FR2785283A1 - Perfluoroalkane sulfonylation method for use in synthesis of perhalogenated sulfanilide, comprises contacting nucleophile with reagent comprising sulfonyl halide, organic base and optional solvent - Google Patents

Abstract

The method comprises contacting nucleophile (preferably with N as nucleophile atom) with reagent comprising, by successive or simultaneous addition, heavy sulfonyl halide (preferably sulfonyl chloride) and organic base comprising metalloid atom M having resonance with a pi bond binding two atoms (preferably imine bond) of which at least one is the atom of element of group VB of Periodic System. The organic part of sulfonyl halide is perhalogenated, preferably perfluorinated, at the C atom bound to S. The acid associated with nucleophile has pKa up to 7, preferably 5. The N atom of nucleophile is bound to electro-attracting group, preferably selected from electron-poor aryl and sulfonyl groups. The metalloid atom M is preferably trivalent atom of group VB, especially tri-substituted N atom. Contacting nucleophile with reagent is preferably conducted in organic solvent, preferably of weakly polar type, and especially miscible with water (at most 10 wt. %, preferably at most 2 wt. %). An Independent claim is also included for the reagent used in method as claimed, which in addition to successively or simultaneously added components as described above, also contains solvent, or mixture of solvents of weak polarity, weak solubility in water and preferably containing no chlorinated aliphatic chain.

Description

METHOD AND REAGENT USEFUL FOR SYNTHESIS

  PERHALOGEN SULFANILIDE ON CARBON CARRIER

  BY THE SULFANILIDE SULFAN ATOM

  The subject of the present invention is a process for the sulfonylation of various nitrogenous nucleophiles. It relates more particularly to the sulfonylation of

  anilines lato sensu, that is to say the amines linked to an aromatic nucleus.

  The reaction also targets a perhalogenosulfonylation reagent. Thus, the present invention relates more particularly to a sulfonylation reaction of an amine carrying an electron-withdrawing radical, especially when its amino functions are made soft, for example by the presence of an aryl radical (the amine then entering into the subcategory anilines). The synthesis of these sulfonamide derivatives is often difficult, especially when starting from sulfonyl halide. Most often, the direct reactions are failures and this in particular with the sulfonyl chlorides, especially when the organic part of the sulfonyls is very electron-withdrawing as in particular in the case where the sulfur-carrying atom of the sulfonyl function is

  perhalogenated and more particularly when it is perfluorinated.

  This is why one of the aims of the present invention is to provide a process which makes it possible to obtain sulfonamides of the preceding type by using sulfonyl halides, in particular when these halides are heavy halides (i.e. halides corresponding to a halogen

  atomic number at least equal to that of chlorine).

  It is preferred to use sulfonyl chlorides for economic reasons. The technique can also be transposed for the synthesis of perfluorosulfonimides. These aims and others which will appear subsequently are achieved by a sulfonylation process comprising a step of bringing a nucleophile, the nucleophilic atom of which is nitrogen, into contact with a reagent comprising for successive or simultaneous addition: - a heavy halide (that is to say a halide whose atomic number is at least equal to that of chlorine), sulfonyl, advantageously sulfonyl chloride and - an organic base comprising a trivalent atom from column V (column of l nitrogen in Mendeleev's table) atom whose doublet is directly or indirectly conjugated to an X bond connecting two atoms, at least one of which is an atom from column V, and - by the fact that the organic part of said sulfonyl is perhalogenated,

  advantageously perfluorinated on the carbon carried by the sulfur.

  The present invention is particularly advantageous for nucleophiles whose associated acid has a pKa at most equal to about 7, advantageously 6, preferably 5, more preferentially 4. Indeed, these nucleophiles are generally particularly difficult to sulfonylate . In particular, the invention is interesting for nucleophiles whose

  the nitrogen is connected to an electron-withdrawing group.

  This electron-withdrawing group can in particular be chosen from aryls,

  advantageously depleted in electrons and sulfonyles.

  Said organic base comprising a trivalent atom from column V the doublet of which is conjugated to an X bond can be used either as a base or

as a reaction catalyst.

