Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
  • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
  • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
  • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
  • C07B39/00—Halogenation
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C17/00—Preparation of halogenated hydrocarbons
  • C07C17/093—Preparation of halogenated hydrocarbons by replacement by halogens
  • C07C17/20—Preparation of halogenated hydrocarbons by replacement by halogens of halogen atoms by other halogen atoms
  • C07C17/202—Preparation of halogenated hydrocarbons by replacement by halogens of halogen atoms by other halogen atoms two or more compounds being involved in the reaction
  • C07C17/208—Preparation of halogenated hydrocarbons by replacement by halogens of halogen atoms by other halogen atoms two or more compounds being involved in the reaction the other compound being MX
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C205/00—Compounds containing nitro groups bound to a carbon skeleton
  • C07C205/07—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by halogen atoms
  • C07C205/11—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by halogen atoms having nitro groups bound to carbon atoms of six-membered aromatic rings
  • C07C205/12—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by halogen atoms having nitro groups bound to carbon atoms of six-membered aromatic rings the six-membered aromatic ring or a condensed ring system containing that ring being substituted by halogen atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
  • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
  • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
  • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
  • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
  • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
  • C07F9/02—Phosphorus compounds
  • C07F9/28—Phosphorus compounds with one or more P—C bonds
  • C07F9/54—Quaternary phosphonium compounds
• • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
  • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
  • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
  • Y02P20/00—Technologies relating to chemical industry
  • Y02P20/50—Improvements relating to the production of bulk chemicals
  • Y02P20/54—Improvements relating to the production of bulk chemicals using solvents, e.g. supercritical solvents or ionic liquids

Definitions

• composition of ionic nature as a substitute reagent, composition constituting a fluorination reagent and process using it
• the subject of the present invention is the use of compounds of ionic nature as reaction medium or as solvent in reactions of the nucleophilic substitution type. It relates more particularly to obtaining fluorinated derivatives by replacing a leaving group, in particular halogen or pseudohalogen, with a fluorine.
• This substitution reaction is a substitution reaction called aromatic nucleophilic substitution (SN A ⁇ ) when the substitution takes place on an aromatic nucleus and nucleophilic substitution of order 2 (SN 2 ) when the substitution takes place on a chain of aliphatic nature and when the kinetics are of order 2, that is to say that the speed depends both on the concentration of substituent agents and on substrates.
• SN A ⁇ aromatic nucleophilic substitution
• SN 2 nucleophilic substitution of order 2
• One of the interesting aspects of the present invention aims to improve the aromatic nucleophilic substitution reactions known as Meisenheimer.
• Aromatic nucleophilic substitution reactions generally involve the following reaction scheme:
• R represents any radicals
• GEA represents an Electro-Attractor Group
• • gp represents a leaving group, or rather the leaving group considered.
• This type of reaction is particularly advantageous for obtaining halogenated aromatic derivatives and in particular used for carrying out exchanges between fluorine on the one hand, and halogen (s) of higher rank or pseudo-halogen (s) on an aromatic substrate on the other hand go.
• the leaving group can thus be a nitro group, advantageously a pseudo-halogen or preferably a halogen atom, especially with an atomic number greater than that of fluorine.
• pseudo-halogen is intended to denote a group whose departure leads to a chalcogenated anion, most often oxygenated, the anionic charge being carried by the chalcogene atom and whose acidity is at least equal to that of the acid.
• acetic acid advantageously at the second acidity of sulfuric acid and preferably that of trifluoroacetic acid.
• pKa for medium to high acidities from carboxylic acids to trifluoroacetic acid and place yourself on the Hammett constants scale ( Figure I ) from trifluoroacetic acid (constant 1), see the acidity scale given in this application.
• the leaving group is a nitro group
• the latter is generally replaced by a chlorine or fluorine atom.
• most of these reagents require operating at very high temperatures and the mechanism does not always turn out to be a nucleophilic substitution.
• the departure from the nitro group leads to the formation of oxygenated and halogenated nitrogen derivatives which are particularly aggressive with respect to the substrate, or even explosive.
• the variant involving the substitution of a halogen atom present on an aromatic nucleus by another halogen atom it generally requires at least partial deactivation of said nucleus.
• the aryl radical to be transformed is preferably depleted in electrons and has a density electronic at most equal to that of benzene, at most close to that of a chlorobenzene, preferably a dichlorobenzene.
• This depletion may be due to the presence in the aromatic cycle of a heteroatom (depletion in this case implies a 6-membered ring) as for example in pyridine, and in quinoline. In this particular case, the depletion is significant enough for the substitution reaction to be very easy and does not require any specific additional activation. Depletion of electrons can also be induced by electro-attractant substituents present on this aromatic cycle. These substituents are preferably chosen from attractor groups by inductive effect or by mesomeric effect as defined in the reference work in organic chemistry "Advanced Organic Chemistry" by MJ MARCH, 3 rd edition, publisher Willey, 1985 (cf. in particular pages 17 and 238).
• electron-attracting groups By way of illustration of these electron-attracting groups, mention may especially be made of the groups N0 2 , quaternary ammoniums, Rf and in particular CF 3 , CHO, CN, COY with Y possibly being a chlorine, bromine, fluorine atom or an alkyloxy group.
• the SN Ar reactions and in particular those of halogen-halogen exchanges mentioned above in fact constitute the main synthetic route for accessing the aromatic fluorinated derivatives.
• esters Nu " is notably then Ac-S “ or Ac-O " , with Ac being acyl [advantageously from 1 to 25 carbon atoms]
• ethers Nu “ is in particular then RO “ with R being alkyl or aryl [advantageously from 1 to 25 carbon atoms]
• thioethers Nu “ is in particular then RS “ with R being alkyl or aryl [advantageously from 1 to 25 carbon atoms]
• nitriles Nu " est CN " ).
