Title of Invention

A NUCLEOPHILIC REAGENT AND PROCESS FOR GRAFTING A SUBSTITUTED DIFLUOROMETHYL GROUP ONTO A COMPOUND CONTAINING AT LEAST ONE ELECTROPHILIC FUNCTION WITH THE EXCLUSION OF OXIDES OF SULPHUR

Abstract Accordingly, the present invention provides a nucleophilic reagent useful for grafting a substituted difluoromethyl group onto a compound containing at least one electrophilic function with the exclusion of oxides of sulphur comprises: a fluorocarboxylic acid of formula Ew-CF2-COOH where Ew represents an electron withdrawing atom or group, at least partially salified with an organic or inorganic cation, and a polar aprotic solvent; wherein the releasable proton content of all the components of the composition, is at most equal to half the molar concentration of the said fluorocarboxylic acid and the content of the transition elements having at least two valency state is less than 1000 mol ppm relative to said fluorocarboxylic acid.
Full Text The present invention relates to a nucleophilic reagent and a process for
grafting a substituted difluoromethyl group onto a compound containing at least one
electrophilic function with the exclusion of oxides of sulphur. The invention relates
more particularly to a technique for perfluoroalkylating various compounds by
nucleophilic substitution reactions or addition reactions typically performed by
organometallic derivatives.
The techniques of perfluoroalkylation, or
equivalent techniques, generally use derivatives of the
perfluoroalkyl iodide type, in the presence of zinc. This
technique is thus expensive, while at the same time
requiring treatment plants for the metallic waste which
should be treated, since zinc is a great pollutant of
water courses.
The other techniques, in which the perfluoroalkyl radical does not form a stabilized reactive intermediate of the orgsnometallic type, are generally difficult to carry out on account of the very low stability of the free perfluoro anions in the reaction media. These anions generally lead to products of the carbene type, by loss of one of their substituents.
Consequently, one of the aims of the present invention is to provide a reagent which allows a per-fluoroalkylation according to a mechanism of the type involving a carbanion, without using organometallic reagents of transition metals such as zinc.
It has often been sought to use as a source of perfluoroalkyl radicals, more generally of trifluoromethyl radicals, perfluorocarboxylic acids, by carrying out decomposition reactions aimed at eliminating the carboxylic fragment from the said acids, releasing carbon dioxide. However, the successes which were obtained were very mitigated and used particularly complex catalytic systems. The perfluoroalkyl radicals or equivalents thereof generated by the decomposition of the said perfluorocarboxylic acids were, in addition, unstable in the reaction medium and required the use of stabilizing agents.
G. Stahly has also reported, in Journal of fluorine Chemistry, 45 (1989) , 431-433 and in

US-A-4,990,699, that the thermal decomposition of perfluoroalkanoic salts in the presence of aromatic compounds such as 1,3,5-trinitrobenzene leads to the formation of trifluoromethyl anions CF3, demonstrated by the formation of a Meisenheimer complex. The complex may subseguently be converted by oxidation to give the perfluoroalkyl derivative on the corresponding aromatic ring.
However, the need to carry out this oxidation makes this route for the perfluoroalkylation of aromatic derivatives tedious.
The present invention proposes to circumvent the drawbacks of the existing processes by providing a reagent which is non-hazardous to the environment and capable of leading to the desired products in a satisfactory yield.
In the course of the study which led to the present Invention, it has been demonstrated that a fluoroalkylation reaction was possible with a fluorocarboxylic acid salt, without a catalyst euid without an agent capable of stabilizing the various envisaged Intermediates obtained during the decomposition of the various perfluorocarboxyllc acids.
It appeared that, in order thus to obtain a decomposition of the fluorocarboxylic acids, two conditions were essential; one is the choice of the solvent, and the other the content of impurities in the mixture constituting the reagent according to the present invention. Thus, it was possible to demonstrate the ebsolutely critical role of the content of labile hydrogens in the system, or more precisely of releasable protons, which must be less than the content of fluoro groups released by the decomposition of the fluorocarboxylic acid salts. The terms labile hydrogen and releasable proton refer to a hydrogen atom which is capable of being removed out in the form of a proton by a strong base. In practice, these are protons of acidic functions which have a pKa of less than about 2 0 (by "about", it is emphasized that the number 20 has only one

