FR2838436A1 - New aminated compounds comprising allyl and difluoromethyl groups, useful for the synthesis of fluorinated compounds - Google Patents

Abstract

Compounds containing amine, allyl and difluoromethyl functions, obtained by allylation of a ketimine or aldimine directly attached to a perfluoromethylene chain are new. Compounds comprising at least one carbon atom are claimed which have an amine function, an allylic or propargylic radical, a difluoromethylene group and a hydrogen or hydrocarbyl radical which has donor or weakly electroattractive properties(deltap less than or equal to 1) are new. The compounds have no more than 30 C atoms, preferably no more than 20 atoms. An Independent claim is also included for the preparation of the compounds.

Description

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Amine compounds bearing at least one allyl and a difluoromethyl and process useful for their synthesis
The present invention relates to amine compounds carrying at least one allyl and a difluoromethyl, and a method useful for their synthesis. The present invention more particularly relates to compounds which are capable of cyclization by metathesis and an original technique of allylation to a difluoromethyl group and an amine.

 During the last few years, new fluorinated compounds have appeared in the field of pharmacy and agriculture. In particular, derivatives which are both difluoromethylated and comprise a nitrogenous heterocycle prove to be more and more interesting. Most often, the difluoromethylene groups are carried by the cycle while being exocyclic.

 At this stage of the description, it is necessary to define a term which will be used later in the description; it is the term metathesis. This term has been known in linguistics since the earliest times to describe the change of place of a letter, a syllable within a word or a group of words, generally a word; this metathesis is called an inverse, when there is an exchange between a letter, or a syllable of a word, with another letter, or another syllable of the same word. In French, one of the most commonly cited examples of metathesis is "licorice" which comes from the Greek glucurrhiza (soft root), with exchange of place of the phoneme "gl" with the phoneme "rh".

 In the rest of the text, the term metathesis refers to a phenomenon relatively far from the linguistic notion; this term will designate the replacement of two unsaturations by another unsaturation, with ejection of an unsaturated molecule corresponding to the ejected part. Both unsaturations can belong to one or two molecules.

 In the field which is the subject of the present invention, some intramolecular metatheses have been demonstrated in the particular case where amino acids, or rather their esters carrying two unsaturations, have been subjected to Grubbs salts. The acid functions to which reference is made are oxygenic acid functions such as carboxylic functions, phosphoric or phosphonic functions, functions which have a high electroattractant capacity, in particular by mesomeric effect.

 In particular, these cyclizing metatheses may be referred to B. Mohr, D. M. Lynn, F. H. Grubbs, Organometallics 1996, 15, 4317; at

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 P. Schwab, R.H. Grubbs, J.W.Ziller, J. Am. Chem. So. 1996, 118, 100. Reference may also be made to A. Furstner, M. Picquet, C. Bruneau, P.H. Nineteen, Chem. Common. 1998.1315.

 One of the aims of the present invention is to provide compounds comprising two unsaturations, an amine function comprising in the position p a difluoromethyl group and not including the acid functions (optionally in ester form) specified above and, in particular, not including of phosphonate functions or carboxylate functions at the P position of the amine function.

 Another object of the present invention is to provide compounds of the above type which are capable of being cyclized by intramolecular metathesis.

 Compounds of this type are very difficult to obtain. Indeed, the difluoromethylene group generally tends to modify the reactivity of the functions of which it is close, which makes the problem more difficult to solve especially as its influence is somewhat erratic.

 Therefore, one of the aims of the present invention is to provide compounds comprising at least one carrier carbon: an amine function; - Of a difluoromethylene group and not carrying an oxygen acid function, esterified or not.

 Another object of the present invention is to provide a compound of the above type, characterized in that it is likely to cyclize under the action of Grubbs complexes.

 Another object of the present invention is to provide a method capable of obtaining a compound of the above type, by using a step of grafting an allyl group on a carbon bearing a trivalent nitrogen and a difluoromethylene group.

 Another object of the present invention is a process which makes it possible to graft an allyl group on a carrier imine on its carbon of a difluoromethyl group (aldimine or ketimine), the imine not carrying a phosphonated or carboxylated function, likewise not having no oxygenated acid electroattractant function.

 These goals, and others which will appear later, are achieved by means of compounds comprising at least one carbon bearing: an amine function; an allyl or propargyl radical; a difluoromethylene group; and

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 a radical advantageously chosen from those which are donor or weakly electron-withdrawing (ap <0.20, advantageously to 0.1), preferably alkyl (lato sensu), more preferably hydrogen; characterized in that the amine function carries a hydrocarbon radical advantageously carrying an unsaturation of ethylenic nature.

 This latter radical is advantageously such that said ethylenic unsaturation is in the allylic or homoallyl position relative to the amine.

Dans cette formule : - Rf représente un radical carboné porteur d'un groupe difluorométhylene assurant le lien ave le reste de la molécule, avantageusement d'au plus 15, de préférence d'au plus 10 atomes de carbone ; - R1 représente un hydrogène, un radical alcoyle, y compris aralcoyle, de préférence de 1 à 2 atomes de carbone ou un des radicaux spécifiques spécifiés ultérieurement ; - R2 représente un hydrogène, un radical alcoyle, y compris aralcoyle, de préférence de 1 à 2 atomes de carbone ou un radical aryle ; - R3 représente un hydrogène ou un radical hydrocarboné tel que alcoyle, y compris aralcoyle, de préférence de 1 à 2 atomes de carbone ou un radical aryle, ou forme avec R4 une double liaison supplémentaire pour transformer le radical allylique en radical propargylique ; - R4 représente un hydrogène, ou un radical hydrocarboné, tel que aryle ou alcoyle, y compris aralcoyle, de préférence de 1 à 2 atomes de carbone ou, avec R3, forme une double liaison supplémentaire, pour que la liaison éthylénique devienne acétylénique, permettant de passer d'un radical allylique à un radical propargylique ; - R5 représente un hydrogène ou un radical hydrocarboné tel qu'un radical aryle, ou un radical alcoyle, y compris aralcoyle, de préférence de 1 à 2 atomes de carbone ;
R5 peut être un groupe dit "Ar" tel que décrit dans le brevet publié sous le numéro EP 565 607 B, brevet intitulé groupe protecteur ; Advantageously, according to the present invention, the above compound has the following formula:
Formula (I)

