JP2003525204A - Method for activating aromatic bases by microwave - Google Patents

Abstract

(57) Abstract: The present invention provides an aromatic base represented by the general formula I: Wherein A represents an aromatic residue motif, X represents a substituent that can be exchanged by a SNAr reaction, and R can deactivate the aromatic base at least partially. Represents one or several substituents), the action of microwaves in the presence of at least one nucleophile and at least one cationic phase transfer catalyst which can be exchanged for X in an organic medium. Wherein the nucleophilic substitution of SNAr type is carried out on an aromatic base.

Description

Detailed Description of the Invention

TECHNICAL FIELD The present invention relates to ArNS-type nucleophilic substitutions, particularly nucleophilic substitutions useful for effecting exchanges between fluorine and higher levels of halogens on aromatic substrates. To a new way of doing.

The invention more particularly relates to an aromatic nucleophilic substitution reaction involving the following reaction scheme: Attacking by a nucleophile on an aromatic base at a carbon bearing a leaving group, A bond is created with the base so that it forms an intermediate compound called the Meisenheimer intermediate, and then the leaving group is released.

[0003]   This type of reaction is particularly advantageous for obtaining halogenated aromatic derivatives.

(Prior Art) The leaving group generally adopted is a nitro group, preferably a pseudohalogen, and more preferably a halogen atom.

The term “pseudohalogen” is an oxygen-containing anion upon leaving, the anion charge of which is held by the chalcogen atom and whose acidity, represented by its Hammett constant, is at least equal to that of acetic acid. , At least equal to the secondary acidity of sulfuric acid, and at least equal to the acidity of trifluoroacetic acid are understood to mean those groups which give rise to the preferred ones.

Examples of this type of pseudohalogen include, inter alia, sulfinic acids and sulphonic acids which are perhalogenated on sulfur-bearing carbons and carboxylic acids which are perfluorinated at the α-position of the carboxyl functional group. it can.

[0007]   When the leaving group is a nitro group, the nitro group is NH_FourCl, PCl₅, SOCl _Two , HCl, Cl_TwoOr CCl_FourIs usually replaced with a chlorine atom using
It However, most of these reactants require high temperatures to operate and their
The mechanism does not always turn out to be a nucleophilic substitution. On top of that, the nitro group leaves
In this case, an oxygen-containing nitrogen derivative which is particularly aggressive in the direction of the base is formed.

Application WO 97/41083 proposes a process in which a primary amine present either on an aromatic system or on an amino acid is replaced by a fluorine atom and the reaction is activated by ultrasound or microwave. ing. In fact, the only tests performed using microwaves are on amino acids. Moreover, the reaction of diazonium salts with fluorine cannot necessarily be linked to ArNS-type nucleophilic substitution. This type of reaction is not relevant to the field of invention.

With respect to its variants, which involve the replacement of a halogen atom present on the aromatic ring by another halogen atom, this usually requires deactivation of at least part of the ring. For this reason, the aryl radicals to be converted are preferably electron-reducing, having an electron density at best equal to benzene and an electron density close to at most halobenzene.

This reduction is due to the presence on the aromatic ring of the heteroatom, such as in pyridine or quinoline. In this particular case, the reduction is so great that the displacement reaction is very easy and no special co-activation is required. The electron depletion may also be triggered by electron withdrawing substituents present on the aromatic ring. These substituents were introduced by Wile in 1985, an organic chemistry reference study.
Y.M. J. March "Advanced Organi"
c Chemistry ", 3rd edition, preferably selected from the group of withdrawing by inductive or resonant phenomena. Examples of these electron-withdrawing groups are in particular NO ₂ groups, quaternary ammonium, Rf and especially CF ₃ , CHO, C
N, COY (wherein Y can be a chlorine, bromine or fluorine atom or an alkoyloxy group) can be mentioned.

The halogen-halogen exchange reaction described above actually constitutes the main synthetic route for obtaining aromatic fluorinated derivatives.

Thus, one of the most frequently employed techniques for making fluorinated derivatives was halogenated to replace the halogen with one or more fluorines of inorganic origin. , Usually in the production of chlorinated, aromatic derivatives. Alkali metal fluorides are commonly used, most often alkali metal fluorides having a high atomic weight, such as potassium fluoride, cesium fluoride or rubidium fluoride.

The fluoride used is usually potassium fluoride, which constitutes an economically satisfactory compromise.

Under these circumstances, for example, the French certificate of the application No. 2 353 516 and the paper Chem. Ind. Numerous processes, such as those described in (1978) -56, are aryl fluorides in which an electron-withdrawing group is grafted onto the aryl, or otherwise a naturally occurring electron such as a pyridine ring. Have been proposed and implemented on an industrial scale to obtain aryls with reduced

However, other than the case where the base is particularly suitable for this type of synthesis, there are drawbacks with this technique, the main drawbacks of which are discussed below.