significant figure).
The abovementioned. aims and others, which will appear later, are achieved by means of a nucleophilic reagent which is useful for grafting a substituted difluoromethyl group onto a compound containing at least one electrophilic function, characterized in that it comprises:
a) a fluorocarboxylic acid of formula Ew-CF2-COOH where Ew represents an electron-withdrawing atom or group, at least partially sallfied with an organic or inorganic cation, and
b) a polar aprotic solvent;
and in that the content of releaseble protons carried by . its various components, including their inpurlties, is at most equal to half the Initial molar concentration of the said fluorocarboxylic acid.
The electrophilic functions capable of reacting with the reagent of the present invention are the functions which usually react with organometallic reagents and will be detailed later.
The lower the content of releasable protons in the reagent, the lower the risk of side reactions will be and the better the yield will be.
Thus, it is preferable for the content of labile hydrogen atoms in the reagent to be at most equal to 10%, prefereibly to 1% (in moles), relative to the initial content of the said fluorocarboxylic acid.
The main impurity, as a carrier of lcbile hydrogen atoms, is generally water, which is capable of releasing up to two hydrogen atoms per molecule.
In general, it is preferadsle to use carefully dehydrated reagents and solvents, so that the weight content of water in the reagent is at most equal to 1 per 1000 relative to the total mass of the reagent.
Depending on the overall reaction conditions, such water contents may be satisfactory, but in certain cases, it may be advantageous to work at lower levels, for example of about 1 per 10,000.
However, it is not necessarily essential to

remove all of the water and a water/f luorocarboxylic acid molar ratio of less than 10% may be tolerated.
Moreover, it was possible to show that other elements, neunely transition elements having two stable valency states, such as copper, may not be beneficial, and could even be harmful.
Although this reagent according to the invention requires no catalyst, such metal elements may be present as isqpurities supplied in particular by the solvent.
Thus, it is preferable for the molar content of these elements to be less than 1000, adveuitageously than 100, and preferably than 10 ppm relative to the initial content of the said fluorocarboxylic acid.
Also, although it has been recommended many times to use elements from column VXXI of the Periodic Table of the Elements with perfluoroacetic acid, in order to promote certain substrates and to promote certain types of reaction, this proved to be particularly harmful for the reaction intended above. Consequently, it is preferable to use reagents containing no metals from
column VIII,in peurticular metals of the platinum ore , vMch is the group consisting of platinum, osmium, iridium, palladium, rhodium and ruthenium.
In the present description, reference is made to the supplement to the Bulletin de la Societe Chimique de France No. 1, January 1966, in which a Periodic Table of the Elements was published.
Thus, it is preferable for the content of platinum ore metals, or even of metals from column VIII, to be less than 100 ppm, advantageously than 10 ppm, preferably than 1 ppm. These values are expressed relative to the starting fluorocarboxylic acid and are expressed in moles.
In a more general and more empirical manner, it may be indicated that these two categories of metals, namely transition metals with two valency states and the elements of column VIII, should be present in the reagent at an overall concentration level at most equal to 1000 mol ppm, preferably to 10 mol ppm.

It will be noted that the various metals present at such an overall concentration level are extremely low in quantity and, in this respect, they play no catalytic role. Their presence does not improve the reaction kinetics, or is even harmful thereto when they are present in too large an amount.
The use, in addition to the components of the abovementioned reagents, of alkali metal fluoride or of guaternary axnmonium fluoride, which are usually present in the reagent systems using fluorocarboxylates, did not turn out to be harmful, but did prove to be of little value, on account of the fact that it produces saline effluents which are difficult to treat.
It is noted, however, that the presence of fluorides in the medium tends to limit the conversion of the fluorocarboxylic acid, but tends to reduce side reactions.
This effect tends to be greater the bulkier the counter-cation of the fluoride. Cations which may be envisaged are the cations of alkali metals higher in rank than sodium. In particular potassitun or caesium, or alternatively ions of "onium" type, namely cations formed by the elements of columns V B and VI B (as defined in the Periodic Table of the Elements published in the supplement to the Bulletin de la Societe Chimigue de France in January 1966), with 4 or 3 hydrocarbon chains. Among the oniums derived from elements of column V B, the preferred reagents are tetraalkyl or tetraaryl ammonium or phosphonlum. The hydrocarbon group advantageously contains from 4 to 12 carbon atoms, prefersdsly from 4 to 8 carbon atoms. The oniums derived from column VI B are preferably derived from elements with an atomic nximber higher than that of oxygen.
Despite the drawbacks which have been mentioned above, the content of fluoride ions is a parameter which may be considered. It may, however, be preferable to limit this content, in particular the initial content, so as to facilitate the final treatment of the reaction mediiim.