In this formula: Rf represents a carbon radical carrying a difluoromethylene group providing the link with the rest of the molecule, advantageously at most 15, preferably at most 10 carbon atoms; R1 represents a hydrogen, an alkyl radical, including aralkyl, preferably from 1 to 2 carbon atoms or one of the specific radicals specified later; R2 represents a hydrogen, an alkyl radical, including aralkyl, preferably from 1 to 2 carbon atoms or an aryl radical; R 3 represents a hydrogen or a hydrocarbon radical such as alkyl, including aralkyl, preferably from 1 to 2 carbon atoms or an aryl radical, or forms with R 4 an additional double bond to convert the allyl radical to a propargyl radical; R 4 represents a hydrogen or a hydrocarbon radical, such as aryl or alkyl, including aralkyl, preferably from 1 to 2 carbon atoms or, with R 3, forms an additional double bond, so that the ethylenic bond becomes acetylenic, allowing to go from an allyl radical to a propargyl radical; - R5 represents a hydrogen or a hydrocarbon radical such as an aryl radical, or an alkyl radical, including aralkyl, preferably 1 to 2 carbon atoms;
R5 may be a group called "Ar" as described in the patent published under the number EP 565 607 B, patent entitled protecting group;

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R5 and R4 may be fractions of said "Ar" group above, so that
R5 and R4 as well as the carbon which carries them, form a radical Ar as defined in the European patent above; one of R 1, R 2, R 4, R 3 and R 5 may also be chosen from trivalent, nitrile or acidic functional groups, optionally and preferably in esterified form.

 The term "alkyl", including aralkyl, is taken in its etymological sense from an alcohol from which the OH function has been removed; an alkyl is a carbon radical in general hydrocarbon where the free function is carried by a sp3 hybridization carbon, said sp3 carbon itself being connected only to hydrogen or carbon atoms.

 It is preferable that at least 2, preferably 3, preferably 4, radicals R 1 to R 5 are at most 5, advantageously at most 3 carbon; however, at least one of the radicals R1 to R5 may be such that the allyl radical corresponds to that of a heavy alcohol, for example an aromatic series, a terpene series, or a steroidal series.

 Thus, one radical and at most 3 radicals R 1 to R 5 may be aryl radicals, mono- or polycyclic radicals, condensed or not, homo- or heterocyclic.

 It is preferable that R, and R2 are as small as possible, if it is desired that the synthesis be easy. Thus, it is preferred that R 1 and R 2 are such that at least one of the 2 is hydrogen and the other is methyl or hydrogen.

 As will be seen later in the synthesis process, it is interesting that the R3 radical is different from carboxylic, especially carboxylic esters, to avoid untimely cyclizations during the synthesis.

 The allylic radical formed by R 1 to R 5 as well as by the carbon atoms which carry them, are advantageously palindromous so that the result of a synthesis of allylic nature which gives the same results as the substitution is of SN or SN 'nature .

 The radical R is a radical or a donor group or little electroattractor; this can be defined by indicating that advantageously #p is at most equal to 0.2.

In general, R is selected from alkyls, hydrogen and aryls. R is preferably hydrogen, R 'may be hydrogen, a protecting group, an aryl or an alkyl, including aralkyl. Among the protecting groups, mention should be made of the protective groups known during the amino acid synthesis for the amine functions, in particular the groups whose binding

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 open is carried by a carbon in the allylic, benzylic or propargyl position.

 R "is an allylic or homoallyl radical, a hydrogen or a metal cation, or a metal cation moiety, when the metal is polyvalent as is preferred.

For use in cyclizing metathesis it is preferable that only one of R 'and R ", a homoallyl radical or allylic.

 The number of carbons of the compounds according to the present invention is advantageously at most 30, preferably at most 20.

 According to the present invention, insofar as it relates to the compounds according to the present invention, and only the compounds, it is preferable that at least one of R 'and R "carry a function, or more exactly unsaturation of ethylenic nature in the allylic or homo-allylic position, preferably allylic.

 The other of R ', R "is generally a protecting group, It should be noted that the allylic radicals may be amino protecting groups It should also be noted that the R group may be a specific alkyl, i.e. In particular, according to the present invention, it has been possible by reacting a derivative of formula II, where R is a halogen and where R 'and Rf have one of the values specified above, in particular when R is a protective radical, advantageously of a benzylic nature, with 2 equivalents of allyl compounds such as allyl halides, a derivative having 2 allylic radicals can be obtained on the carbon bearing both the Rf radical and the amine function .

Advantageously the Rf group, which advantageously comprises between 1 and 10, more preferably from 1 to 4 carbon atoms; responds to the following formula:
GEA - (CX2) poù: X, similar or different, represent a chlorine, a fluorine or a radical of formula CnF2n + 1 'with n integer at most equal to 5, preferably to 2, with the proviso that at least one of X is preferably fluorine or fluorine carried by the carbon bearing the open bond; p represents an integer at most equal to 2; - GEA represents an electron-withdrawing group (that is to say sigma p greater than zero, preferably 0.1, preferably 0.2) whose possible functions are inert under the reaction conditions, advantageously

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 fluorine or a perfluorinated residue of formula CnF2n + 1 'with n being at most equal to 8, advantageously to 5; the total number of Rf carbons advantageously being between 1 and 15, preferably between 1 and 10.

 It is desirable that half, preferably the% (rounded to the higher number if the fraction does not fall right), preferably all, X is fluorines or CnF2n + 1 'preferably fluors.

According to an implementation of the present invention, the radical Rf must be understood sensu stricto, that is to say that it corresponds to the formula Cv, F2v + 1 'where v is an integer varying from 1 to 10, preferably at most 4, most often at most 2.

 Rf is most often perfluoroethyl, difluoromethyl, chlorodifluoromethyl and especially trifluoromethyl.

 As indicated above, another object of the present invention is to provide processes comprising key steps making it possible to obtain in particular compounds according to the present invention.

 This object is achieved by the allylation process of a ketimine or an aldimine directly linked to at least one perfluoromethylene (-CF 2) - to the action of an allylic halide or pseudohalogenide, in the presence of an elemental metal whose oxidized form advantageously has only a stable valence in the medium, a metal at least as reducing as hydrogen, in other words, that the redox potential (Mn + + ne # M0) is at most equal at 0 volts with respect to the hydrogen electrode, advantageously at most equal to that of zinc.

formule dans laquelle les radicaux Rf, R et R' sont choisis parmi les valeurs spécifiées ci-dessus, avec en outre la possibilité que R soit choisi parmi les halogènes. Mais cette valeur halogénure de R ne présente un intérêt que lorsque l'on désire obtenir un dérivé diallylé sur le carbone porteur de l'amine future et du radical Rf. Cetimine or aldimine advantageously corresponds to formula II below:

wherein the radicals Rf, R and R 'are selected from the values specified above, with the further possibility that R is selected from halogens. But this halide value of R is only of interest when it is desired to obtain a diallyl derivative on the carrier carbon of the future amine and of the Rf radical.

 According to the present invention, it is possible to use previously synthesized organometallic derivatives and to contact the organometallic allyl derivative with imine only in a second time.