  Indeed, the sulfonylation reaction releases a hydrohalic acid which salifies the nucleophile and makes the nucleophile more or less inert. It is therefore desirable to add bases which will make it possible to release the nucleophile from the various acids present in the reaction medium so that it plays

  fully its nucleophilic role.

  Said organic base comprising a trivalent atom in column V conjugated to an X bond is such that said trivalent atom in column V is a

  trisubstituted atom and forms a tertiary base.

  According to a particularly advantageous implementation of the present invention, said bond has connecting two atoms is the bond X of an imine function. It is preferable that this imine function is arranged in such a way that the nitrogen is as far apart as possible. In other words, the nitrogen of the imine function is that of the two atoms linked by the bond X which is the farthest from the trivalent atom of column V. What has just been said about the function imine is general for all the atoms of column V linked by the bond x, in the case where the bond x comprises a carbon atom and an atom of column V. According to the present invention, it is preferred that the organic base comprising a trivalent atom from column V, the doublet of which is conjugated to a bond r, has a chain or skeleton, of formula> N- [C = C] nC = N- with n equal to zero or an integer chosen from the interval closed (that is to say comprising the limits) 1 to 4, advantageously from 1 to 3, preferably from 1 to 2. Preferably the preceding sequence corresponds to the formula> N- [C (R1) = C (R2)] nC (R3) = N- with n equal to zero or an integer chosen from the closed interval (i.e. including the limits) 1 to 4 , advantageously from 1 to 3, preferably from 1 to 2 and o R1, R2 and R3 which are similar or different, are chosen from hydrocarbon derivatives,

  advantageously alkyls of at most 4 carbon atoms and hydrogen.

  Advantageously according to the method, said trivalent atom from column V forms,

or constitutes, a tertiary amine.

  More specifically, it is desirable that said organic base comprising a trivalent atom from column V, the doublet of which is conjugated to an α bond, constitutes a molecule of the following formula (R5) (R4) N- [C (Rl) = C (R2 ) 1] -C = N-R6 with n equal to zero or an integer chosen from the closed interval (that is to say including the limits) 1 to 4, advantageously from 1 to 3, preferably from 1 to 2 and o R1, R2 and R6 similar or different, are chosen from hydrocarbon groups, advantageously alkyls of at most 4 carbon atoms and hydrogen and o R4 and R5, similar or different, are chosen from hydrocarbon groups, advantageously alkyls of at most 4 carbon atoms, one or two of the substituents R ", R2, R3, R4, R5 and R6, which may be

  linked to other substituent (s) remaining to form one or more rings.

  The catalytic effect observed is particularly marked when said bond X connecting two atoms is intracyclic, especially when it is intracyclic in an aromatic cycle. This is particularly the case for pyridine cycles and cycles derived therefrom such as quinoline or isoquinoline. The organic base comprising a trivalent atom from column V, the doublet of which is conjugated to an X bond, can advantageously be dialkoylaminopyridines, in particular in the para or ortho position (that is to say in

  position 2 or 4 of pyridine); DBU also gives an interesting result.

  Although the present invention can be used to form usual sulfonimides, this reaction is particularly advantageous in the case of imide formation from a nucleophilic substrate constituted by an aniline and this more particularly when this aniline is linked to a nucleus

aromatic depleted in electrons.

  This depletion can be correlated with the introduction of a heteroatom into the cycle (in the case of 6-chain cycles) or else by the presence of substituents on the nucleus carrying the aniline function to be sulfonylated from

  globally substituting electro-attractor (s).

  In the case of an electronic depletion of a 6-membered ring by the introduction of a heteroatom, it should be noted that, or more precisely the substrates can be autocatalytic, that is to say that they

  may not require the presence of an amine according to the present invention.

  As regards the depletion by the substituents, it can be given by way of indication that the invention is particularly well suited for the treatment of arylamines in which the substituents, apart from the nucleophilic function to be sulfonylated, of the nucleus carrying the nucleophilic atom are such that the sum of their Hammett op constants is at least 0.14,

  advantageously at 0.20, preferably at 0.30.