Thus, it is adveuitageous for the content o£ fluoride, which is qualified as being ionic, that is to say capahle of being ionized in the polarizing medium of the reagent, to be at least equal to the initial molar i concentration of the said fluorocarboxylic acid salt, advantageously to a half and prefercibly to a quarter of this concentration.
As has been mentioned ahove, the solvent plays an important role in the present invention and must be aprotic and advantageously polar and contain very few ioipurities carrying acidic hydrogen.
It is thus preferable for the polar aprotic solvent which can be used to have a significant dipolar . moment. ThuS/ its relative dielectric constant e is advantageously at least equal to edsout 5 (the positional zeros are not considered as being significant figures in the present description unless specified otherwise). Preferably, e is less than or equal to 50 and greater than or ecpial to 5, and is in particular between 30 and 40.
It is moreover preferred for the solvents of the invention to be capable of fully solvating the cations, which may be classified by the donor number Dof these solvents. It is thus prefered>le for the donor nximber DNof these solvents to be between 10 and 30. The said donor number corresponds to the AH (enthalpy difference), expressed in kilocalories per mole, for the association of the said polar aprotic solvent with auitimony pentachloride.
According to the present invention, it is prefereOsle for the reagent to have no acidic hydrogen on the polar solvent or solvents which it uses. In particular, when the polar nature of the solvent or solvents is obtained by the presence of electron-withdrawing groups, it is desirable for there to be no hydrogen alpha to the electron-withdrawing function.
More generally, as for all the components of the reagents, it is preferable for the pKa corresponding to the first acidity of the solvent to be at least ecfual to

acouc iJO ("eUaout" emphasizing that only the first figure is significant) , advantageously at least equal to eJsout 25, preferably between 25 and 35.
The acidic nature may also be expressed by the acceptor number ANof the solvent, as defined by Reichardt in "Solvents and solvent effects in Organic Chemistry", 2nd edition, VCH (RFA), 1990, pages 23-24. Advantageously, this acceptor nxjmber ANis less than 20, in particular less than 18.
It is preferable for the said fluorocarboxylic acid or acid salt to be at least partially (at least 10 mol%) / preferably fully, soluble in the medixim constituting the reagent.
The solvents which give good results may in particular be solvents of amide type* Among the amides, amides of specific nature are also included, such as tetrasubstituted ureas including cyclic tetrasubstituted ureas, in particular 5- or 6-membered ureas, for exanqple DMPU (dimethylpropylenylurea or 1,3-dimethyl-3,4,5,6-tetrahydro-2(lH)pyrimidinone) and DMEU (dimethyl-ethylenylurea), or 1,3-dimethyl-2-imidazolldinone suid monosubstituted lactams. The amides are preferably substituted (disubstituted for ordinary amides). Exanles which may be mentioned are pyrrolidine derivatives, such as N-methylpyrrolidone, or alternatively N, N-dime thy 1-formamide or N,N-dimethylacetamide.
Solvents such as 1,3-dimethyl-3,4,5,6-tetrahydro-2(lH}pyrimidinone (DMPU) or benzonitrile are also advantageous.
Another particularly advantageous category of solvents consists of ethers, whether these are symmetrical or unsymmetrical ethers and whether or not they are open. The various glycol ether derivatives such as the various glymes, for exeunple diglyme, should also be incorporated into the category of ethers.
In the fluorocarboxylic acid of the constituent a) of the reagent of the invention, the species Ew which exerts an electron-withdrawing effect on the difluoro carbon atom is preferedjly ggjected from functional groups

wnose Hammett constant c is at least equal to 0.1. It is moreover prefereUsle for the inductive component of a , ai to be at least equal to 0.2, advantageously to 0.3. In this respect, reference will be made to the book by I March, "Advanced Organic Chemistry", third edition, John Wiley £md Son, pages 242 to 250, and in particular to Table 4 of this section.
More particularly. the electron-withdrawing species zoay be selected fron halogen atoms, preferably light ones, in particular chlorine and fluorine. The corresponding fluorocarboxylic acid is a halofluoroacetlc acid of formula (1) Z - CFj - COOH where X is a halogen atom, advantageously a light one (chlorine or fluorine) . .
Ew may also be advantageously .eledbsd"from nitrlle
(with the risk, as a side reaction, of an a-elimination) ,
carbonylated, sulphcliatied fluorocarboxylic acids of this type which may be used
correspond to the formula (2) R-G-CFj-COOH where R-6
represents a nitrile group or alternatively 6 represents
C B 0,__S = 0, or - (CFj)- where n is greater than
or equal to 1, and R represents, without discrimination,
an organic or even an inorgeuiic residue, preferably an
/ organic radical such as aryl, alkyl or aralkyl, which is
optionally substituted. R may also represent an organic
solid support, such as a resin, or £ui inorganic solid
support.
In the case where G represents a perfluoro-alkylene group -(CFj)"" is advauitageously between 1 and 10, preferably between 1 suid 5. Still in this case, R may also represent a halogen atom, in particular fluorine.
In general, except in the case where the fluoro¬carboxylic acid is a polymer, the total number of carbon atoms in the fluorocarboxylic acid advamtageously does not exceed 50.
The counter-cations capable of forming a salt with the said fluorocarboxylic acid are advantageously bulky. Thus, alkali metal salts, advantageously those in which the alkali metal is selected fron sodium, potassium.

