase with 2 x 20 ml of toluene. The organic extracts are dried and dosed by CPG (gas chromatography). We thus obtain:

- 2,2,2 trifluoro-1 (4-hydroxyphenyl) ethanol RR = 42%

- 2,2,2 trifluoro-1 (2-hydroxyphenyl) ethanol RR = 40%. EXAMPLE 2

2,2,2 trifluoro-1 (2-hydroxy 5-methylphenyl) ethanol.

15 g (139 mmol) of p-cresol, 15 ml of 10 N sodium hydroxide are introduced into a 100 ml three-necked reactor, the mixture is stirred and 22.5 g (145 mmol) of 75% hydrated fluorine are added. p / p in water. Stirred at 50 ° C for 12 hours. After treatment of the reaction mass as described in Example 1, a 88% yield of expected alcohol is obtained for a conversion rate TT = 95%.

EXAMPLE 3

2,2,2 trifluoro-1 (2-hydroxynaphthalene) ethanol.

10 g (69 mmol) of β-naphthol and 11 g (63.8 mmol) of fluorine hydrated at 75% w / w in water are introduced into a 100 ml three-necked reactor. 1.0 g of MgO is added. Stir while heating 105 ° C for 5 hours. After treatment of the reaction mass as described in Example 1, a TT conversion rate to β-naphthol equal to 92% is obtained with a yield of 85%.

EXAMPLE 4

2,2,2 trifluoro-1 (2-hydroxyphenyl) ethanol.

9.3 g (100 mmol) of phenol and 3.9 g (25 mmol) of 75% hydrated fluorine are introduced into a 100 ml reactor. 5.0 g of hydrotalcite Mg ₆ AI ₂ (O ₄ ) ₁₆ , 4H ₂ O are added. The mixture is heated at 100 ° C. for 5 hours. After treatment of the reaction medium according to the protocol described in Example 1, a yield of 88% in corresponding alcohol is obtained with an ortho / para ratio equal to 1.

EXAMPLE 5

2,2,2 trifluoro-1 (2-hydroxy 5-methylphenyl) ethanol.

11.6 g (100 mmol) of p-cresol and 3.9 g 25 mmol of 75% hydrated fluorine are introduced into a 100 ml reactor. 5.0 g of MgO are added. The mixture is heated at 100 ° C for 6 hours. After treatment according to the protocol described in Example 1, a 90% yield of expected alcohol is obtained. EXAMPLE 6

2,2,2 trifluoro-1 (2-hydroxy 5-methylphenyl) ethanol.

5.8 g (50 mmol) of p-cresol and 15.5 g (100 mmol) of 75% hydrated fluorine are introduced into a 100 ml reactor. 5 g of MgO are added. The mixture is heated at 105 ° C for 8 hours. After treatment according to the protocol described in Example 1, 70% of dihydroxyalkylated product is obtained.

EXAMPLE 7

2,2,2 trifluoro-1 (2-hydroxy 5-chlorophenyl) ethanol.

12.5 g (100 mmol) of p-chlorophenol and 3.9 g (25 mmol) of 75% hydrated fluorine are introduced into a 100 ml reactor. 6 g of hydrotalcite Mg ₆ AIGa (O ₄ ) ₁₆ , 4H ₂ O are added and the mixture is heated at 100 ° C. for 7 hours. After treatment of the reaction medium according to the protocol described in Example 1, a yield of 45% in expected product is obtained.

EXAMPLE 8

2,2,2 trifluoro-1 (2-hydroxyphenyl) ethanol.

9.3 g (100 mmol) of phenol and 3.9 g (25 mmol) of 75% hydrated fluorine are introduced into a 100 ml reactor. 5.0 g of a catalyst are added and the mixture is heated at 50 ° C. for 5 hours. Table I below gives an account of the nature of the catalyst used, the yields of mono-condensed product obtained with their ortho / para ratio.

Board

EXAMPLE 9

2,2 difluoro-1 (2-hydroxyphenyl) ethanol. 2,2 difluoro-1 (4-hydroxyphenyl) ethanol.