  When this sum of Hammett constants reaches values greater than 1, the reaction becomes particularly lazy, so it is preferable that the sum of Hammett constants of the cycle carrying the amine function is at most equal to 1, preferably at most equal to 0.9, plus

  preferably at most equal to 0.7.

  When the organic base comprising a trivalent atom from column V whose doublet is conjugated directly or indirectly to an X bond is

  used as a catalyst (i.e. it is used in a sub-quantity)

  stoichiometric, more generally in an amount between 1% 0 and 1/5 of the QS [stoichiometric amount], advantageously between 1/100 and 1/10 of QS), it is then necessary to provide another base so that the reaction vis opposite

  nucleophilic substrate is as complete as possible.

  In this case, the reagent used also comprises, for successive or simultaneous addition, an organic base, preferably non-alkylable. In particular, the hindered dialkylphosphines, the trialkylphosphines, the phosphonium hydroxides, the

  hindered dialkoylamines, trialkoylamines, ammonium hydroxides.

  The concept of bulk of dialkoylphosphines or dialkoylamines hindered so that they are not alkylable is well known from

the skilled person.

  In a large number of cases, and in particular when solvents are used, it is preferable that said non-alkylable base is liposoluble and has at least a significant benzene solubility (symbol sw in the "Handbook of chemistry and physics"), advantageously high

  (symbol v in the "Handbook of chemistry and physics") high.

  As seen above, it is most often desirable to carry out the contacting in an organic solvent. This solvent is advantageously not very polar and, preferably, not very miscible with water. More particularly, it is desirable that at most 10% by mass, advantageously

  at most 5%, preferably at most 2% by mass, or miscible with water.

  The amounts of base to be added, the amount of non-alkylable base used during the reaction is advantageously at least equal to the

  amount necessary to neutralize the hydrohalic acid released.

  In other words, the amount of base must be sufficient to ensure that the nucleophile is always present in the free state (i.e. in the true state

  nucleophile) during the entire reaction.

  The techniques targeted by the present invention are particularly well suited to sulfonylation with perfluorinated alkylsulfonyl chlorides,

  especially perfluorinated on the carbon carried by sulfur.

  The most useful chloride is triflyle chloride (CF3SO2CI). More generally, the organic part of the sulfonyl chloride corresponds to the formula (Rf) - (CX2) p-GEA where the similar or different X represent a chlorine, a fluorine or a radical of formula CnF2n + 1 with n integer at most equal to 5 preferably to 2, with the condition that at least one of the X is fluorine; o p represents an integer at most equal to 2; o GEA represents an electron-withdrawing group the possible functions of which are inert under the conditions of the reaction, advantageously fluorine or a disturbed residue of formula CnF2n + l with n integer at most equal

to 8, advantageously to 5.

  The total number of Rf carbon is advantageously between 1 and 15,

preferably between 1 and 10.

  The present invention also relates to a reagent which is useful for implementing the method according to the invention. This reagent comprises for successive or simultaneous addition: * n heavy halide (that is to say whose atomic number is at least equal to that of chlorine), of sulfonyl advantageously sulfonyl chloride and: * an organic base comprising an atom trivalent from column V (nitrogen column), the doublet of which is directly or indirectly conjugated to an x bond connecting two atoms of which at least one is an atom from column V; the organic part of said sulfonyl being perhalogenated, advantageously

  perfluorinated, on the carbon carried by the sulfur.

  The reagent according to the present invention can also comprise, also for successive or simultaneous addition, a solvent. This solvent, including the mixture of solvents, is advantageously not very polar and chosen from those having a low solubility in water. In some cases, strings

  chlorinated aliphatics are not satisfactory.

  As a touchstone of the polarity, it can be specified that said slightly polar solvent is chosen from those, or mixtures of those, whose polarity (E. expressed in kcal / mol) is at most equal to 40, (advantageously with two

significant figures).

  These weakly polar solvents are usually chosen from oxygenated organic compounds, in particular ethers, esters, even ketones, hydrocarbons, including petroleum fractions, aromatic hydrocarbons halogenated on the medium. The latter are particularly interesting, in particular substituted benzenes and hydrocarbons

halogenated on the nucleus.