rubidium, caesiiixa or francium, are preferred. Preferedsly, the said metal is from a period at least equal in rank to that of sodiijm, advantageously to that of potassium. Quaternary eumnonitun salts are also preferred.
It is also possible to improve the reaction by using cations which are either naturally bulky, such as quaternary ammonium cations or quaternary phosphonium cations, or which are rendered bulky by the addition of chelating agents or preferably crypteuads, such as, for example, crown ethers or derivatives which are both aminated and oxygenated.
The chelating or sequestering agents which may thus be used are advantageously selected* on the one heuid, . from amines and, on the other hand, from ethers whose molecules contain at least one other ether function.
Thus, the sequestering agents iiilch may be used are advantageously selected such that they contain either at least one amine function, or alternatively an ether function and at least one amine and/or ether function In order to form a conlexlng agent which Is advantageously at least bldentate, preferably trldentate, the ether cmd/or amine functions being separated by at least 1 atom, advantageously 2 atoms and by not more than 4 atoms, advemtageously not more than 3 atoms, these generally being carbon atoms.
When the carbon atoms supposed to provide the coordination are connected together by 2 branches thus forming a ring, it is preferable for at least one branch to be at lea.st 3-membered, advantageously 4-membered, and for the other branch to be at least 2-membered, advantageously 3-membered.
The bulk and the mobility should be such that the bi-, tri- or polydentate agents are complexing. Such is not the case with 1,4-diazabicyclo (2 .2 .2 .) octajie.
In general, this constraint may be quantified by showing that the bicyclic systems obtained by bridging of a ring (which are in fact tricyclic) , and which are at most 8-membered, especially when the bridgeheads are the atoms providing the coordination, of the diazeibicyclo-

octeuie, -heptane and lower type and, to a lesser extent, -nonane, should be avoided.
More generally, it is advantageous to avoid any bicyclic system:
- whose bridgeheads are atoms intended to provide
the coordination
and
- 2 branches of which have, not taking the
bridgeheads into account, a chain length of not more than
2, preferably of not more than 3 when the third brsuxch is
less than 7-membered in length.
The at least bidentate nature with preferably at least one amine ftinctlon is necessary for phosgene and . derivatives, but not for oxalyl hallde and equivalents. At least 3 classes of conplexlng agents
may be mentioned as being particularly Interesting- cccoprising :
Q3 containing or sulphur-containing polyethers, which can be cyclic or macrocycllc; cryptands.
The first class consists of sequestering agents of general formula:
il-[-CHRi-CHR2-0-(CHR3-CHR4-0)-R5]3 (I)
Ln which n is an integer greater than or equal to 0 and Less than or equal to about 10 (0 out 12.
The second class of complexing agents consists of lyclic, prefer£d3ly macrocyclic, polyethers having from 6 ;o 30 atoms in the ring and preferably from 15 to 30 .toms in the ring atnd consisting of 2 to 10, preferably if 4 to 10, units -0-X in which X is either -CHRg-CHR-ir -CHRg-CHRg-CRgR7, Rg, R7, Rg and Rg, which may be
dentical or different, being a hydrogen atom or an alkyl
adical having from 1 to 4 carbon atoms, it being possible for one of the Xs to be -CHRg-CHRg-CRgR- when