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 Thus, according to this procedure, the present invention is directed to a process in which an organometallic is prepared by the action of an allyl halide on an element in the appropriate metallic state.

 The metals suitable for this operation are the metals which have a sufficiently reducing redox potential to pass from an allyl halide to an organometallic.

 It is preferable to use metals having only one stable valence state in the medium considered (apart from the metallic state of course). Mention may in particular be made of magnesium, zinc, nickel, cobalt, indium or even lithium. However, it should be noted that alkalis do not always give satisfactory results.

 Indeed, the reaction seems favored when the amide corresponding to the product of the reaction, is relatively little dissociated, which explains why there is no competition between the first allylation and an N-allylation of the metal derivative from the first condensation.

 The preferred metal is zinc.

 However, according to the present invention, a different procedure is preferred because it is likely to walk more frequently. It is a question of simultaneously putting the three reagents, namely the imine, the allyl halide and the metal: it is about a qualified technique of Barbier method.

 According to this method, it is possible to mix the first two reagents and then add the metal but in fact, most often, the reagents can be used simultaneously, the metal not reacting immediately with the other constituents of the mixture reaction. Indeed, either the reaction is slow to start, or it is desirable to add a zinc activator element, such as traces of iodine or silyl chloride, to activate the metal surface. Electrolytic activation can also be achieved. Prior activation with dilute HCI is also possible.

 The reaction mixture can advantageously be made conductive, for example by adding salts deemed well dissociated from the metal used during this allylation reaction. In particular, zinc bromide can be used.

 The preferred solvents are polar aprotic solvents known in organometallic synthesis. More specifically, it is preferable that said polar aprotic solvent has a significant dipole moment. Thus, its relative dielectric constant ε (epsilon) is advantageously at least about 5, and advantageously at most equal to about 50. It is furthermore preferable that the polar solvents used in the invention are capable of solvating well. cations, which can be codified by the D donor index of

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 these solvents, which is thus at least 10, advantageously at least 20. It is thus preferable that the donor index D of these solvents is between 10 and 30, advantageously between 20 and 30.

 Said donor index corresponds to the AH (enthalpy variation), expressed in kilocalories, of the combination of said polar aprotic solvent with antimony pentachloride. More precisely, reference may be made to Christian Reichardt's book "Solvents and solvent effects in organic chemistry" (VCH 19, 1988).

It contains the definition of the donor number ("donor number" in English) which is defined as the negative (-AH) of the enthalpy (kilocalorie per mole) of the interaction between the solvent and the pentachloride. antimony, in a dilute solution of dichloroethane.

 Solvents of particular interest for the reaction of the present invention are the solvents which are essentially amides and, more particularly, formamides, including lactams and urea derivatives (urea is here considered a diamide of carbonic acid) and ethers, and especially cyclic ethers.

 The reaction works with all the metal shaping but the shape of turn works better than the powders which itself works better than the shots rather than in the form of powder.

 These can however be used when the reaction can be electrolytically implemented.

GP représente le groupe partant, halogène, pseudohalogène, avantageusement halogène, tel que chlore, de préférence brome ou iode, plus préférentiellement brome. Les autres radicaux ont déjà été définis ci-dessus, ils ont les mêmes valeurs dans la formule III que dans les formules 9 et II précédentes. The leaving carrier allyl derivative which is condensed with imine, advantageously has formula III below:

GP represents the leaving group, halogen, pseudohalogen, advantageously halogen, such as chlorine, preferably bromine or iodine, more preferably bromine. The other radicals have already been defined above, they have the same values in formula III as in formulas 9 and II above.

 Particular mention must be made when the R 3 group is a carboxylate, especially an alkyl carboxylate (ester). Indeed, in this case, the reaction must be conducted at low temperature so as to avoid a parasitic reaction, namely the formation in mechanistic ways which are not completely understood, namely the formation of a lactam which is not other than a pyrolidone carrying a difluoromethylene group in position a nitrogen of the amide function.

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 Another point to consider is the choice of solvent. To avoid untimely cyclization as specified above, it is also possible to choose a more donor solvent and thus solvating the cations better.

 Thus, by choosing solvents whose donor index is greater than that of THF (approximately 20), it is possible to carry out a reaction without parasitic cyclization. As can be seen in the table below, amides are among the solvents that have the best, or at least the highest, donor index.

 These amides are particularly suitable for the implementation of the invention.

 However, when there is no problem of a carboxylic group in the position of R3, then larger conditions can be used, in particular, solvents having a lower donor index can be easily used.

Board

<Tb>
<tb> Solvent <SEP> s <SEP> DN <SEP> AN
<tb> DMSO <SEP> (Dimethylsulfoxide) <SEP> 48.9 <SEP> 29.8 <SEP> 19.3
<Tb>

CH,,CN Acétonitrile 38 14,1 18,3 DMF Diméth Iformamide 36,7 26,6 16,0 NMP (Diméthy)pyrro)idone)~~~~32,2 27,3 13,3 Benzonitrile 25,2 11,9 15,5 DMPU Diméth I ro lène-urée 36,1

CH ,, CN Acetonitrile 38 14.1 18.3 DMF Dimeth Iformamide 36.7 26.6 16.0 NMP (Dimethyl) pyrrolidone) ~~~~ 32.2 27.3 13.3 Benzonitrile 25.2 11 , 9 15.5 DMPU Dimeth I ro-urea urea 36.1

<Tb>
<tb> DMAC <SEP> (Dimethylacetamide) <SEP> 37.8 <SEP> 27.8 <SEP> 13.6
<tb> Anisole <SEP> 4.3 <SEP>
<tb> Xylene <SEP> 2,4 <SEP> / <SEP> /
<tb> Diglyme <SEP> 5.7 <SEP> / <SEP> 9.9
<Tb>

DMEU Diméth léth lène-urée 37,6 / /
Les solvants visés dans le tableau sont des solvants donnant de bons résultats mais il convient de signaler que le DMSO est susceptible de donner des réactions parasites en présence d'un métal réducteur et que l'acétonitrile présente un l'indice donneur un peu bas, ce qui rend les réactions assez paresseuses et un risque de cyclisation lorsque R3 est une fonction carboxylique.

DMEU Dimeth lethene-urea 37.6 / /
The solvents referred to in the table are solvents giving good results, but it should be pointed out that DMSO is likely to give parasitic reactions in the presence of a reducing metal and that acetonitrile has a donor index which is a little low, which makes the reactions rather lazy and a risk of cyclization when R3 is a carboxylic function.

 The reaction is generally carried out at a temperature between the melting point and the boiling point of the solvent, more generally between 0 and 50 ° C., when solvents having a donor index at least equal to 20.

 In the case of amides, the reaction generally takes place at room temperature (ie around 20 C with a significant figure).