9.3 g (100 mmol) of phenol and 4.9 g (25 mmol) of difluoroacetaldehyde hydrated at 50% w / w in water are introduced into a 100 ml reactor. 50 g of MgO are added. Stir and heat at 100 ° C for 7 hours. The catalyst is filtered.

By analysis in gas phase chromatography (CPG), a yield of 82% is obtained in the two expected alcohols.

EXAMPLE 10

Condensation on 3-hydroxypyridine.

9.5 g (100 mmol) of 3-hydroxypyridine and 7.8 g (50 mmol) of fluorine 75% hydrated in water are introduced into a 100 ml reactor. 2.5 g of MgO are added and the mixture is heated to 100% with stirring for 8 hours. The catalyst is filtered at 70 ° C.

By CPG analysis, an expected alcohol yield of 75% is obtained (isomers 2 and 4).

Claims

1. Method for condensing at least one carbonyl compound carrying at least one electron-withdrawing group on an aromatic derivative carrying at least one hydroxyl function, characterized in that the electron-withdrawing group present on the carbonyl compound is chosen from fluoroalkyl derivatives, esters including orthoesters and nitriles and in that said condensation is carried out in basic medium.

2. Method according to claim 1 characterized in that the electron-withdrawing group present on the carbonyl compound has a sigma p at least equal to 0.30.

3. Method according to claim 2 characterized in that the sigma p is greater than or equal to 0.40 and less than 0.75.

4. Method according to one of claims 1, 2 or 3 characterized in that the electron-withdrawing group present on the carbonyl compound is a polyfluoroalkyl derivative.

5. Method according to claim 4 characterized in that the polyfluoroalkyl derivative corresponds to a radical of formula:

- (CX ₂ ) _P -GEA in which - the X, identical or different, represent a hydrogen atom, preferably halogen fluorine or a radical of formula C _n χ _{2n + 1} with n representing an integer at most equal to 5 preferably to 2;

- p represents an integer at most equal to 2;

the symbol GEA represents an electron-withdrawing group the possible functions of which are inert under the conditions of the reaction, advantageously a fluorine atom or a perfluorinated residue of formula C _{n '} X _{2n +1} with n' representing an integer at most equal to 8 , advantageously to 5 provided that at least one of the X or GEA present on the carbon at α of the carbonyl function represents a fluorine atom and with the total number of carbon atoms of the polyfluoroalkyl derivative of between 1 and 15 , preferably between 1 and 10.

6. Method according to one of claims 1 to 5 characterized in that the carbonyl compound also carries at the level of its carbonyl function either a hydrogen atom or a group chosen from C ₅ to C ₁₈ aryls, alkyls linear or branched in C ₁ to C ₁₃ , linear or branched alkenyls in C ₂ to C ₁₄ if necessary substituted.

7. Method according to one of claims 1 to 6 characterized in that the carbonyl compound is trifluoroacetaldehyde, in its hydrated form or not.

8. Method according to one of claims 1 to 7 characterized in that the aromatic derivative corresponds to the general formula I

in which: - X ,, X ₂ and X ₃ represent independently of each other:

- a heteroatom and preferably a nitrogen atom, or

- C (R ^" ) = with R ^" being as defined below and

- R ', R "and R'" independently of one another represent a hydrogen atom, or an electron donating substituent or R 'and R "together form with the carbon atoms which carry them a ring preferably C ₆ aromatic hydrocarbon comprising, where appropriate, one or more heteroatoms with at least one of R ', R "and R'" representing a hydrogen atom.