the units -0-X- comprise the group -O-CHRg-CHR.
The third class of complexing agents consists of the compounds described in patent application EP 0,423,008, page 3, line 29 to page 6, line 45.
Perfluorocarboxylic acid salts may advantageously be used, such as the trifluoroacetate, perfluoropropionate and perfluorobutyrate of an alkali metal, in particular potassium.
It is noted that the use of sequestering agents of the crovm ether type, in solvents which are relatively non-polar (less polar than DMF), markedly accelerates the conversion of the starting fluorocarboxylic acid.
Such sequestering agents may advantageously be . used in a proportion of from 5 to 100 mol%, in particular from 5 to 25 mol%, relative to their initial fluorocarboxylic acid content.
However/ certain combinations with the other partners o£ the reaction medium. In particular certain solvents, may have a less favourable effect as regards the stability of the product formed, and will thus not be considered as being advantageous.
Another aim of the present invention is to provide a process for the synthesis of an organic derivative containing a difluoromethylene group, which uses the reagent according to the present Invention.
This aim is achieved:
a) by placing the said reagent together with a compound containing at least one electrophllic function, and
b) by heating the resulting mixture to a teoerature of between 100"C and 200°C, prefersQsly of between 110 and 150 °C, for a period of at least half an hour, advantageously of at least one hour, and of not more than one day, advantageously of less than 20 hours.
The placing of the reagent together with or in contact with the substrate may or may not be gradual. In particular, it is possible to wait until one of the two is at the right temperature in order to introduce the other. This introduction may or may not be gradual. The reagent may be poured into the substrate or vice versa.

/
The fluorocarboxylate and the svibstrate may be introduced into the solvent both simultaneously and gradually.
The reagent of the invention reacts according to the invention with an electrophilic coatpound, containing an electrophilic atom, it being possible for this atom to be a carbon atom or a hetero atom, for exeui>le sulphur, selenium or tellurium. It advemtageously reacts with hydrocarbon conorinds on an electrophilic carbon atom not belonging to an aromatic system.
According to a first aspect of the invention, the reagent preferably reacts with conoainds containing an electrophilic atom, advemtageously an electrophilic hetero atom, linked to a halogen atom or to a . pseudohalogen group In order to achieve the substitution of the said halogen or pseudohalogen In a single step.
The reaction works proportionately better. In contrast with an SN2 reaction, when It passes via a reaction Intermediate originating from an addition onto a multiple bond or onto a doublet.
When the electrophilic atom Is a sulphur atom, mention may be made of the reaction with:
- the halo or pseudohalo derivatives of organosulphur
confounds. In particular sulphenyl, sulphlnyl or
sulphonyl halldes. In which the halogen atom or the
pseudohalogen group Is substituted during the reaction
with a substituted difluoromethyl group;
disulphldes, for example optionally substituted aryldlsulphides. In which the S-S bond is broken and replaced by .a sxibstituted. difluoromethyl group; sultedsle disulphldes may in particular be C-CQ aryl disulphldes, optionally substituted with a CJ-CJQ alkyl, CJ-CJQ alkoxy or nitro group or with one or more (s 3) halogen atom(s) ;
- compotinds of thiocyanate type in which the cyano group
is substituted during the reaction with a substituted
difluoromethyl group; preferred thiocyanates are C-C-Q
aryl thiocyanates, including alkylaryl thiocyanates, and
i"io alkyl thiocyanates, including aralkyl thiocyanates.
In the eUsove compounds, the halogen atom may be selectedfrom iodine, bromine, chlorine and fluorine atoms.

A "pseudobalogen" group is a group which, when leaving, in anionic form, has em associated acid whose pKa is less than 4, preferetbly less than 3, in particular less than 0.
Groups whose associated acid has an acidity (measured by the Heunmett constant) at least equal to that of acetic acid, advemtageously to that of sulphonic acids, or trihalo acids, are preferred. One of the typical pseudohalogens is a perfluoroalkanesulphonyloxy group which releases a perfluoroalkanesulphonate. Preferred pseudohalogen groups may be selected from the tosylate (p-toluenesulphonyloxy), mesylate (methane-sulphonyloxy), trifluoromethanesulphonyloxy or . trifluoroacetoxy group. The acetate group may also be considered as such a leaving group.
According to a second aspect, the reagent also reacts advantageously with a con>otind selected from > carbonyl confounds of ketone, aldehyde, acid halide, activated ester or anhydride type, by performing an addition on the carbonyl function. Preferred and non-limiting exasles which may be mentioned are aromatic aldehydes, prefersQsly Cg-Co aldehydes, in which the aromatic ring may optionally be substituted with a C-Co allcyl, Cj-Cjo alkoxy or nitro group or with a halogen atom; cyclic ketones such as cyclohexeuione; non-enolizable ketones activated with a donor group, such as trifluoromethylacetophenone; aromatic euihydrides, such as benzoic anhydride.
When there is. a risk of reaction between the substrate and the fluorocarboxylate, it may then be preferable to introduce the substrate or the fluorocarboxylate only under conditions of decarboxylation of the said carboxylate (see the above implementation conditions).
The reaction product is generally eua alcohol in this case (for excunple in alkoxide form), the carbon atom of which bearing the hydroxyl function is substituted with a s\ibstituted difluoromethyl group. This product may optionally react subsequently with the reagent or with