• one of the techniques most used to manufacture a fluorinated derivative consists in reacting a halogenated aromatic derivative, generally chlorinated, to exchange the halogen (s) with one or more fluorine (s) of mineral origin.
• a halogenated aromatic derivative generally chlorinated
• fluorine (s) of mineral origin e.g., sodium fluorides and especially potassium, cesium and / or rubidium.
• an alkali metal fluoride is used, most often of a high atomic weight such as for example sodium fluorides and especially potassium, cesium and / or rubidium.
• Onium fluorides can also be used.
• the fluoride used is potassium fluoride which constitutes a satisfactory economic compromise.
• reaction is slow and, due to a long residence time, requires significant investment.
• This technique as already mentioned, especially for the treatment of nuclei that are poor in electrons, is generally used at high temperatures which can reach around 250 ° C, even 300 ° C - say in the area where the most stable organic solvents begin to decompose.
• one of the aims of the present invention is to provide reagents and operating conditions which allow a significant improvement in the kinetics of the SN Ar reactions.
• Another object of the present invention is to provide reagents and to give operating conditions which in particular allow improved kinetics of the SN A ⁇ reactions, even when the nucleus seat of said SN A ⁇ is only slightly depleted in electrons.
• Another object of the present invention is to provide reaction media for nucleophilic substitution which make it possible to obtain good yields without it being necessary to greatly exceed 200 ° C. for SN Ar on Ar- ⁇ of which Ar is phenyl. the sum of the Hammett constants ⁇ p of its substituents does not exceed 0.5.
• Another aspect of the invention is to facilitate so-called nucleophilic substitution reactions, in particular those considered as second-order nucleophilic substitutions.
• the carbon comprises, in addition to the halogen, or the halogens, to be exchanged, an atom or an electro-attracting group, in particular by inductive effect.
• Fluorinated compounds are generally difficult to access.
• the reactivity of fluorine is such that it is difficult if not impossible to obtain the fluorinated derivatives directly.
• One of the techniques most used to manufacture the fluorinated derivative consists in reacting a halogenated derivative, in general chlorinated, to exchange the halogen with a mineral fluorine, in general an alkali metal fluoride, generally of high atomic weight.
• the fluoride used is potassium fluoride which constitutes a satisfactory economic compromise. Except in cases where the substrate is particularly suitable for this type of synthesis, this technique has drawbacks, the main of which are those which will be analyzed below.
• reaction requires reagents such as alkali metal fluorides such as potassium fluoride which are made relatively expensive by the specifications which they must meet in order to be suitable for this type of synthesis; they must be very pure, dry and in a suitable physical form, generally in atomized form.
• alkali metal fluorides such as potassium fluoride
• this reaction does not work for a whole class of products, in particular those relating to the halophore carbon (ie the carbon carrying the halogen (s) intended to be exchanged with fluorine).
• Reagents such as hydrofluoric acid, liquid or diluted with dipolar aprotic solvents, are also used.
• hydrofluoric acid is too strong a reagent and often leads to unwanted polymerization reactions or tars.
• arsenic, antimony and heavy metals such as silver or quicksilver (mercury).
• Another object of the present invention is to provide a process which is capable of carrying out the exchange between on the one hand heavy halogens such as chlorine and on the other hand fluorine by significantly improving the specificity of the reaction.
• Another object of the present invention is to provide a process which is capable of carrying out the exchange between on the one hand heavy halogens such as chlorine and on the other hand fluorine by using mild reaction conditions.
• Another object of the present invention is to provide a process which makes it possible to use a source of fluoride whose morphology is less critical.
• Another object of the present invention is to provide a process which makes it possible to exchange only one halogen atom (in particular chlorine) out of two (in particular two chlorines) or out of three possible (in particular three chlorines).
• one halogen atom in particular chlorine
• Another object of the present invention is to provide a process which makes it possible to exchange only two of the three possible halogen atoms.
• Another object of the present invention is to provide a process which, on the same sp 3 carbon, makes it possible to exchange only one halogen atom (in particular chlorine) out of two (in particular two chlorines) or out of three possible (especially three chlorines).
• one halogen atom in particular chlorine
• Another object of the present invention is to provide a process which, on the same sp 3 carbon, makes it possible to exchange only two of the three possible halogen atoms.
• Another object of the present invention is to provide a process which makes it possible to exchange molecules or atoms only insofar as this makes it possible to obtain carbon atoms which are only carriers of a fluorine atom concomitantly with one or two other halogens distinct from fluorine.
• Another object of the present invention is to provide a process which makes it possible to exchange molecules or atoms only insofar as this makes it possible to obtain carbon atoms which are only carriers of two fluorine atoms concomitantly with a another halogen separate from fluorine.
• Another object of the present invention is to provide a process which makes it possible to avoid the use of large quantities of metals deemed to be expensive or toxic, such as mercury and / or silver.
• Another object of the present invention is to provide a process which makes it possible to reduce the quantities of heavy elements, in particular deemed to be expensive or toxic, such as mercury and / or silver, so that the molar ratio between the metal and the substrate whose halogen atoms are to be exchanged, is at a value at most equal to 0.5, advantageously 0.2, preferably 0.1.
• Another object of the present invention is to provide a process which makes it possible to completely avoid the use of elements, and in particular of heavy metals, in particular deemed to be expensive or toxic such as mercury and / or silver, so as to do not add to the reaction mixture any of the elements mentioned above; in other words that the concentrations in each of said metals do not not exceed the values of 10 -3 M; advantageously 10 -4 M, preferably 10-5 M.
• the present invention aims to carry out nucleophilic substitution reactions, in particular of aromatic nucleophilic substitution and / or of nucleophilic substitution of order 2 making it possible to carry out the reaction with relatively weak vigorous nucleophiles.