  What has just been explained above is particularly suitable for anilines, in particular those in which said nitrogen atom is linked to a 6-membered aromatic, preferably homocyclic, preferably benzene, not condensed, are advantageously depleted in electrons as has already been specified above. Overall, taking into account any substituents which are particularly well suited to the amines linked to an aryl whose electron richness is at most equal to a parachlorophenyl (Wealth evaluated at

using Hammett's constants).

  Among the most used electron-withdrawing groups, mention may be made of halogens (chlorine and fluorine), esters (of CO-OR type), ketones, amides not liable to interfere with sulfonylation, perhalogenated alkyls on the bound carbon. directly on the nucleus, in particular the perfluorinated alkyls on the atom close to the nucleus, the nitriles, the groups having a function

  sulfone or phosphone directly linked to the nucleus.

  The technique mainly targets the sulfonylation of anilines lato sensu (i.e.

  say amines carried by an aryl) but one can also transpose this teaching to the sulfonamidation of ammonia and the sulfimidation of sulfonamides. In this case, the latter are advantageously in the form of a salt

  organic base, non-alkylable (the base is non-alkylable).

  Under these conditions, nitrogen carries a hydrogen or more preferably a negative charge (anion), while in the case of the anilines which has been referred to above, the aniline function comprises at least one

  hydrogen, preferably two, for reasons of steric hindrance.

  For reasons of industrial hygiene, aliphatic chlorinated derivatives are generally to be avoided, although they constitute a family giving good results, although it is not the best performing family, because their solubility, and in particular that of methylene chloride is about 2% in

volume, or 2.6% by weight.

  The reaction can be carried out from -20 C to about 200 C, more generally

from 0 to about 100 C.

  It is easier to work at room temperature but one can also be under different, higher pressures. You can also work in a closed enclosure (such as an autoclave or sealed tube) and under

autogenous pressure.

  The following nonlimiting examples illustrate the invention.

EXAMPLES

  PreDaration of acetamido-5-dimethyl-2.4-trifluoromethanesuifonanilide Reaction in the presence of catalyst: In a reactor, 350 g of dichloromethane are successively charged,

  , 1 g of 2,4-amino-5-dimethyl-acetanilide and 6.9 g of 4- 4-dimethylamino

  pyridine. The suspension obtained is then stirred and cooled to 10 C.

  then add 57.4 g of triethylamine 15 min at 10 C.

  A solution of 56.8 g of trifluoromethanesulfonyl chloride in 59 g of dichloromethane is then poured in 2 h while maintaining the temperature of the

medium at 10 C.

  The medium is then kept stirring for 2 h at 10 ° C., then the temperature is allowed to rise to 20 ° C. and stirring is continued for 2 h. The medium is acidified in the reactor by adding 265 g of a solution

4.2% aqueous HCl.

  The precipitate formed is then filtered and rinsed (3 times) with deionized water then with dichloromethane. It is then dried at 95 ° C. under reduced pressure.

  67 g of a beige solid are thus obtained, ie an isolated yield of 77%.

  Characteristic of the compound: Fusion = 180 C.

  - Reaction in the absence of catalyst: The preceding conditions are repeated but in the absence of 4-dimethylaminopyridine. Analysis of the reaction medium shows a 90% degradation of the

  trifluoromethanesulfonyl chloride.

  Yield of expected product much less than 10%.

  Preparation of methyl chloro-5- (N-trifluoromethylsulfonyl) amino-benzoate - Reaction in the presence of catalyst: 17 g of methyl chloro-5-anthranilate, 120 g of dichloromethane, 2.26 g are successively charged of 4-dimethylamino pyridine and then 18.5 g of trifluoromethanesulfonyl chloride. The solution is stirred at 15 ° C. and a solution of 18.7 g of triethylamine in 19 g of dichloromethane is poured in over 3 hours. After addition, the medium is stirred for 3 hours at 15 ° C., then 10 hours at

ambient temperature.

  The medium is then washed successively with 150 g of deionized water, with 100 g of a concentrated hydrochloric acid solution, then again with

g of permuted water.