9. Method according to one of claims 1 to 8 characterized in that said aromatic compound corresponds to the general formula IA

in which :

- X ₄ represents a nitrogen atom or -C (R ₂ ) = and - R- ,, R ₂ , R ₃ , R ₄ and R ₅ , identical or different, represent a hydrogen atom, halogen or a group selected from: alkyls C -C ₁₀ linear or branched alkoxy, C -C ₁₀ alkyl ethers of C ₁ -C _10, amino, mono- or di-alkylamino, cycloalkyl or heterocycloalkyl, C ₃ -C ₉ optionally themselves substituted by a halogen atom or a hydroxy, amino or mono- or di-alkylamino group, or either R 1 and R ₂ or R ₂ and R ₃ constitute, with the bond established between them, an aromatic or heteroaromatic ring, with at least one of the substituents Ri, R ₂₎ R ₃ , R ₄ and R ₅ representing a hydrogen atom.

10. Method according to one of claims 1 to 9 characterized in that the aromatic derivative is a derivative of phenol, 3-hydroxypyridine, naphthol, hydroxyquinoline or hydroxyisoquinoline type.

1 1. Method according to one of the preceding claims, characterized in that the aromatic derivative comprises at least one electron donor substituent.

12. Method according to one of the preceding claims, characterized in that the condensation is carried out in the presence of a defect in the carbonyl compound.

13. The method of claim 12 characterized in that the condensation implements at most one equivalent of carbonyl compound for 2 equivalents of the aromatic derivative.

14. Method according to one of the preceding claims characterized in that the condensation is carried out in the presence of a water-soluble mineral base.

15. The method of claim 14 characterized in that the base has at least one unit of pKa of difference with the anionic form of the aromatic derivative.

16. The method of claim 14 or 15 characterized in that the base is a water-soluble alkaline salt of the hydroxide and carbonate type.

17. Method according to one of claims 13 to 15 characterized in that the base is used in an amount of at least one equivalent relative to the aromatic derivative.

18. Method according to one of claims 14 to 17 characterized in that the base is sodium hydroxide.

19. Method according to one of claims 14 to 18 characterized in that the condensation is carried out by progressive introduction of the carbonyl compound into the mixture composed of the aromatic derivative and the water-soluble base.

20. Method according to one of claims 1 to 13 characterized in that the condensation is carried out in the presence of a heterogeneous basic catalyst.

21. Process according to Claim 20, characterized in that the heterogeneous catalyst is based on hydroxides and / or oxides of metal salts.

22. The method of claim 20 or 21 characterized in that the catalyst is chosen from oxides, hydroxides and basic salts of alkaline earth and / or rare earths not having a degree of valence IV and from minerals containing it .

23. The method of claim 20 or 22 characterized in that the catalyst is magnesia.

24. The method of claim 20 or 22 characterized in that the catalyst is a natural hydrotalcite or a synthetic analog.

25. The method of claim 20 or 22 characterized in that the catalyst is an oxide or carbonate of dΥtterbium or Lanthanum.

26. Method according to one of claims 20 to 25 characterized in that the catalyst is present in an amount of 10% to 50% by weight relative to the aromatic derivative.

27. Method according to one of claims 20 to 26 characterized in that the condensation is carried out by introducing the heterogeneous basic catalyst into a mixture of the aromatic derivative and the carbonyl compound.

28. The method of claim 27 characterized in that the condensation is carried out under heating of the reaction medium at a temperature greater than or equal to 50 ° C.

29. Method according to one of the preceding claims, characterized in that the product or products resulting from the condensation of at least one carbonyl compound on the aromatic derivative are recovered by extraction, after neutralization of the reaction medium or filtration without neutralization when the a heterogeneous basic catalyst is used.

30. Compound obtained by implementing the method according to one of claims 1 to 29.

31. Compound characterized in that it is chosen from:

- 2,2,2 trifluoro-1 (2-hydroxyphenyl) ethanol

- 2,2,2 thfluoro-1 (2-hydroxy 5-methylphenyl) ethanol, - 2,2,2 trifluoro-1 (2-chlorophenyl) ethanol,

- 2,2 difluoro-1 (2-hydroxyphenyl) ethanol,

- 2.2 difluoro-1 (4-hydroxyphenyl) ethanol,

- 2,2,2 trifluoro-4 (3-hydroxypyridinyl) ethanol, and

- 2,2,2 trifluoro-2 (3-hydroxypyridinyl) ethanol.