The reaction is slow and requires a considerable investment because of its long residence time. This technique, as already mentioned, is usually used at high temperatures, probably up to around 250 ° C., ie in the region where the most stable organic solvents start to decompose.

The yields remain relatively low unless particularly expensive reactants are used, such as alkali metal fluorides, which have an atomic mass greater than that of potassium.

Finally, because of the cost of these alkali metals, their industrial use is
Other than products with high added value, they cannot be justified, except that the increase in reaction rate and yield makes them reasonable, and such things are rare. is there.

SUMMARY OF THE INVENTION The inventors have unexpectedly been able to significantly activate these aromatic nucleophilic substitutions by subjecting the aromatic base to be converted to microwaves. Proved that.

Thus, the object of the invention is more particularly to activate anionic or neutral, preferably neutral, aromatic bases. This is particularly advantageous because the process activates a cationically charged aromatic base whose at least one resonance formula transfers the cationic charge to the aromatic ring. This is because it is not known to exist.

[0021]     (Disclosure of the invention)   More particularly, the subject of the present invention is the aromatic bases of the general formula I:

[Chemical 4] Wherein A is the residue of a monocyclic aromatic unit or polycyclic aromatic unit, optionally containing one or more heteroatoms, or two or more monocyclic aromatic units. Represents a divalent group consisting of a bond, X is a substituent that can be exchanged by an ArNS reaction and is different from a nitro group or a quaternary ammonium, and R is the same or different. , At least one of them represents one or more capable of at least partially reducing the aromatic base, n represents 0 or an integer in the range of 1 to 4, and p represents Represents an integer in the range 1-3, preferably 1 or 2, where n + p represents an integer which cannot be greater than the number of carbon atoms which can be substituted in the ring symbolized by A. ) In an organic medium Microwave action in the presence of at least one nucleophile and at least one cationic phase transfer catalyst which can be exchanged with a substituent X or at least one of the substituents X. Is a useful method for making ArNS-type nucleophilic substitutions on aromatic substrates.

[0022]     (Specific description of the invention)   When A represents an aromatic heterocycle, n may advantageously be equal to 0.

According to a preferred variant of the invention, the compounds of general formula I satisfy the general formula Ia:

[Chemical 5] Where: m represents an integer equal to 0 or 1 and the symbols X, R, n and p are as defined above.

[0024]   More preferably, the aromatic base satisfies the following general formula Ib:

[Chemical 6] Where X, R, m and n are as defined above.

With respect to the substituent X present on the aromatic cycle, this represents at least one pseudohalogen group or preferably a halogen atom selected from chlorine, bromine and iodine.

The term “pseudohalogen” is an oxygen-containing anion upon leaving, the anion charge of which is held by the chalcogen atom and whose acidity, represented by its Hammett constant, is at least equal to that of acetic acid. , At least equal to the secondary acidity of sulfuric acid, and at least equal to the acidity of trifluoroacetic acid are understood to mean those groups which give rise to the preferred ones.

Examples of pseudohalogens of this type include, inter alia, sulfinic acids and sulphonic acids which are perhalogenated on sulfur-bearing carbons and carboxylic acids which are perfluorinated at the α-position of the carboxyl functional group. it can.

When X represents an iodine atom or a fluorine atom, the nucleophilic substitution reaction is relatively easy, and therefore the process described in the claims is carried out according to the process described in the claims, where X is a chlorine or bromine atom or a pseudo atom. It is even more particularly advantageous when it represents halogen.

With respect to the R groups present on the aromatic ring, these are generally such that they induce electron depletion in the ring, which depletion leads to activation of the base and stabilization of the Meisenheimer complex. Choose to do.

The aromatic base thus substituted has an electron density at best equal to that of benzene, and preferably at most close to that of halobenzene.

This reduction can also be obtained by the presence on the aromatic ring of the heteroatom, such as in pyridine or quinoline. This type of reduction is indicated by the fact that A represents a ring containing 6 carbon atoms and the heteroatom was Bulletin de in January 1966.
la Society Chimeque de France (Bulle
tin of the Chemical Society of Franc
It is important to emphasize that it is only observed when it belongs to column V as defined in the periodic table of elements published in the e) addendum.

At least one R group is preferably an electron-withdrawing and non-leaving substituent, and more preferably different from the carbon-containing substituent.

The presence of hydrocarbon-based substituents, especially those such as aldehyde functionalities, is thus the reason why this type of substituent causes side reactions, such as the Canisaro reaction in the case of aldehydes. Can be contraindicated because it can be

[0034]   Therefore, it is preferred that R be different from the aldehyde functional group.

The substituents R, when they are electron withdrawing, can be selected from halogen atoms and the following groups: NO ₂ SO ₂ Alk and SO ₃ Alk RF, preferably CF ₃ CN COAlk, preferably Ketone functional groups having no hydrogen atom in the alpha position COOH COOAlk Phosphones and phosphonates wherein the symbol Alk represents a linear or branched alkyl group, preferably a C ₁ -C ₄ alkyl group.