• Another object of the present invention is to provide a technique which makes it possible to carry out a nucleophilic substitution reaction with nucleophiles of neutral or anionic nature whose associated acid has a pKa at most equal to 5, preferably at most equal to 4, said pKa being measured in the aqueous phase.
• Another object of the present invention is to provide a process which makes it possible to carry out a reaction of SN Ar type and / or of SN 2 type making it possible to replace with fluorine a halogen heavier than fluorine.
• Another object of the present invention is to provide a process which allows the replacement of a pseudo-halogen with a fluorine.
• Another object of the present invention is to provide a method for carrying out the chlorine-fluorine exchange on an aliphatic atom (that is to say sp 3 hybridization) carrying at least one other halogen heavier than fluorine to be exchanged with fluorine.
• Another object of the present invention is to provide a process making it possible to carry out the halogen-fluorine exchange, and in particular chlorine-fluorine, on a substrate where the halogen is carried by a halogen-bearing carbon which also carries:
• n is equal to 1 which means that A is then advantageously phosphorus. And therefore that the compound of general formula G is very preferably a phosphonium. In this case the most interesting results are obtained for SN A ⁇ -
• composition constituting a reagent or a reaction medium is more versatile but their interest is especially manifest for the synthesis of aliphatic fluorinated derivatives from substrates carrying a sp 3 carbon halogenophore itself of a radical or of an electron-withdrawing group of Hammett constant ⁇ p at least equal to 0.1.
• the invention (with n equal to zero or one) is of interest for SN Ar with one of the leaving groups mentioned above and with anionic nucleophiles, in particular those mentioned above. It is particularly advantageous with one, or more, halogen or pseudo halogen as a leaving group. Halogens and in particular chlorine are preferred as leaving groups. The replacement of at least one halogen heavier than fluorine, and in particular of at least one chlorine, is particularly targeted by the present invention.
• the concepts and preferred values of aryls and alkyls are the same in both variants.
• cations and amounts of cations so that there is a concentration of cation (s) according to formula G at least equal to 2 moles per liter or more exactly two equivalents of cationic per liter, preferably 3 equivalents and even 4 equivalents per liter.
• concentration of cation (s) according to formula G at least equal to 2 moles per liter or more exactly two equivalents of cationic per liter, preferably 3 equivalents and even 4 equivalents per liter.
• the molecular mass of the cation is at most equal to 300, advantageously to 250, more preferably to 200.
• the cations are polyvalent (ie say carries several positive charges), these values must be reduced by unit of charge; in other words, a divalent cation could be of molecular mass twice greater than the masses stated above.
• the compounds of formula G according to the invention have a molecular mass at least equal to 100.
• the reaction medium consisting mainly of the ionic solvent is as dry as possible.
• the reaction medium before use is advantageously such that the mass ratio between the salt whose cation corresponds to formula G and water is at most equal to 200 ppm, preferably to 100 ppm (in this ratio, the numerator is constituted by l water, of course).
• a good way to dehydrate is to heat under vacuum for 2 h, preferably 8 h under vacuum at 70 ° C, the vacuum being the vacuum of the vane pump, or 10 "2 mm of mercury.
• said reaction medium is aprotic and anhydrous.
• anhydrous is such that the strongest acid present in the medium, without taking into account the substrate, has a pKa at least equal to.
• the content of labile hydrogen atoms is such that the ratio between the equivalent amount of labile hydrogen (numerator) and the quantity of cation of formula G expressed in equivalent, ie at most equal to 1%, advantageously to 1 per thousand, preferably to 1000 ppm (in moles, or equivalent when the species considered are polyfunctional).
• the ionic compounds according to the present invention is advantageously less a phosphonium salt containing at least 4 carbon atoms.
• it is used as reaction medium in a nucleophilic substitution reaction, advantageously aromatic, at least one phosphonium (quaternary) salt having at least one carbon atoms.
• the medium according to the present invention can be considered as a molten organic salt, a salt which can comprise a proportion of compound known as polar solvent.
• polar solvent a compound known as polar solvent
• said reaction medium prefferably has a mass ratio between the sum of the polar solvents and the sum of the phosphonium salts ([SP] / [P + ]) at most equal to 1, advantageously 1/2, preferably 1/5.
• said phosphonium corresponds to formula (I):
• R 3 where Ri, R 2 , R3 and R 4 , which are identical or different, are chosen from hydrocarbon radicals and which can be linked together.
• the phosphonium (s) constituting the medium (s) according to the present invention is or are such that said hydrocarbon radicals Ri, R 2 , R3, and R 4 , are chosen from among the list below established in order of preference:
• the total number of carbon of the phosphoniums of formula I is at most equal to 50, advantageously to 35, preferably to 25.
• the number of carbon atoms can become fractional.
• the phosphonium (s) of formula I has (s) a total number of carbon at most equal to 30, advantageously 25, of preferably 20.
• This preference can also be expressed by indicating that the average mass of the substituents of the phosphonium (s) preferably does not exceed 700 per atom of phosphorus in the form of phosphonium, advantageously not 500.
• the minimum value to be advised being 56 , advantageously 80, preferably 100.
• the total number of quasi-optimal carbon is established at values at most equal to 25, preferably to 20.
• alkyl is taken in its etymological sense from the rest of an alcohol from which the OH function has been removed. Thus it covers in particular the radicals, the free bond of which is carried by a carbon atom of sp 3 hybridization, which carbon atom is linked only to carbons or to hydrogens.
• Said alkyls can also carry quaternary phosphonium or ammonium functions; in which case the phosphonium compounds are polycationic. Without being excluded, they are not among the favorites.
• the Ri, R 2 , R 3 , and R 4 advantageously have at most 20 carbon atoms and in total at most 50 carbon atoms.