 When the reaction takes place on an allyl which is not palindrome, it may be mentioned that in general the point of attachment of said allyl radical will be that which corresponds to the most stable carbocation.

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 This last point is not an indication of the mechanism, but simply a rule facilitating the prediction of the reaction product.

 The pressure is of little importance on the reaction unless it is desired to control the temperature by the boiling of a solvent or if it is desired to remove one of the products of the reaction as and when its formation.

 The products obtained by the step of condensation of an imine with an allyl derivative may be continued by other steps so as to give either a particularly advantageous component or the biallyl derivatives of the invention.

 If it is desired, from the monoallylated products obtained in the preceding step, a cyclization to give a pyrolidone, it suffices to carry out the reaction at a higher temperature or to take up the monoallylated product and heat it for periods significantly longer than those necessary for the synthesis of said monoallylated product.

 In order to obtain the biallylated products, one of the simplest ways is to achieve a release of the monoallylated amine formed and to make it act, according to known techniques for the amines, on the corresponding desired allylic derivative.

 Thus, the allylation step of the imine can be followed by an amine release step, itself followed by a condensation step of the amine on an allylic derivative comprising a leaving group iduan, advantageously such as bromide and iodide.

Le dérivé allylique à condenser avec l'amine intermédiaire répond avantageusement à la formule IV :

The reaction on the first step can be symbolized by the equation n 1:

The allyl derivative to be condensed with the intermediate amine advantageously corresponds to formula IV:

GP 'has the same values as GP but the preference for the halides is less marked than in the context of the formula III.

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 The R ', at R'5 have the same values and with the same preferred combinations as for the radicals ranging from R1 to R5.

dans laquelle le produit obtenu lors de l'étape de condensation avec l'imine (soit sous la forme hydrogène, soit sous une forme anionique) est condensé avec un dérivé allylique comportant un groupe partant. Les conditions opératoires sont des conditions douces, R' est le plus souvent un groupe protecteur qui permet en outre d'éviter une double allylation de l'amine ; cette double allylation est en effet souvent favorisée car l'effet donneur du groupe allyle rend plus réactif le doublet de l'azote de l'amine. The second allylation can be symbolized by the following equation 2:

wherein the product obtained in the imine condensation step (either in the hydrogen form or in an anionic form) is condensed with an allylic derivative having a leaving group. The operating conditions are mild conditions, R 'is most often a protecting group which also makes it possible to avoid a double allylation of the amine; this double allylation is indeed often favored because the donor effect of the allyl group renders more reactive the doublet of the nitrogen of the amine.

 The basics are the usual bases in the field. In the equation, bicarbonate has been included, but other bases may be used, especially non-quaternizable amines. The solvent is in the indicated example of acetonitrile but other solvents can also be used.

The following nonlimiting examples illustrate the invention.

General procedure
Unless otherwise specified, the procedure is according to the following procedure. The imine and allyl bromide used are dissolved in dimethylformamide, the allyl bromide being put in an excess of about 30% with respect to the imine. The solution is stirred at room temperature, then zinc chips is added in excess of about 10% relative to the imine, then a few drops of TMSCI are added to the mixture (the zinc can also be previously activated with a solution diluted with HCl, in which case the addition takes place at 0 ° C). After 1 h 30, the reaction mixture is cooled to 0 ° C. and then hydrolysed with a saturated aqueous solution of ammonium chlorohydrate. The aqueous solution obtained is extracted with diethyl ether three times in succession. The organic phases are combined and washed with a saturated aqueous solution of sodium chloride and then dried over sodium sulfate.

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magnesium. After evaporation of the solvent, the product is purified by chromatography on silica gel using a mixture of petroleum ether-ethyl acetate in a ratio of 80.10 to 10. After evaporation-dilution of the eluent, the product is obtained. desired amine in the form of a colorless liquid.

Synthesis of Homoallyl Amines and Homoproparcin (a) - CF3 Mode of Operation
The 9F, 1H and 13C NMR analyzes were performed on a 200 MHz Bruker apparatus. The chemical shifts (#) are given in ppm, according to CFCI3 for 19F NMR analyzes, and according to TMS for 1H and 13C NMR analyzes.

All of these assays were performed in CDCl3 as the solvent. GPC analyzes were performed on an HP 4890 with a SE 30 apolar column (10 m). Apart from the methallyl bromide which was distilled, all the reagents were used as such, without purification procedure.

où Rf est un trifl uo ro méthyle, où R est hydrogène et où R' est benzyle.

Derivatives of benzylimine The imine # corresponds to

where Rf is methyl triflo, where R is hydrogen and R 'is benzyl.

L'imine 1 (1,03 g, 5,5 mmol) et le bromure d'allyle (865 mg, 7,15 mmol) sont dissous dans le DMF (10 ml) et mis sous atmosphère d'argon. La solution est refroidie à 0 C et placée sous agitation, puis le zinc activé (393 mg, 6,05 mmol) est ajouté en une seule fois. Le mélange réactionnel est maintenu à cette température pendant 1 min. puis laissé remonté à température ambiante (l'évolution de la réaction est suivi par CPG). Au bout de 1 h30, le mélange réactionnel est refroidi à 0 C et hydrolysé avec une solution aqueuse saturée en NH4Cl (20 ml) puis extrait par le diéthyl éther (3 x 20 ml). Les phases organiques rassemblées sont lavées par une solution aqueuse saturée en NaCI (50 ml), séchées sur MgSO4, filtrées, puis les solvants sont évaporés. Le produit brut est Example 1 Synthesis of 4-benzylamino-5.5.5-trifluoropent-1-ene

Imine 1 (1.03 g, 5.5 mmol) and allyl bromide (865 mg, 7.15 mmol) are dissolved in DMF (10 mL) and placed under an argon atmosphere. The solution is cooled to 0 ° C. and stirred, and then the activated zinc (393 mg, 6.05 mmol) is added all at once. The reaction mixture is maintained at this temperature for 1 min. then allowed to rise to room temperature (the evolution of the reaction is monitored by GC). After 1 h 30, the reaction mixture is cooled to 0 ° C. and hydrolysed with a saturated aqueous solution of NH 4 Cl (20 ml) and then extracted with diethyl ether (3 × 20 ml). The combined organic phases are washed with a saturated aqueous solution of NaCl (50 ml), dried over MgSO 4, filtered and the solvents are evaporated. The gross product is

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 purified by silica gel chromatography (petroleum ether / AcOEt, 90:10) to obtain the homoallyl amine as a colorless liquid (1.16 g, 92%).