  The solvent is removed under reduced pressure.

  27.7 g of a yellowish solid are thus obtained, ie an isolated gross yield of%.

  Characteristic of the compound: Fusion = 81 C.

  - Reaction in the absence of catalyst: 1 / Reaction with triethylamine: The previous conditions are repeated but in the absence of 4-dimethylaminopyridine. Analysis of the reaction medium shows a total degradation of the

  trifluoromethanesulfonyl chloride.

  The expected product has not been formed.

  2 / Reaction with diisopropylethylamine: In the same way, the test in the absence of catalyst and in the presence

  of diisopropylethylamine does not lead to the expected product.

  3 / Reaction with 1,4-diazabicyclo [2,2,2] octane or DABCO:

  Again the expected product is not formed.

Claims (29)

  1. A sulfonylation process, characterized in that it comprises a step of bringing a nucleophile, the nucleophilic atom of which is a nitrogen, into contact with a reagent comprising, for successive or simultaneous addition: a heavy halide (that is, i.e. the atomic number of which is at least equal to that of chlorine) of sulfonyl, advantageously suffonyl chloride and: - an organic base comprising a trivalent atom from column V, the doublet of which is conjugated, directly or indirectly, to a bond X connecting two atoms of which at least one is an atom from column V; - and by the fact that the organic part of said sulfonyl is perhalogenated,   advantageously perfluorinated, on the carbon carried by the sulfur.   2. Method according to claim 1, characterized in that the associated acid of said nucleophile has a pKa at most equal to approximately 7,   advantageously 6, preferably 5.   3. Method according to claims 1 and 2, characterized in that said   nitrogen from said nucleophile is linked to an electro-emitter group.   4. Method according to claim 3, characterized in that said electro-emitter group is chosen from aryls advantageously depleted in electron and sulfonyles.   5. Method according to claims 1 to 4, characterized in that said   trivalent atom in column V is a trisubstituted atom.   6. Method according to claims 1 to 5, characterized in that said   trivalent atom in column V is a trisubstituted nitrogen.   7. Method according to claims 1 to 6, characterized in that said   bond x connecting two atoms is the bond X of an imine.   8. Method according to claims 1 to 7, characterized in that said   organic base comprising a trivalent atom from column V (nitrogen column) the doublet of which is directly or indirectly conjugated to a bond a comprises a sequence of formula> N- [C = C] nC = N- with n equal to zero or an integer chosen from the closed interval (that is to say including the limits) 1 to 4, advantageously from 1 to 3, preferably from 1 to 2.   9. Method according to claims 1 to 7, characterized in that said   organic base comprising a trivalent atom from column V (nitrogen column) whose doublet is directly or indirectly conjugated to a bond x comprises a sequence of formula> N- [C (R1) = C (R2)] nC ( R3)   = N- with n equal to zero or an integer chosen in the closed interval (i.e.   say comprising the limits) 1 to 4, advantageously from 1 to 3, preferably from 1 to 2 and o R1, R2 and R3, similar or different, are chosen from hydrocarbon derivatives, advantageously alkyls of   plus 4 carbon atoms and hydrogen.   10. Method according to claims 1 to 9, characterized in that said   trivalent atom of column V is tertiary (forms a tertiary base).   11. Method according to claims 1 to 10, characterized in that said   trivalent atom in column V is a tertiary amine (forms a tertiary amine).   12. Method according to claims 1 to 11, characterized in that said   organic base comprising a trivalent atom from column V (nitrogen column), the doublet of which is directly or indirectly conjugated to an X bond comprises a sequence of formula (R5) (R4) N- [C (Rl) = C ( R2)] nC = N-R6 with n equal to zero or an integer chosen from the closed interval (that is to say including the limits) 1 to 4, advantageously from 1 to 3, preferably from 1 to 2 and o R1, R2 and R6 similar or different, are chosen from hydrocarbon groups, advantageously alkyls of at most 4 carbon atoms and hydrogen and o R4 and R5, similar or different, are chosen from hydrocarbon groups, advantageously alkyls of at most 4 carbon atoms, one or two of the substituents R1, R2, R3, R4, R5 and R6, which can be linked to other substituent (s) remaining to form a or more cycles.   