• Ri, R 2 , R 3 and R 4 can be linked together and form cycles, although this is not the most preferred compounds, they can also form cycles with a other phosphonium, for example the compounds resulting from the quaternization of diphosphabicyclooctane.
• Ri, R 2 , R3 can be linked together and form cycles.
• X " represents an anion (or a mixture of anions) ensuring electrical neutrality, advantageously, the one or more, X " represents (s) a single charged anion.
• X " is an anion such that XH is at least as acid as acetic acid, advantageously as the second acidity of sulfuric acid.
• counterions are advantageously chosen from anions and mixtures of anions X "which are not very nucleophilic, that is to say when they are unique, are such that XH has a pKa at most equal to 3, advantageously at 2, preferably 1, more preferably zero, and when they are made up of a mixture of anions at least one of the anions is not very nucleophilic.
• X is chosen " so that X " is at most as nucleophilic as the nucleophile, advantageously less, and even significantly less (that is to say that the pKa of XH is 1, advantageously 2, preferably 3, less than the pKa of the acid associated with the nucleophile).
• X ′′ or one of the anions which it represents is the, or one of, the nucleophile (s) of said nucleophilic substitution.
• X " is chosen from halogens, pseudo-halogens and mixtures of these halogens or pseudo-halogens, advantageously halogens of periods greater than that of fluorine (except when the fluoride is the soluble nucleophile) and mixtures of halides.
• bromide and chloride constitute preferred X " co-anions, in particular it is advisable to ensure that the sum of bromide ions and chloride ions is at least equal to times, advantageously at% times the amount of cation of formula G (expressed in equivalent).
• Chloride is preferred for SN A ⁇ , so it is advantageous that the chloride ions are in an amount at least equal to Vs times, advantageously at% times the amount of cation of formula G (expressed in equivalent).
• Another object of the present invention is to provide a composition capable of serving as a reagent for implementing the use described above.
• composition useful as a nucleophilic substitution reagent comprising, outside the substrate, in a liquid phase for successive or simultaneous addition:
• (d) third-party components in which, when (d) contains a possible polar solvent, the latter is present in an amount such that the mass ratio between the sum of the polar solvents and the sum of the salts of compound (s) of formula G advantageously phosphonium (s) ([SP] / [P +]), that is to say, [SP] / (a + b) is at most equal to 1/2, advantageously to 1/3, preferably ⁇ A, more preferably 1/5 and by the fact that the sum of (a) + (b) + (c) + (d) represents 100% of said liquid phase.
• the quantity of the third components assembled under (d) is advantageously low.
• the mass ratio between the component (d), on the one hand, and the components (a) + (b) + (c), on the other hand is at most equal to 1, advantageously 1/2, preferably 1/3.
• the nucleophile when the nucleophile is ionic, at least part of the co-anion is formed of said nucleophile; in other words, the sum of the anions (of course expressed in equivalents) other than the nucleophile is less than the amount of compound (s) of formula G, advantageously phosphonium (s) and counter-cation ( s) (of course expressed in equivalents) of said nucleophile, advantageously less than the amount of compound (s) of formula G, advantageously of phosphonium (s) alone.
• the molar ratio between the cation (s) [i.e. the cations forming counterions of an anionic nucleophile ] of component (c), expressed in equivalent, and component (a), expressed in equivalent of compound (s) of formula G, advantageously of phosphonium, is greater than 0.01, advantageously than 0.02.
• nucleophile When the nucleophile is anionic, it may be advantageous to use the nucleophile both as co-anion of compound (s) of formula G, advantageously phosphoniums ensuring electrical neutrality and as nucleophile; in this case, the molar ratio (or in equivalents when the components are polyfunctional) between component (c), expressed in equivalent of monovalent anions, and component (a), expressed in equivalent of compound (s) of formula G , advantageously of phosphonium (s), is at least equal to 0.5; advantageously 0.6, preferably 0.7.
• Said composition can also comprise one (or more) solid phase (s) in kinetic or thermodynamic equilibrium with the above liquid phase.
• said solid phase, or said solid phases comprise (s) at least one salt formed from an inorganic cation and from the anion corresponding to said nucleophile and / or to the group starting from said nucleophilic substitution.
• the molar ratio (or equivalent) between said dissolved mineral cation (CM) and component (a) is advantageously at least equal to 1/100, preferably to 1/20, more preferably to 1/10.
• nucleophile is the fluoride ion, which is advantageously in the form of an alkaline salt; generally potassium or cesium.
• n is zero
• ionic solvents in general when the melting point of the salt is at most equal to 100 ° C.
• anions advantageously monovalent, whose associated acid has an acidity at least equal to that of trifluoroacetic acid and
• these ionic solvents, or molten salts also allow the selectivity of the exchange with extremely high selectivity coefficients high. As we will see below, it is possible to play on lipophilicity and the molecular mass of the cation to favor certain reactions over others.
• the preferred coanions are not those which are usually preferred.
• the anions giving the best results in the two exchanges are anions which are neither complex nor very largely delocalized in charge.
• the anions of the PF 6- , BF -, triflic and triflimide type, although giving good results, are not those which give the best.
• the preferred ones are the halide anions and this without being able to give a fully satisfactory mechanistic explanation. If the phosphoniums, where n is equal to zero, give particularly interesting results for the reactions of SN Ar nature with a real or assumed Meisenheimer intermediary, the other cations, in particular those where n is equal to zero are more versatile, and present an advantage of being liquid at a lower temperature, at least in general.
• the compound of formula G is advantageously such that A is nitrogen; the possibility that it is phosphorus certainly exists, but this limits the use of the media, because of the oxidizability of these compounds and their relative instability.
• divalent radical E is such that E represents a radical D-A "equal to form a compound of formula (IIa):
• A is an atom from column VB or else a carbon atom carrying hydrogen or substituted by a hydrocarbon radical R5, where the radical D is chosen from
• the metalloids of column VB are preferably nitrogen, whether for A "or for A '.