the starting material according to the reaction conditions.
In general, the amoxint of reagent employed in the process o£ the invention will be set in a manner known per se according to the fimctionality of the electrophilic confound.
It should be pointed out that the product derived from the deconosition of the fluorocarboxylic acid may react with itself if it contains one of the functions liable to react, such as those mentioned above.
It may be noted that confounds, in liquid form, containing em electrophilic fxuiction are capzQle of being used as solvent according to the present invention, . provided that they are aprotlc. The reaction of the present invention may thus be advantageously performed by placing together
a) a fluorocarboxylic acid salt as defined above with
b) a confound containing at least one electrophilic
function acting both as solvent and as reaction
substrate.
Khen using the reagent according to the invention with a substrate containing at least one electrophilic fxinction, it is iioportant that the latter siibstrate disrupts the conditions described above as little as possible.
Thus, it is preferable to use a sufficiently dehydrated substrate, or one which neither contains acidic hydrogen which may be reioDved Y strong bases nor contains harmful impurities, that is to say, in general, a siibstrate which satisfies the seune constraints as those outlined for the reagent.
It has been possible to observe that, all factors being otherwise equal, the yield of the intended organic derivative depends on the degree of progress of the reaction and that a very low final yield may be obtained despite a considereible level of conversion of the reagents. Without wishing to be linked to any particular scientific theory, it appears that everything takes place as if there were formation kinetics and degradation

kinetics for the products obtained.
In order to avoid an excessive degradation of the final products, and thus to ensure good selectively of the reaction, it is preferable not to seek to convert the starting fluorocarboxylic acid completely. The progress of the reaction may be controlled by the rate conversion (RC) of the acid, which is the molar ratio of the amount of acid consumed to the initial amount of acid in the reaction medium, this rate being readily calculated after assay of the acid remaining in the medium.
Advantageously, the reaction will only be carried out until a rate of conversion of 40 to 80%, preferably of 50 to 70%, is produced, and the reaction products will then be separated. It is thus possible to achieve a selectively of the order of 80% expressed by the desired product/converted fluorocarboxylic acid molar ratio.
In order to be within optimum reaction conditions, it is possible to limit the rate of conversion by acting at the same time on the duration of the reaction, the nature of the solvent and the presence of additives which have a tendency to limit this conversion, for example such as fluoride ions. The reaction kinetics depend, in addition, on the reaction partners (fluorocarboxylic acid and electrophilic reagent) and the appropriate reaction time may readily be adapted to each individual case as a function of these kinetics.
Once the desired rate of conversion has been achieved, the reaction mixture may be treated in a manner which is known per se in order to separate out the product obtained, it being possible for the starting materials to be recycled in order to produce an additional amount of the intended organic derivative.
An additional chemical reaction which allows the desired product to be converted into a more volatile and readily distilled derivative may, if necessary, be carried out for the separation.

Accordingly, the present invention provides a nucleophilic reagent useful for grafting a substituted difluoromethyl group onto a compound containing at least one electrophilic function with the exclusion of oxides of sulphur comprises:
a) a fluorocarboxylic acid of formula EW-CF2-COOH where Ew represents an electron-withdrawing atom or group, at least partially salified with an organic or inorganic cation, and
b) a polar aprotic solvent; wherein the releasable proton content of all the components of the composition, is at most equal to half the molar concentration of the said fluorocarboxylic acid and the content of the transition elements having at least two valency state is less than 1000 mol ppm relative to said fluorocarboxylic acid.
Accordingly, the present invention also provides a process for the preparation of a derivative containing a difluoromethylene group, characterized in that it includes the steps of:
a) placing a reagent according to any one of claims 1 to 14 together with a compound containing at least one electrophilic function with the exclusion of oxides of sulphur and
b) heating the resulting mixture to a temperature of between 100 and 200°C for a period of between 1/2 hour and one day.
The examples which follow illustrate the