13. Method according to claims 1 to 12, characterized in that said   bond X connecting two atoms is intracyclic.   14. Method according to claims 1 to 13, characterized in that said   bond C connecting two atoms is intracyclic of an aromatic cycle. 15. The method of claim 14, characterized in that said cycle is a pyridine cycle.   16. Method according to claims 1 to 15, characterized in that said   base is chosen from para- or ortho- or di-alkyllaminopyridines and DBU.   17. Method according to claims 1 to 16, characterized in that said   nucleophile is an arylamine in which the substituents, apart from the nucleophilic function, of the nucleus carrying the nucleophilic atom are such that the sum of their Hammett constants cp is at least equal to 0.14, advantageously at 0.20.   18. Method according to claims 1 to 17, characterized in that said   reagent includes, in addition, for successive or simultaneous addition a non-alkyl organic base.   19. The method of claim 18, characterized in that said non-alkylable organic base is chosen from hindered dialkoylphosphines, trialkylphosphines, phosphonium hydroxides, hindered dialkoylamines, trialkylamines, ammonium hydroxides. 20. The method of claim 1 to 19, characterized in that said non-alkylable base is liposoluble and has at least significant benzene solubility (symbol "s" in the RHandbook of Chemistry and Physics "), advantageously (symbol" v in the "Handbook of Chemistry and Physics ") high.   21. Method according to claims 1 to 20, characterized in that said   contacting is carried out in an organic solvent, advantageously not very polar, preferably not very miscible with water (at most 10% by mass, advantageously at most 5% by mass, preferably at most 2% by mass).   22. Method according to claims 1 to 21, characterized in that the   quantity of said non-alkylable and liposoluble base used during the reaction is at least equal to the quantity necessary to neutralize the hydrohalic acid released.   23. Method according to claims 1 to 22, characterized in that the   organic part of said sulfonyl chloride is perfluorinated on carbon carried by sulfur.   24. Method according to claims 1 to 23, characterized in that the   organic part of said sulfonyl chloride is chosen from the radicals of formula (Rf) - (CX2) p-GEA where the similar or different X represent a chlorine, a fluorine or a radical of formula CnF2n + 1 with n integer at most equal to 5, preferably 2, with the condition that at least one of the X is fluorine; o p represents an integer at most equal to 2; o GEA represents an electron-withdrawing group the possible functions of which are inert under the conditions of the reaction, advantageously fluorine or a perfluorinated residue of formula CnF2n + 1, with n integer at most equal to 8, advantageously to 5.   The total number of Rf carbon is advantageously between 1 and 15, preferably between 1 and 10.   25. Reagent useful for implementing the method according to claims 1   to 24, characterized in that it comprises for successive or simultaneous addition: a heavy halide (that is to say the atomic number of which is at least equal to that of chlorine) of sulfonyl, advantageously sulfonyl chloride and : * an organic base comprising a trivalent atom from column V (column of nitrogen) the doublet of which is conjugated directly or indirectly to a bond X connecting two atoms of which at least one is an atom of column V; and by the fact that the organic part of said sulfonyl is perhalogenated,   advantageously perfluorinated on the carbon carried by the sulfur.   26. Reagent according to claim 25, characterized in that it further comprises, for successive or simultaneous addition of a solvent, said solvent, including solvent mixture, being slightly polar and chosen from those having a low solubility in l water, and advantageously does   not having a chlorinated aliphatic chain.   27. Reagent according to claims 25 and 26, characterized in that said   slightly polar solvent is chosen from those whose polarity (Eft expressed in kcal per mol) is at most equal to 40 (advantageously two significant figures).   28. Reagent according to claims 25 to 27, characterized in that said   slightly polar solvent is chosen from oxygenated organic compounds (in particular ethers, esters, even ketones), hydrocarbons (including petroleum fractions), halogenated aromatic hydrocarbons on the nucleus.   29. Reagent according to claims 25 to 28, characterized in that said   slightly polar solvent is chosen from substituted benzenes and   halogenated hydrocarbons on the core.