• a ′′ is a column atom VB, and in particular a nitrogen, it is preferred that D is chosen from sp 2 carbon atoms substituted by a function or by a bivalent radical R 7 carrying a hydrogen or optionally substituted by a carbon radical R 6 to give a formula of D specified below.
• R 7 carrying a hydrogen or optionally substituted by a carbon radical R 6 to give a formula of D specified below.
• the cation of formula G in which n is equal to zero comprises a metalloid atom (saturated, that is to say non-carrier of double bond), having a resonance with a bond ⁇ connecting two atoms, at least one of which is a disubstituted and positively charged atom from column VB; advantageously an organic cation comprising a trivalent atom from column VB (column of nitrogen in Mendeleev's table), advantageously nitrogen, an atom whose doublet is directly or indirectly conjugated to a ⁇ bond connecting two atoms, including minus one is an atom from column VB (i.e. A) °.
• the metalloid atoms having a resonance (directly or indirectly through double (s) bond (s), advantageously carbon-carbon) with a bond, in general a doublet conjugated with a ⁇ bond, are advantageously chosen from those having a strong donor mesomeric effect, ie those which, with their possible substituents, present an R factor (contribution of resonance; see in particular the "March", third edition, table 6 on page 248) significantly negative, more precisely at more equal to - 0.4, advantageously at most equal to - 0.6; preferably at most equal to - 1.5; more preferably at most equal to - 2.
• Said organic cation comprising a saturated metalloid atom, having a resonance with a ⁇ bond is advantageously such that said metalloid atom is a chalcogen substituted by an aromatic or aliphatic radical, or preferably a trivalent atom from the column VB, which is preferably a trisubstituted atom forming a tertiary base.
• Said organic cation may comprise several saturated metalloid atoms having a resonance with said ⁇ bond. This has the advantage of better offshoring the positive charge.
• a metalloid of column VB in particular nitrogen or phosphorus, preferably nitrogen;
• R 7 carrying a hydrogen or optionally substituted by a carbon radical R ⁇ .
• R 5 chosen from hydrogen, the values of D and from hydrocarbon radicals, advantageously aryl and especially alkyl.
• the radical D and this iminium function be arranged in such a way that the atoms of nitrogen and of said metalloid are as far apart as possible, in other words and for example, that the nitrogen of the iminium function is that of the two atoms linked by the ⁇ bond which is the farthest from the trivalent atom of column V.
• the iminium function is general for all the atoms of column VB linked by the bond ⁇ , in the case where the bond ⁇ has a carbon atom and an atom from column V.
• the previous sequence corresponds to the formula
• R3 identical or different, are chosen from hydrocarbon derivatives, advantageously alkyls of at most 4 carbon atoms and hydrogen.
• said trivalent atom of the column VB forms or constitutes a tertiary amine.
• said organic base comprising a trivalent atom from column VB, the doublet of which is conjugated to a ⁇ bond, constitutes a molecule of the following formula:
• the delocalization effect is particularly marked when said ⁇ bond connecting two atoms is intracyclic (or when a mesomeric form is intracyclic), especially when it is intracyclic in an aromatic cycle.
• the pyridine rings in particular enriched by the presence of one or more metalloid atoms, in particular when the sum of the Rs (see above) is at most equal to - 1.5, advantageously to - 2, constitute particularly satisfactory cations.
• the organic base comprising a saturated metalloid atom, having a resonance with a ⁇ bond can be advantageously chosen from dialkoylaminopyridiniums, in particular in the para- or ortho- position (that is to say in the position 2 of pyridine or 4 see formula above); DBU (diazabicycloundecene) also gives an interesting cation.
• Five-membered rings are particularly interesting when they have two or three heteroatoms.
• R ⁇ 'and Re "have the same value as R 6 . It is possible to substitute free aryl vertices (engaged in an aromatic) or aliphatic (whose attachment point is a sp 3 carbon). But this is of little interest and the disadvantage of weighing down the cation.
• R ⁇ '"and R 6 "" are chosen from the same values as R ⁇ , they can be identical or different from the other R 6 , as well as from Ri and R 2. It is preferable if we want compounds with low points of fusion that the molecule is asymmetrical. R ⁇ ′ ′′ and R 6 ′′ ′′ can be linked together to form rings, advantageously aromatic.
• the nitrogen substituents are preferably of different size.
• the radicals R 1 to Rio are chosen so that none of the atoms in the column of nitrogen and none of the chalcogens is carrying a hydrogen except for this reserve: the radicals ⁇ to R 10 which can be independently identical or different are advantageously chosen from alkyls and aryls.
• R 5 and R 5 may be aryloxyl, alkyloxyl, amino groups substituted by two alkyls, by two aryls or by an alkyl and an aryle.
• R 6 when carried by a carbon, can also be a dimethylamino, an aryloxyl or an alkyloxyl.
• R 5 can be chosen from hydrogen, the values of D and from hydrocarbon radicals, advantageously aryl and especially alkyl.
• the total number of carbons when n is equal to zero in formula G is advantageously at most equal to 30, preferably at most equal to 20, more preferably at most equal to 15. It is desirable that at most two, and even preferable that at most only one, hydrocarbon groups, when they are, Ri, R2, R5, Re, R ⁇ "R9 and R10 have a number of carbons greater than 6.
• the cation of formula G is stable in the presence of water and that it is not miscible in any proportion.
• alkyl is taken in its etymological sense from the rest of an alcohol from which the OH function has been removed. Thus, it covers in particular the radicals, the free bond of which is carried by a carbon atom of sp 3 hybridization, which carbon atom is linked only to carbons or hydrogens.