4.98 g (32.7 nmol) of potassliua trifluoroacetate and 2 g (18.8 nmol) of benzaldehyde are mixed together in 26 g of anhydrous DMF, under a nitrogen atmosphere.
The molar ratio of the trifluoroacetate to the benzaldehyde is 1.7.
The mixture obtained ie transferred to a 50 ml Hastelloy reactor. Once the reactor is closed, the mixture is heated at 104C for 3 h 30.
After cooling to 5*C, the reaction crude is drawn off/ diluted in CH2CI2 and washed with water.
The organic phase is dried and then assayed by gas chromatography.
The rate of conversion (AC) of the benzaldehyde is 50% (in terms of number of moles of benzaldehyde converted relative to the initial number of moles of benzaldehyde) and the actual yield (AY) of 1-trifluoromethylbenzyl alcohol is 20%.
Example 2.
The reaction between potassium trifluoroacetate and benzaldehyde is carried out as in Exasle 1, replacing the DMF by NMP (N-methylpyrrolidone) .
7.6 g of CF3C02K+ (50 mmol) and 3.2 g of benzaldehyde (30 mmol) are dissolved in 40 g of NMP.
The water content of the medium is less than 4 mol% relative to the trifluoroacetate.
The mixture is heated at 140°C for 3 h 30.
The processing and assay of the reaction crude performed as in Example 1 gives
Rate " conversion of the benzaldehyde = 55%
Yield of 1-trifluoromethylbenzyl alcohol = 15%

Example 3.
The reaction between potassium trifluoroacetate and benzaldehyde is carried out as in Example 1, the DMF being replaced by acetonitrile. 2 g of benzaldehyde and 4.75 g of potassium trifluoroacetate are dissolved in 25 ml of CH3CN.
The mixture is heated at 140°C for 3 h 30.
After processing and assay of the reaction crude, the following are obtained
Bate of conversion of the benzaldehyde s 53%
Yield of 1-trifluoromethylbenzyl alcohol = 2.5%
The main product formed in this reaction is cinnamonitrile (Z and E isomers).
Cinnamonitrile is formed by condensation of the anion of acetonitrile with benzaldehyde, followed by dehydration.
This example shows that the solvent to be used should not have excessively acidic protons.
Example 4.
The reaction between potassium trifluoroacetate (5.05 g; 32.7 mmol) and para-fluorobenzaldehyde (2.5 g; 20.2 mmol) in 25 ml of DMF is performed Tinder the conditions of Example 1.
The mixture is heated at 140oc for 4 h 00.
After processing, gas chromatographic (6C) assay


may take place.
Example 5.
A mixture consisting of 1.43 g of CF2CO3K+ (9.44 mmol) and 0.55 g of cyclohexanone (5.6 mmol) diluted in 6.4 g of DMF is heated at 140°C for 5 h 30. GC analysis of the reaction crude after hydrolysis gives

Example 7 : Reaction between benzoic anhydride and potassium trifluoroacetate.
A mixture of 0.81 g (5.32 mmol) of CF3CO2-K+ and 0.7 g (3.1 mmol) of benzoic anhydride in 6.15 g of NMP is heated at 140"C for 5 h 30. After hydrolysis, GC analysis of the reaction medium gives





WE CLAIM;
1. A nucleophilic reagent useful for grafting a substituted difluoromethyl group
onto a compound containing at least one electrophilic function with the exclusion of
oxides of sulphur comprises:
a) a fluorocarboxylic acid of formula EW-CF2-COOH where Ew represents an electron-withdrawing atom or group, at least partially salified with an organic or inorganic cation, and
b) a polar aprotic solvent; wherein the releasable proton content of all the components of the composition, is at most equal to half the molar concentration of the said fluorocarboxylic acid and the content of the transition elements having at least two valency state is less than 1000 mo1 ppm relative to said fluorocarboxylic acid.

2. The reagent according to claim 1, wherein the said polar aprotic solvent is the compound containing at least one electrophilic function.
3. The reagent according to claim 1 or 2, wherein the said proton content is at most equal to 10% of the initial molar concentration of the said fluorocarboxylic acid salt.
4. The reagent according to any one of the preceding claims, wherein the water content is less than 10% of the molar concentration of the said fluorocarboxylic acid.
5. The reagent according to any one of the preceding claims, wherein the content of transition elements having at least two stable valency states is less than 1000 mol ppm, relative to the said fluorocarboxylic acid salt.