RM N 1 H ô 1. 5 (s, br, 1 H), 2.3 (m, 1 H), 2.5 (m, 1 H), 3.1 (m, 1 H), 3.8 (d, J = 13 Hz, 1 H), 4. 0 (d, J = 13 Hz, 1 H), 5. 1 (m, 1 H), 5.2 (m, 1 H), 5. 7 (m, 1 H), 7.2-7.4 (m, 5H); RMN 13C 8 33. 3 (q,3JC-F = 2. 2 Hz, CF3CHCH2), 52.1, 57. 8 (q,2JC-F = 28 Hz, CF3CH), 118.8, 126.9 (q, 1JC-f = 284 Hz, CF3), 127. 2, 128. 2, 128. 4, 133. 1, 139. 6. Anal. cale. pour C12H14F3N (229.24) : C, 62.87 ; H, 6.16 ; N, 6.11. Trouvé : C, 62.65 ;H, 6.31 ; N, 5.99. IR v (cm-1) 1644 (C = C); 19F NMR 8-74. 9 (d, JH-F = 7.3 Hz, CF3);

RM 1 H n 1.5 (s, br, 1 H), 2.3 (m, 1H), 2.5 (m, 1H), 3.1 (m, 1H), 3.8 (d, J = 13 Hz, 1H), 4. 0 (d, J = 13Hz, 1H), 5. 1 (m, 1H), 5.2 (m, 1H), 5.7 (m, 1H), 7.2-7.4 (m, 5H); NMR 13 C 8 33.3 (q, 3 JC-F = 2.2 Hz, CF 3 CHCH 2), 52.1, 57.8 (q, 2 JC-F = 28 Hz, CF 3 CH), 118.8, 126.9 (q, 1 JC-f = 284). Hz, CF3), 127. 2, 128. 2, 128. 4, 133. 1, 139. 6. Anal. down. for C12H14F3N (229.24): C, 62.87; H, 6.16; N, 6.11. Found: C, 62.65; H, 6.31; N, 5.99.

A partir de l'imine1 (1,03 g, 5,5 mmol), du bromure de méthallyle (965 mg, 7,15 mmol) et de Zn* (393 mg, 6,05 mmol), le produit est obtenu sous la forme d'un liquide jaune pâle (1,0 g, 75%). Example 2 - 4-Benzylamino-2-methyl-5.5.5-trifluoropent-1-ene

From imine (1.03 g, 5.5 mmol), methallyl bromide (965 mg, 7.15 mmol) and Zn * (393 mg, 6.05 mmol), the product is obtained under the form of a pale yellow liquid (1.0 g, 75%).

RMN '3C 8 21.2, 37.3 (q, 3J~F = 2.7 Hz, CF3CHCH2), 52.6, 55.8 (q, 2J~F = 28 Hz, CF3CH), 114.8, 127.0 (q,'J~F= 283 Hz, CF3), 127.2, 128.3, 128.4, 139.4, 140.3. IR v (cm-1) 1651 (C = C); 19F NMR # -75.7 (d, JH-F = 7.0Hz, CF3); NMR δ H 1.8 (s, 3H), 2.O (dd, J = 14Hz, J = 11Hz, 1H), 2.3 (m, 1H), 3. 0 (m, 1H) , 3.6 (d, J = 13Hz, 1H), 3.9 (d, J = 13Hz, 1H), 4.6 (s, 1H), 4.7 (s, 1H), 7.1-7.3 (m , 5H);

NMR δ 3 C 8 21.2, 37.3 (q, 3 J ~ F = 2.7 Hz, CF 3 CHCH 2), 52.6, 55.8 (q, 2 J ~ F = 28 Hz, CF 3 CH), 114.8, 127.0 (q, J = F = 283 Hz, CF3), 127.2, 128.3, 128.4, 139.4, 140.3.

A partir de l'imine 1 (1,03 g, 5,5 mmol), du bromure de diméthylallyle (1,07 g, 7,15 mmol) et de Zn* (393 mg, 6,05 mmol), le produit est obtenu sous la forme d'un liquide jaune pâle (1,36 g, 96%).

Example 3 - 3-dimethyl-4-benzulamino-5.5m5-trifiluoropent-1-ene

From imine 1 (1.03 g, 5.5 mmol), dimethylallyl bromide (1.07 g, 7.15 mmol) and Zn * (393 mg, 6.05 mmol), the product is obtained in the form of a pale yellow liquid (1.36 g, 96%).

I.R. v (cr ') 1639 (C = C) 19F NMR # -67.1 (d, JH-F = 8.4 Hz, CF3);

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RMN 3C a 24.4, 40.1, 54.4, 66.3 (q, 2J~F = 25 Hz, CF3CH), 112.8, 127.2, 127.7 (q, 1 JC-F = 286 Hz, CF3), 128.3, 128.4, 139.9, 144.3. 1H NMR # 1. 0-1.1 (m, 6H), 1. 4 (s, br, 1H), 2.7 (q, JH-F = 8.3 Hz), 3. 7 (d, J = 13 Hz , 1H), 4. 0 (d, J = 13 Hz, 1H), 4.9 (dd, J = 12 Hz, J = 5 Hz, 2H), 5.8 (dd, J = 16 Hz, J = 9Hz, 1H), 7. 1-7.3 (m, 5H);

NMR 3C a 24.4, 40.1, 54.4, 66.3 (q, 2J ~ F = 25 Hz, CF3CH), 112.8, 127.2, 127.7 (q, 1 JC-F = 286 Hz, CF3), 128.3, 128.4, 139.9, 144.3.

A partir de l'imine 1 (374 mg, 2 mmol), du 2-(bromométhyl)-acrylate d'éthyle (502 mg, 2,6 mmol) et de Zn* (143 mg, 2,2 mmol), le produit est obtenu sous la forme d'un liquide incolore (1,0 g, 75%).

Example 4 - Ethyl 2-trifluoropropyl- (2-benzylamino) propen-2-olate

From imine 1 (374 mg, 2 mmol), 2- (bromomethyl) ethyl acrylate (502 mg, 2.6 mmol) and Zn (143 mg, 2.2 mmol), the product is obtained in the form of a colorless liquid (1.0 g, 75%).