• radicals of formula C n H 2n + ⁇ those which are derived therefrom by substitution with atoms and / or functions (it is preferable to avoid parasitic reactions by choosing functions which are inert under the conditions for implementing the invention) and in particular those which carry ether functions and in particular mono-, oligo-, poly- or poly-ethoxylate sequences obtained from epoxides alkene and especially ethylene.
• the radicals R 1 to R 10 can be linked together to form rings, and in particular heterocycles of aromatic nature.
• Imidazoliniums give particularly interesting results, in particular with regard to chlorine and fluorine exchanges on sp 3 hybridization carbons.
• the imidazoliniums which have given the best results are those where R5 is hydrogen and where Ri and R 6 are alkyl while not having the same chain length.
• the preferred and most active chain lengths are those which are such that when R 1 is methyl and R 6 is between methyl and butyl. Tests where the chain length of R 6 is 8 carbon atoms are less efficient but show great selectivity.
• the substrate for the exchange on aliphatic carbons is advantageously a substrate comprising a halophore carbon of sp 3 hybridization carrying at least two halogens, at least of which is a halogen of atomic number greater than that fluorine, the two other carbon substituents possibly being two alkyls, a chalcogene atom or another halogen atom carrying a doublet, or else an aryl and an alkyl, or else two aryls.
• halogenophore carbon is linked to at least one weak hybridization atom carrying an unsaturation.
• said weak hybridization atom carrying an unsaturation is engaged in a carbon-carbon bond (acetylenic, preferably ethylenic, which ethylenic bond is advantageously engaged in a cycle of aromatic character)
• said weak hybridization atom carrying an unsaturation is an atom engaged in one of the following double bonds [where * C is the halophore carbon]:
• R-CX'X '"- X" where R is chosen from hydrocarbon residues (that is to say containing carbon and hydrogen, in particular aryl or alkyl), halogens, electro-attracting groups ( preferably by inducing effect); with X 'chosen from halogens preferably chlorine; with X '"chosen from halogens, preferably chlorine; with of course the condition that R, X and X' cannot be simultaneously fluorine, and that one of them represents at least one halogen heavier than fluorine to be exchanged with fluorine, preferably chlorine; with X "chosen from aryls, halogens, alkyloxy, thioalkyloxy, acylalkyloxy, thioacylalkyloxy, aryls and alkyls as well as by a radical of formula below :
• Z is chosen from trivalent metalloids with r equal to zero or tetravalent with r equal to 1 (respectively phosphorus and advantageously nitrogen on the one hand and carbon on the other hand, preferably carbon); and Z ′ is chosen from metalloids advantageously chalcogens (with s and t equal to zero), nitrogen and phosphorus (with s equal to zero) and carbon with s and t equal to 1); r, s, and t can take the values zero or one, depending on what represents Z and Z '.
• R can be hydrogen and give rise to an easy exchange especially when the compound is of formula two, preferably when Ar is homocylic.
• R can also be of type -ZfR ⁇ r ⁇ Z'fRi ⁇ ) s - (Rs) ty including of type Ar (Rn) s . to give or not a symmetrical molecule.
• R 15 can be hydrogen or any radical, advantageously hydrocarbon
• R12 can independently take the same values as R 15
• R-11 can independently take the same values as R 15, however according to the present invention R-
• R, X ′ and X 1 ′′ are such that there are among them at least two halogens distinct from fluorine and that there is at least one halogen which is chlorine.
• the halogen-fluorine exchange reactions are particularly selective in the case where in the general formula n is equal to one.
• selectivity it is sufficient either to limit the quantity of the nucleophile, in general fluoride, or to limit the temperature, or to limit the duration. As can be seen in the examples, this selectivity of exchanges is particularly spectacular.
• the nucleophiles are those which have already been mentioned in the body of the present description, in particular the anionic or even neutral nucleophiles, the pKa of the associated acid of which is at most equal to 4 when the nucleophile is a fluoride
• the fluorides can be introduced in the form of alkaline fluoride, preferably alkaline fluoride, the alkali metal of which is greater than or equal to that of sodium, preferably at least equal to that of potassium.
• the fluoride ions can also be introduced in the form of the coanion of the compound of formula G or finally be introduced in the form of ammonium or phosphonium.
• the coanions are preferably coanions corresponding to very strong acids, in particular those whose Hammett constant is greater than or equal to that of trifluoroacetic acid.
• the anionic nucleophiles which will act on the substrate can be used as a coanion.
• the preferred anions are the anions corresponding to heavy halides (iodide, chloride and bromide) and more particularly to chlorides and bromides.
• iodide, chloride and bromide heavy halides
• chloride and bromide for exchange by SN 2 on a sp 3 carbon carrying at least two halogens, at least one of which is chlorine, bromide is preferred.
• the bromides are those which have given the best results, excluding the fluorides which play the times the role of nucleophiles and coanions.
• the presence of the bromide ion in the exchanges on aliphatic carbons is eminently profitable. Its role begins to be felt and to become significant when its molar ratio between the bromide and the cation of formula G is at least equal to 5%, preferably to 10%.
• the operating conditions are substantially the same as those which employ a conventional polar aprotic solvent, such as sulfolane. It is however possible to lower the temperature somewhat due to the high reactivity of the reaction medium according to the present invention.
• Another object of the present invention is to provide an advantageously aromatic nucleophilic substitution method implementing the present invention.
• Ar- ⁇ (III) where Ar is an aromatic radical in which the nucleus carrying ⁇ is depleted in electrons, either because it contains at least one heteroatom in its cycle (6-membered aromatic cycle), or because the sum ⁇ p of its substituents, apart from the ⁇ considered, is at least equal to 0.2, advantageously to 0.4, preferably to 0.5, and where ⁇ is a leaving group, advantageously in the form of an anion ⁇ " , with a composition comprising, outside the substrate, in a liquid phase for successive or simultaneous addition: (a) at least one compound of formula G, advantageously a quaternary phosphonium, or a mixture of quaternary phosphoniums, comprising at least 4 carbon atoms,
• any solvents in particular polar solvents, do not dilute too much the, or the, at least one compound of formula G, advantageously a phosphonium (s).