6. The reagent according to any one of the preceding claims, wherein the content
of elements from column VIII of the Periodic Table of the Elements is less than 100 mo1 ppm, relative to the said fluorocarboxylic acid salt.
7. The reagent according to any one of the preceding claims, wherein the content, expressed as equivalents, of ionic fluoride is at most equal to the initial molar concentration of the said fluorocarboxylic acid salt.
8. The reagent according to any one of the preceding claims, wherein the donor number of the said polar aprotic solvent is between 10 and 30.
9. The reagent according to any one of the preceding claims, wherein the acceptor number of the said solvent is less than 20.
10. The reagent according to any one of the preceding claims, wherein the pKa corresponding to the first acidity of the said solvent is at least equal to 20.
11. The reagent according to any one of the preceding claims, wherein it comprises a sequestering crown ether.
12. The reagent according to any one of the preceding claims, wherein the said electron-withdrawing atom or group is selected from electron-withdrawing groups whose Hammett constant an is at least equal to 1.

13. The reagent according to any one of the preceding claims, wherein the said acid is selected from the compounds of formula (1) X - CF2 - COOH, where X represents a halogen atom, and the compounds of formula (2) R-G-CF2-COOH, where R-G represents a nitrile group or alternatively G represents C=0,S=0 or - (CF2)n - with n greater than or equal to 1 and R represents, without discrimination, an organic or inorganic residue.
14. The reagent according to any one of the preceding claims, wherein the said fluorocarboxylic acid or acid salt is fully soluble in the reagent medium.
15. The reagent according to any one of the preceding claims, wherein the said acid salt is a salt of an alkali metal selected from sodium, potassium, rubidium, caesium and francium, or a quaternary ammonium salt.
16. The reagent according to any one of the preceding claims, wherein the solvents are selected from N-disubstituted amides, including tetrasubstituted ureas and monosubstituted lactams, cyclic or acyclic ethers, and benzonitrile.
17. A process for the preparation of a derivative containing a difluoromethylene group, characterized in that it includes the steps of:

a) placing a reagent according to any one of claims 1 to 14 together with a compound containing at least one electrophilic function with the exclusion of oxides of sulphur and
b) heating the resulting mixture to a temperature of between 100 and 200°C for a period of between 1/2 hour and one day.

18. A process for the preparation of a derivative containing a difluormethylene
group, characterized in that it includes the step of heating a reagent according to claim
2 to a temperature of between 100 and 200°C, for a period of between 1/2 hour and
one day.
19. The process according to claim 17 or 18, wherein the said compound containing
an electrophilic function is selected halo or pseudohalo derivatives of organosulphur
compounds, in particular sulphenyl, sulphinyl or sulphonyl halides; disulphides;
thiocyanates; and carbonylated compounds, in particular ketones, aldehydes, acid
halides, activated esters and anhydrides.
20. The process according to any one of claims 17 to 19, wherein the said
compound contains at least one electrophilic function not containing any hydrogen
which can be removed by a strong base.
21. A nucleophilic reagent useful for grafting a substituted difluoromethyl group
onto a compound containing at least one electrophilic function with the exclusion of
oxides of sulphur substantially as herein described and exemplified.
22. A process for the preparation of a derivative containing a difluoromethylene
group substantially as herein described and exemplified.

Documents:

0437-mas-1996 abstract-duplicate.pdf

0437-mas-1996 abstract.pdf

0437-mas-1996 claims-duplicate.pdf

0437-mas-1996 claims.pdf

0437-mas-1996 correspondence-others.pdf

0437-mas-1996 correspondence-po.pdf

0437-mas-1996 description(complete)-duplicate.pdf

0437-mas-1996 description(complete).pdf

0437-mas-1996 form-2.pdf

0437-mas-1996 form-4.pdf

0437-mas-1996 form-6.pdf


Patent Number 198838
Indian Patent Application Number 437/MAS/1996
PG Journal Number 27/2006
Publication Date 07-Jul-2006
Grant Date 14-Apr-2006
Date of Filing 19-Mar-1996
Name of Patentee M/S. RHONE POULENC AGROCHIMIE
Applicant Address 14-20 RUE PIERRE BAIZET 69009 LYON,
Inventors:
# Inventor's Name Inventor's Address
1 MAS JEAN MANUEL 11, CHEMIN DU COIN, 69390 MILLERY,
2 FORAT GERARD 276, RUE DUGUESCLIN, 69003 LYON,
3 SAINT JALMES LAURENT 16, RUE LATOUCHE TREVILLE, 69330 MEYZIEU,
PCT International Classification Number C07C 29/38
PCT International Application Number N/A
PCT International Filing date
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 95 03512 1995-03-24 France
2 95 15763 1995-12-29 France