RMN 13C a 13.9, 32.0 (q, 3Jc~F = 2.7 Hz, CF3CHCH2, 52.0, 57.3 (q, 2J~F = 27 Hz, CF3CH), 60.7, 127.0 (q, 1JC-F = 284 Hz, CF3), 127. 1, 128. 1, 128. 2, 136. 2, 139. 5, 166. 3. 1. R n (cm -1) 1632 (C = C), 1713 (CO 2 Et); 19 F NMR 0-75.3 (d, JH-F = 7.4 Hz, CF 3); 1 H NMR 1.2 (t, J = 7.2Hz, 3H), 2.4 (dd, J = 15Hz, J = 10Hz, 1H), 2.8 (dd, J = 13Hz, J = 3. 0Hz, 1 H), 3. 3 (m, 1H), 3. 7 (d, J = 3.6 Hz, 1H), 4. 0 (d, J = 3. 6 Hz, 1H), 4. 2 (q, J = 7.2 Hz, 2H), 5.6 (m, 1H), 6. 3 (m, 1H), 7. 2-7.4 (m, 5H);

13 C NMR at 13.9, 32.0 (q, 3 Jc ~ F = 2.7 Hz, CF 3 CHCH 2, 52.0, 57.3 (q, 2 J ~ F = 27 Hz, CF 3 CH), 60.7, 127.0 (q, 1 JC-F = 284 Hz, CF 3), 127. 1, 128. 1, 128. 2, 136. 2, 139. 5, 166. 3.

A partir de l'imine 1 (187 mg, 1 mmol), du 3-bromocyclohéxène (322 mg, 2 mmol) et de Zn* (85 mg, 1,3 mmol), le produit est obtenu sous la forme d'un liquide incolore (235 g, 87%).

Example 5 - Synthesis of the compound of formula:

From imine 1 (187 mg, 1 mmol), 3-bromocyclohexene (322 mg, 2 mmol) and Zn * (85 mg, 1.3 mmol), the product is obtained in the form of a colorless liquid (235 g, 87%).

I.R. 0 (cm -1) 1650 (C = C); 19F NMR # -71. 8 (d, JH-F = 8. 7 Hz, CF 3); 1 H NMR # 1.3-1.5 (m, 5H), 1.9 (m, 2H), 2.5 (m, 1H), 2.9 (qd, J = 8.6 Hz, J = 3.1Hz, 1 H), 3.7 (d, J = 13Hz, 1H), 3.9 (d, J = 13Hz, 1H), 5.6 (m, 1H), 5.8 (m, 1H). H), 7. 1-7.3 (m, 5H);

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13C NMR # 21.8, 24. 8, 27. 2, 35. 7 (q, 3 JC-F = 1. 6 Hz, CF 3 CHCH), 53.0, 62.1 (q, 2 JC-F = 35 Hz, CF 3 CH ), 124. 5, 125. 3, 127. 4 (q, 1JC-F = 287 Hz, CF 3), 128. 2, 128.3, 131.5, 139.8.

A partir de l'imine 1 (1,03 g, 5,5 mmol), du bromure de propargyle 80% en solution dans le toluène (1,06 g, 7,15 mmol) et de Zn* (393 mg, 6,05 mmol), le produit est obtenu sous la forme d'un liquide incolore (944 g, 76%). Example 6 - 4-Benzylamino-5,5,5-trifluoropent-1-yne

From imine 1 (1.03 g, 5.5 mmol), 80% propargyl bromide dissolved in toluene (1.06 g, 7.15 mmol) and Zn * (393 mg, 6%) 0.5 mmol), the product is obtained as a colorless liquid (944 g, 76%).

Dérivé de la ParaMéhtoxvPhénylimine

Exemple 7 - 4-(4-méthoxyphénylamino)-2-méthyl-5,5,5-trifluoropent-1-ène

A partir de l'imine 2 (1,12 g, 5,5 mmol), du bromure de méthallyle (1,11 g, 8,25 mmol) et de Zn* (393 mg, 6,05 mmol), le produit est obtenu sous la forme d'une huile marron (1,28 g, 83%). IR # (cm-1) 3308 (C = CH); 19F NMR # -75. 1 (d, JH-F = 7.0Hz, CF3); 1 H NMR # 2. 0 (, br, 1H), 2. 3 (t, J = 2. 6 Hz, 1H), 2.7 (ddd, J = 17 Hz, J = 7. 6 Hz, J = 2. 6 Hz, 1 H), 2.9 (ddd, J = 17 Hz, J = 4.8 Hz, J = 2.8 Hz, 1 H), 3.5 (m, 1 H), 4. 2 (d, J = 13Hz, 1H), 4. 3 (d, J = 13Hz, 1H), 7. 4-7.6 (m, 5H); 13 C NMR D 19.3 (q, 3 JC-F = 3.2 Hz, CF 3 CHCH 2), 51.9, 57.1 (q, 2 JC-F = 28 Hz, CF 3 CH), 71.2, 78.6, 126.0 (q. , 1JC-F = 284 Hz, CF 3), 127. 3, 128. 2, 128. 4, 139. 2.

Derivative of ParaMethyloxyphenylimine

Example 7 4- (4-Methoxyphenylamino) -2-methyl-5,5,5-trifluoropent-1-ene

From imine 2 (1.12 g, 5.5 mmol), methallyl bromide (1.11 g, 8.25 mmol) and Zn * (393 mg, 6.05 mmol), the product is obtained in the form of a brown oil (1.28 g, 83%).

RMN 19 F 0 -76.4 (d, .IH~F = 6.6 Hz, CF3) ; RMN 1H # 1. 7 (s, 3H), 2. 3 (dd, J = 15 Hz, J = 11 Hz, 1 H), 2.6 (m, 1H), 3. 2 (s, br, 1 H), 3. 7 (s, 3H), 3. 9 (m, 1 H), 4. 8 (s, 1 H), 4. 9 (s, 1 H), 6. 6 (d, J = 9.1Hz, 2H), 6. 8 (d, J = 9.1 Hz, 2H) ; RMN 13C # 21. 5, 37. 5 (q,3JC-F = 1. 9 Hz, CF3CHCH2), 55. 3 (q,2JC-F = 29 Hz, CF3CH), 55. 4, 114. 6, 114. 8, 114. 9, 132. 0 (q, 1JCF = 283 Hz, CF3), 139. 9, 141. 1, 153. 0. IR # 1652 (C = C);

NMR 19 F 0 -76.4 (d, 1H-F = 6.6 Hz, CF 3); 1H NMR # 7 (s, 3H), 2. 3 (dd, J = 15Hz, J = 11Hz, 1H), 2.6 (m, 1H), 3.2 (s, br, 1H) , 3.7 (s, 3H), 3.9 (m, 1H), 4.8 (s, 1H), 4.9 (s, 1H), 6. 6 (d, J = 9.1 Hz , 2H), 6.8 (d, J = 9.1 Hz, 2H); 13 C NMR # 21. 5, 37. 5 (q, 3 JC-F = 1. 9 Hz, CF 3 CHCH 2), 55. 3 (q, 2 J C-F = 29 Hz, CF 3 CH), 55. 4, 114. 6, 114 8, 114. 9, 132. 0 (q, 1JCF = 283 Hz, CF 3), 139. 9, 141. 1, 153. 0.