• this solvent is present in an amount such that the mass ratio between the sum of the polar solvents and the sum of the salts of at least one compound of formula G, advantageously a phosphonium ([SPJ / tP *] ), that is to say [SP] / (a + b), or at most equal to 1, advantageously to Vz, preferably to 1/5. It is preferable that the above constraint applies to all possible solvents, polar or not.
• ⁇ is individualized only for the ease of writing the reaction and that Ar can carry at least one other leaving group than ⁇ , leaving groups which may be identical to, or different from ⁇ .
• one of the chlorines can play the role of leaving group, while the others will play the role of electro-attracting groups, once the exchange has taken place, another chlorine may be leaving group and so on.
• the present invention is particularly suitable for treating pyridine and weakly depleted nuclei, such that the sum of the ⁇ p (Hammett constant) of the substituents of Ar, excluding the ⁇ , is at most equal to 1, advantageously 0.8, of preferably 0.6.
• the method according to the present invention makes it possible to treat the cases where Ar is such that the aromatic nucleus carrying ⁇ is a 6-membered nucleus in which the, or at least one of the electron-attracting groups, is in the meta position with respect to ⁇ , and is advantageously a chlorine and / or a fluorine.
• ⁇ " is less nucleophile than the nucleophile agent with which it will be exchanged; as the nucleophilia scales are difficult to use, the person skilled in the art may use the rule of thumb that ⁇ H is advantageously more acid than the nucleophile in the form on can be a nitro or quaternary ammonium group, but it is preferable that it is a pseudohalogen group or preferably a halogen atom chosen from chlorine, bromine and iodine.
• pseudo-halogen is intended to denote a group whose departure leads to an oxygenated anion, the anionic charge being carried by the chalcogene atom and whose acidity, expressed by the Hammett constant, is at least equal to that of acetic acid, advantageously at the second acidity of sulfuric acid and preferably that of trifluoroacetic acid.
• the nucleophilic substitution reaction being relatively facilitated when ⁇ represents an iodine atom, the claimed process is more particularly interesting when ⁇ symbolizes a chlorine, bromine or pseudo-halogen atom.
• the aromatic substrate thus substituted has an electronic density at most equal to that of phenyl, advantageously at most close to that of a chlorophenyl and, preferably, a difluorophenyl.
• This depletion may also be due to the presence in the aromatic cycle of a heteroatom such as, for example, in pyridine, quinoline. he is important to emphasize that this type of depletion is only observed when Ar symbolizes a compound having a 6-membered ring and the heteroatom belongs to column V (essentially nitrogen or phosphorus) as defined in the classification table of the elements published in the supplement to the Bulletin de la cios Chimique de France in January 1966.
• the or at least one of the groups R is an electron-withdrawing substituent and not a leaving agent and more preferably is different from a carbon substituent.
• the substituent (s) R when it (s) is (are) attractor (s) can (can) be chosen (s) among the halogen atoms and the following groups:
• O ⁇ ⁇ ' is chosen from the same values as ⁇ , with the same preferences
• Alk representing a hydrogen, advantageously an alkyl group, linear or branched, preferably from Ci to C 4 .
• R groups As examples of preferred R groups, mention may more particularly be made of halogen atoms and the nitro group.
• the electron-attracting substituent (s) R are more preferably located in the ortho and / or para position relative to the (x) groupings) leaving) ⁇ .
• nucleophilic agent intended to replace the leaving group (s) X at the level of the aromatic substrate, it can be generated in situ during the irradiation reaction.
• nucleophilic agent capable of being used according to the invention there may be mentioned in particular:
• Nitrogen nucleophilic derivatives are of particular interest in the context of the claimed process.
• Another object of the present invention is to provide a process which is particularly useful for carrying out exchange reactions between fluorine and halogens of higher atomic number, present on the aromatic substrate, and in particular exchange reactions between fluorine and chlorine.
• Reverse exchange reactions that is to say the replacement of a halogen by a halogen of higher rank, are also possible.
• this type of reaction is of less interest and is moreover more difficult to carry out. Nevertheless, it is within the reach of those skilled in the art to take advantage of the teaching of the present process to carry out other exchange reactions, and in particular these reverse exchange reactions.
• the fluoride is a fluoride of an alkali metal of atomic number at least equal to that of sodium and preferably is a potassium fluoride.
• the fluoride, alkaline or alkaline earth is at least partially present in the form of a solid phase.
• reaction is carried out at a temperature lower than that used for a reaction carried out under the usual conditions.
• reaction can be carried out in the presence of a solvent.
• the heating is carried out partially or completely by microwave of the present invention; in this case it is preferable that the microwaves are emitted by short periods (from 10 seconds to 15 min) alternating with cooling phases.
• the respective durations of the microwave emission periods and the cooling periods are chosen so that the temperature at the end of each microwave emission period waves remains below an initial temperature set and which is generally lower than that of the resistance of the ingredients of the reaction mixture.
• the power released by the microwaves is then chosen so that, for a fixed initial temperature, generally that of operation, it is equivalent to the energy evacuated by the cooling system and this to heat released or absorbed by the reaction.
• Such an actinic heating method also has the advantage of being compatible with a continuous operating mode.
• This mode of use advantageously makes it possible to overcome the problems of heat exchange which may be generated during the opening and closing operations of the reactor where the microwaves are emitted.
• the materials to be activated are introduced continuously via an inlet orifice within the reactor where they undergo activation by microwave and the products are continuously removed from said reactor via an outlet orifice. enabled.
• the medium according to the invention can be used concomitantly with a catalyst deemed to be a phase transfer catalyst, especially when this catalyst is a catalyst of cationic nature.
• a catalyst deemed to be a phase transfer catalyst, especially when this catalyst is a catalyst of cationic nature.
• They may in particular be encrypted cations, for example crown ethers encrypting alkalis.
• phase transfer catalysts can be used in the presence or in the absence, preferably in the presence of a particularly heavy alkaline cation and therefore of high atomic rank such as cesium and rubidium.
• the content of alkaline cation when used as promoter is advantageously between 1 and 5%, preferably between 2 and 3 mol% of the nucleophilic agent used.
• These domains are closed domains, that is to say that they have their limits.
• the reagent can include, as promoter, phase transfer agents which are oniums (organic cations whose name ends with onium).
• Oniums generally represent 1 to 10%, preferably 2 to 5% by moles of the aromatic substrate, the counter ion is indifferent but most often halogen.
• phase transfer agents are usually used when the reaction mixture comprises at least two condensed phases (remember that "condensed phase” covers the liquid and solid phases) in the present invention these agents are of much less interest, the phosphoniums being, for a large number of them, considered as phase transfer agents.
• tetraalkylammoniums of 4 to 28 carbon atoms, preferably of 4 to 16 carbon atoms.
• Tetraaicoyiammonium is generally tetramethylammonium. It should however be pointed out that the advantage of such compounds in the medium according to the present invention is of less interest than in the usual technique.
• the polar aprotic solvents are those which advantageously have a significant dipole moment and a relatively high donor number.
• its relative dielectric constant epsilon is advantageously at least equal to around 10, preferably the epsilon is less than or equal to 100 and greater than or equal to 25 and its donor index is between 10 and 50, said donor index being ⁇ H ( change in enthalpy) expressed in kilocalories of the association of said dipolar aprotic solvent with antimony pentachloride.
• these solvents act as a third solvent, but their presence is detrimental to the kinetics of the reaction, so their proportion must be limited to the values specified above.
• said suspended solid In general, it is known that a fine particle size has an influence on the kinetics.
• said suspended solid it is desirable for said suspended solid to have a particle size such that its d 90 (defined as the mesh allowing 90% by mass of the solid to pass) is at most equal to 100 ⁇ m, advantageously at most equal to 50 ⁇ m, preferably at most equal to 200 ⁇ m.
• the lower limit is advantageously characterized by the fact that the d ⁇ 0 of said suspended solid is at least equal to 0.1 ⁇ m, preferably at least equal to 1 ⁇ m.
• the ratio between said nucleophilic agent, preferably alkaline fluoride, and said substrate is between 1 and 1.5, preferably around 5/4 relative to the stoichiometry of the exchange.
• the mass content of solids present in the reaction medium is advantageously at least equal to 1/5, advantageously 1/4, preferably 1/3.
• the agitation is advantageously carried out so that at least 80%, preferably at least 90%, of the solids is kept in suspension by the agitation.
• the reaction is advantageously carried out at a temperature ranging from approximately 150 to approximately 250 ° C.
• a temperature ranging from approximately 150 to approximately 250 ° C.
• approximately is used to highlight the fact that the values which follow it correspond to mathematical roundings and in particular that, in the absence of comma, when the digit (s) furthest to the right of a number are zeros, these zeros are position zeros and not significant figures, except of course if specified otherwise.
• Example 3 Comparison between different ionic solvents The comparison is made between:
• EmimBr 62% 17% 0% 1% 20%
• the anion and the length of the alkyl chain influence the result.
• lengthening the alkyl chain increase in hydrophobicity, the reactivity is reduced.
• the second part of the synthesis consists in exchanging the chloride ion for the desired anion; 3 methods have been described in the literature:
• this method is limited by the price of the silver salts used (ex: AgBF 4 5g / 514 frs Aldrich).
• the method using the acid solution has the advantage of being a complete reaction and the traces of acids can be eliminated if care is taken to wash the ionic solvent formed with water until neutral pH. If the solvent is stored for a long time, it is useful to rewash it with water before use.
• the monofluorination reaction is complete using 2 equivalents of potassium fluoride, after 6 hours. at 150 ° C. At the start of the reaction, the ionic solvent turns red, and this coloring persists even after washing with water and ether, but the proton NMR indicates that the solvent is clean.
• Tetramethylammonium chloride was used in preliminary studies to catalyze this reaction. However, under the conditions described here, for the monofluorination reaction, the catalyst has no influence on the kinetics of the reaction as it is possible to see by comparing the following curves (Graph 1):
• the tubes are closed by a septum and a screw cap, then heated with stirring for 3 hours at 230 ° C. After returning to ambient temperature, the organic compounds are dissolved in dichloromethane, and analyzed by GC.
• the S-shape of the above curves shows that the effect of phosphoniums is not linear and that the effect of phosphonium at high ratios cannot be reduced to that of low ratios. From a ratio of the order of% and above all of a third, the increase in conversion becomes considerable.
• Example 10 Test in a perfectly stirred reactor
• the mixture is heated to 120 ° C, stirred (homogeneous suspension), then heated to 190-210 ° C for 4 hours.
• the volatile compounds formed during the reaction are continuously distilled.
• Reaction medium is heated for approximately 3 hours at 210-220 ° C under slight reflux.
• a first fraction (1) is distilled under atmospheric pressure, then a partial vacuum distillation is carried out (up to 33 mbar, 220 ° C. in the reaction mass) leading to fraction (2).
• Reaction medium is heated for approximately 3 hours at 205-215 ° C under slight reflux.
• a first fraction (1) is distilled under atmospheric pressure, then a partial vacuum distillation is carried out (up to 280 mbar, 220 ° C. in the reaction mass) leading to fraction (2).

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