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Synthesis of #, unsaturated amines General procedure
The homoallyl amine or homopropargyl amine (1 mmol), the allyl bromide (3 eq, 3 mmol), the NaHCO 3 (5 eq, 5 mmol) and the KI (10 mol%, 0.1 mmol) are placed in acetonitrile ( 3 ml) and heated to reflux (the evolution of the reaction is monitored by GPC). The reaction medium is allowed to return to t. amb., hydrolyzed with brine (10 mL) and extracted with Et2O (3 x 10 mL). The combined organic phases are dried over MgSO 4, filtered and the solvents are evaporated. The crude product is purified by filtration on silica gel (petroleum ether) to obtain the D, D-unsaturated amine.

Example 8 Synthesis of the compound of formula

Amine A (229 mg, 1 mmol), allyl bromide (363 mg, 3 mmol), NaHCO3 (420 mg, 5 mmol) and KI (17 mg, 0.1 mmol) are heated 3 days. at reflux of MeCN (3 ml). The product is obtained in the form of a colorless liquid (215 mg, 80%).

19F NMR # -69. (D, JH-F = 8. 7 Hz, CF 3); 1H NMR # 2. 6 (m, 2H), 3.5 (m, 3H), 3.9 (d, J = 14Hz, 1H), 4. 2 (d, J = 14Hz, 1H), 3 (m, 4H), 5.9 (m, 2H), 7. 3-7.5 (m, 5H); 13 C NMR # 30. (Q, 3 JC-F = 1. 6 Hz, CF 3 CHCH 2), 53. 1, 53. 8, 59.3 (q, 2 C-F = 25 Hz, CF 3 CH), 117. 2, 117. 6 , 127. 0, 127. 6 (q, 1C-F = 291 Hz, CF 3), 128. 2, 128. 7, 134.5, 136.3, 139.3.

Example 9 Synthesis of the compound of formula

Amine A (229 mg, 1 mmol), 2- (bromomethyl) ethyl acrylate (290 mg, 1.5 mmol), NaHCO3 (420 mg, 5 mmol) and KI (17 mg, 0.1 mmol) are heated 3 days. at reflux of MeCN (3 ml). The product is obtained in the form of a colorless liquid (215 mg, 80%).

IR (cm) 1716 (CO 2 Et); 19F NMR # -69. 2 (d, J = 8. 3 Hz, CF 3);

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RMN 13C 0 14.0, 31.0 (q, 3 JC-F = 1.5 Hz, CF3CHCH2), 50.9, 54.4, 59.8 (q, 2 JC-F = 25 Hz, CF3CH), 60. 5, 117. 3, 127.2, 127. 3 (q, 1JC-F = 290 Hz, CF3), 128. 2, 128. 9, 134.4, 138.2, 138.4. 1H NMR # 1. 2 (t, J = 7.2 Hz, 3H), 2. 3 (m, 2H), 3. 1 (m, 1H), 3. 4 (d, J = 14 Hz, 1 H), 3.6 (m, 2H), 3.9 (d, J = 14 Hz, 1H), 4. 1 (m, 1H), 4. 2 (q, J = 7. 2 Hz, 2H), 4.96 (m, 1H), 5.7 (m, 1H), 5.8 (m, 1H), 6.1 (m, 1H), 7.1-7.3 (m, 5H);

13 C NMR 14.0, 31.0 (q, 3 JC-F = 1.5 Hz, CF 3 CHCH 2), 50.9, 54.4, 59.8 (q, 2 JC-F = 25 Hz, CF 3 CH), 60.5, 117. 3, 127.2, 127 3 (q, 1C-F = 290 Hz, CF 3), 128. 2, 128. 9, 134.4, 138.2, 138.4.

Example 10 Synthesis of the compound of formula:

Amine B (243 mg, 1 mmol), allyl bromide (363 mg, 3 mmol), NaHCO3 (420 mg, 5 mmol) and KI (17 mg, 0.1 mmol) are heated. . at reflux of MeCN (3 ml). The product is obtained in the form of a colorless liquid (226 mg, 80%).

RMN 13C 0 21.5, 34.9 (q, 3JC-F = 1.6 Hz, CF3CHCH2), 53.0, 53.8, 57.3 (q, 2Jc~F = 25 Hz, CF3CH), 114. 1, 117. 7, 127. 1, 127. 8 (q, 1 JC-F= 291 Hz, CF3), 128. 2, 128. 8, 136.5, 139. 4, 141. 0.

19F NMR # -69. 1 (d, JH-F = 8. 3 Hz, CF 3); 1 H NMR # 1. 7 (s, 3H), 2.4 (dd, J = 4.8 Hz, J = 14.5 Hz, 1H), 2. 6 (dd, J = 10 Hz, J = 14. Hz, 1H), 3.4 (m, 3H), 3.7 (d, J = 14Hz, 1H), 4. 1 (d, J = 14Hz, 1H), 4.9 (d, J) = 14Hz, 2H), 5. 22 (m, 2H), 5.7 (m, 1H), 7. 2-7.5 (m, 5H);

13 C NMR 0 21.5, 34.9 (q, 3 JC-F = 1.6 Hz, CF 3 CHCH 2), 53.0, 53.8, 57.3 (q, 2 Jc-F = 25 Hz, CF 3 CH), 114. 1, 117. 7, 127. 1, 127 8 (q, 1 JC-F = 291 Hz, CF 3), 128. 2, 128. 8, 136.5, 139. 4, 141. 0.

 Amine C (257 mg, 1 mmol), allyl bromide (363 mg, 3 mmol), NaHCO 3 (420 mg, 5 mmol) and KI (17 mg, 0.1 mmol) are heated. . at reflux of MeCN (3 ml). The product is obtained in the form of a colorless liquid (124 mg, 42%).

19F NMR # -59. (D, JH-F = 8. 0 Hz, CF 3); 1H NMR # 1 (m, 2H), 3.5 (q, JH-F = 8. 0 Hz, 1H, CF 3 CH), 3. 7 (dq, J = 14 Hz, J = 1.5 Hz , 1H), 4. 1 (m, 1H), 4.9 (m, 2H), 5.2 (m, 2H), 5.9 (m, 2H), 7.2-7.4 (m, 5H) ;

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Example 11 - Synthesis of the compound of formula:

Amine F (227 mg, 1 mmol), allyl bromide (363 mg, 3 mmol), NaHCO3 (420 mg, 5 mmol) and KI (17 mg, 0.1 mmol) are heated. . at reflux of MeCN (3 ml). The product is obtained in the form of a colorless liquid (211 mg, 79%).

IR # (cm -1) 3308 (C = C-H); 19F NMR # -71. 0 (d, JH-F = 7.

9 Hz, CF3); 1H NMR (ddd, J = 17Hz, J = 5.

4 Hz, J = 2.

9 Hz, 1H), 2.5 (ddd, J = 17 Hz, J = 9.0 Hz, J = 2.6 Hz, 1H), 3. 3 (m, 3H), 3.6 (d, J = 14 Hz, 1H), 3.8 (d, J = 14Hz, 1H), 5. 1 (m, 3H), 5.7 (m, 1H), 7. 0-7.3 (m, 5H); 13C NMR # 16. 8 (q, 3C-F = 2.

2 Hz, CF 3 CHCH 2), 53. 4, 53. 9, 58. 6 (q, 2C-F = 26 Hz, CF 3 CH), 70.6, 80. 0, 117. 9, 126. (q, 1C-F = 289 Hz, CF 3), 127. 1, 128.2, 128.6, 136.1, 139. 0.

Claims (2)

 CLAIMS 1. Compound comprising at least one carrier carbon: - an amine function; an allyl or propargyl radical; a difluoromethylene group; and a hydrogen or a hydrocarbon radical, advantageously chosen from those which are donor or weakly electroattractive (#p # 0,1). Compound according to Claim 1, characterized in that the number of carbons of said compound is at most 30 carbon atoms, advantageously at most 20 carbon atoms. 3. Process for synthesizing a compound of formula #

 seen. Rf represents a carbon radical carrying a difluoromethylene group which binds to the rest of the molecule, advantageously at most 15, preferably at most 10 carbon atoms; - R1 represents a hydrogen, an alkyl radical, including aralkyl, preferably 1 to 2 carbon atoms or one of the specific radicals specified later; R2 represents a hydrogen, an alkyl radical, including aralkyl, preferably from 1 to 2 carbon atoms or an aryl radical; - R3 represents a hydrogen or a hydrocarbon radical such as alkyl, including aralkyl, preferably 1 to 2 carbon atoms or an aryl radical, or form with R4, an additional double bond to convert the allylic radical to propargyl radical; R 4 represents a hydrogen or a hydrocarbon radical, such as aryl or alkyl, including aralkyl, preferably from 1 to 2 carbon atoms or, with R 3, forms an additional double bond, for the ethylenic bond to become acetylenic, making it possible to to pass from an allyl radical to a propargyl radical; <Desc / Clms Page number 20>  R5 represents a hydrogen or a hydrocarbon radical, such as an aryl radical or an alkyl radical, including aralkyl, preferably from 1 to 2 carbon atoms; - R5 and R4 may be fractions of said group "Ar" above, so that R5 and R4 and the carbon that carries them form a radical Ar; one of R 1, R 2, R 4, R 3 and R 5 may also be chosen from the trivalent, nitrile or acid specific functional groups, optionally and preferably in esterified form; R 'can be a hydrogen, a protecting group, an aryl or an alkyl, including aralkyl; R "is an allyl radical, a hydrogen or a metal cation, or a metal cation fraction, when the metal is polyvalent, by the action of an allylic organometallic on an imine carrying difluoromethylene groups. 4. Method according to claim 3, characterized in that said organometallic is made in situ, according to a technique called Barbier. 5. Process according to claims 3 and 4, characterized in that the imine is of formula (II):

 wherein R is selected from halogens and hydrocarbon radicals selected from donor or weakly electron withdrawing, and Rf has the same value as above. 6. Process according to claims 3 to 5, characterized in that the allyl radial of said organometallic compound corresponds to formula III:

 7. Process according to claims 3 to 6, characterized in that the reaction is carried out in a polar aprotic solvent whose donor index is at least equal to 10, advantageously at least equal to 20. <Desc / Clms Page number 21> 8. Process according to claims 3 to 7, characterized in that it further comprises an N-allylation step, by the action of an allyl derivative of formula IV on the free amine. 9. Process according to claims 3 to 8, characterized in that the Rf group corresponds to the following formula: GEA- (CX2) p- where: X, the same or different, represent a chlorine, a fluorine or a radical of formula CnF2n + 1 'with n being at most equal to 5, preferably 2, with the proviso that at least one of X is fluorine, fluorine advantageously carried by the carbon carrier of the open bond; p represents an integer at most equal to 2, that is to say 1 or 2; - GEA represents an electron-withdrawing group (that is to say sigma p greater than zero, preferably 0.1, preferably 0.2) whose possible functions are inert under the reaction conditions, advantageously fluorine or a perfluorinated residue of formula CnF2n + 1, with n being at most equal to 8, advantageously to 5; the total carbon number of Rf being advantageously between 1 and 15, preferably between 1 and 10. 10. Process according to claim 9, characterized in that the total number of carbons of the radical Rf between 1 and 10, more preferably from 1 to 4. 11. Process according to claims 9 and 10, characterized in that the radical Rf is a radical sensu stricto, that is to say that it corresponds to the formula Cv, F2v + 1 'where v is an integer ranging from 1 to 10, advantageously at most 4, most often at most 2. 12. Process according to claims 9 to 11, characterized in that the Rf radical is chosen from the difluoromethyl radical (CHF2) and the trifluoromethyl radical, the latter being preferred. 13. Use as a Cyclizing Metathesis Substrate of the Compounds of Formula (I) <Desc / Clms Page number 22>

 where: Rf represents a carbon radical carrying a difluoromethyl group ensuring the link with the rest of the molecule, advantageously at most 15, preferably at most 10 carbon atoms; - R1 represents a hydrogen, an alkyl radical, including aralkyl, preferably 1 to 2 carbon atoms or one of the specific radicals specified later; R2 represents a hydrogen, an alkyl radical, including aralkyl, preferably from 1 to 2 carbon atoms or an aryl radical; R 3 represents a hydrogen or a hydrocarbon radical such as alkyl, including aralkyl, preferably from 1 to 2 carbon atoms, or an aryl radical, or forms with R 4 an additional double bond to convert the allyl radical to a propargyl radical; R 4 represents a hydrogen or a hydrocarbon radical, such as aryl or alkyl, including aralkyl, preferably from 1 to 2 carbon atoms or, with R 3, form an additional double bond, so that the ethylenic bond becomes acetylenic, allowing to pass from an allyl radical to a propargyl radical; R5 represents a hydrogen or a hydrocarbon radical, such as an aryl radical or an alkyl radical, including aralkyl, preferably from 1 to 2 carbon atoms; - R5 and R4 can be fractions of said group "Ar" above, so that R5 and R4, as well as the carbon which carries them, form a radical Ar; one of the R 1, R 2, R 4, R 3 and R 5 may also be chosen from the trivalent, nitrile or acid specific functional groups, optionally and preferably in esterified form; R 'can be a hydrogen, a protecting group, an aryl or an alkyl, including aralkyl; R "is an allyl or homoallyl radical. 14. Use according to claim 13, characterized in that only one of R 'and R "is a homoallyl or allyl radical.