As examples of suitable R, mention may be made more particularly of halogen atoms and nitro groups.

More preferably, the electron-withdrawing substituent R is arranged in the ortho and / or para position with respect to the leaving group X.

For nucleophiles intended to substitute at the leaving group X in the aromatic base, this is
It can be generated in situ during the irradiation reaction.

Among the nucleophiles that can be used according to the invention, mention may be made in particular: phosphines, arsines, ammonia; phosphines, arsines, amines bearing at least one hydrogen atom; water; alcohols and alkoxides; at least Hydrazines bearing one hydrogen atom, semicarbazides; salts of weak acids such as carboxylates, thiolates, thiols, carbonates; cyanides; malonic acid derivatives; and imines.

These nucleophiles advantageously carry at least either a negative charge or a hydrogen atom.

Nitrogen-containing nucleophilic derivatives are most particularly advantageous in the context of the claimed process.

Another object of the invention is to carry out an exchange reaction between the fluorine present on the aromatic base and a halogen atom having a higher atomic number, in particular an exchange reaction between fluorine and chlorine. In order to provide a particularly useful activation method for that purpose.

It is also possible to carry out the reverse exchange reaction, ie the halogen is replaced by a higher rank halogen. However, this type of reaction is less advantageous and more difficult to carry out thereon. Nevertheless, it is within the skill of the artisan to utilize the teachings of the present method to carry out other exchange reactions, especially these reverse exchange reactions.

Fluoride is preferably used as the nucleophile in the case of exchange reactions between fluorine and halogen atoms having a higher atomic number.

The fluoride is an alkali metal fluoride whose atomic number is at least equal to the atomic number of sodium, advantageously potassium fluoride or cesium fluoride.

The alkali or alkaline earth metal fluoride is present at least partly in the form of a solid phase.

Also included among the fluorides that can be used are KHF ₂ type complex fluorides. However, it is preferred to use a fluoride bearing hydrogen atoms.

The reaction is usually carried out for conventional reactions, ie below the temperatures used without the use of actinic radiation activation according to the invention.

The reaction is usually carried out in a solvent in which case the reaction is at least 10 ° C., preferably 20 ° C. below the temperature limits normally accepted for the solvent used by actinic activation. Suitably, it is carried out at a temperature preferably 40 ° C. lower.

According to one of the possible, if not preferred, modes of carrying out the invention, microwaves are emitted for a short period (10 seconds to 15 minutes) alternating with cooling steps. The respective durations of the microwave emission time and the cooling time are chosen such that the temperature at the end of each microwave time remains below the defined initial temperature, the defined initial temperature being the components of the reaction mixture. It is usually lower than the temperature intensity of.

It is also possible to carry out the invention according to the method of working in which the reaction mixture is microwaved at the same time as it is being cooled. According to this embodiment, the power generated by the microwaves is then transferred to the energy which is extracted by the cooling system, generated or absorbed by the reaction, for the defined initial temperature, usually the working temperature. The heat is selected within the range of heat.

Moreover, the claimed activation method has the advantage that it is comparable to a continuous process. This method of use makes it possible to successfully avoid the problems of heat exchange that often occur when opening and closing the microwave-generating reactor.

According to this method of operation, the substance to be activated is continuously introduced into the reactor via the inlet, where the substance undergoes microactivation and the activated product is passed via the outlet. Take out continuously from the reactor.

It is also possible to continuously recover the more volatile compounds as they are formed. This recovery may be carried out, for example, by distillation.

In a preferred embodiment of the invention, microwave power of 1 to 1 meq of aromatic base is used.
It is recommended to use 50 watts. Similarly, microwaves have a frequency of 300
It is preferable to use at 3 MHz to 3 GHz, and the frequency to be used is 2.45 GHz.
And the associated wavelengths are close to 12 cm in air and the penetration depth of the electromagnetic field is probably in the range of 2-10 cm depending on the magnitude of the loss.

It is also desirable to comply with the constraints whereby the microwave power is from 2 to 100 Watts per gram of reaction mixture.

This activation is most particularly effective when microwaves are used with the catalysts that are incidentally identified as phase transfer catalysts, especially when the catalyst is a cationic species catalyst.

The best phase transfer catalysts that can be used are usually oniums, ie organic cations whose charge is supported by the metalloid. Among the oniums, mention should be made of ammonium, phosphonium and sulfonium. Preference is given to using ammonium.

These phase transfer catalysts are also particularly represented by heavy alkali metal cations and thus high atomic level alkali metal cations such as cesium and rhodium, or in the presence or absence of such alkali metal cations. , Preferably in the presence of such alkali metal cations.

According to a variant, when the nucleophile is an anion, the cationic transfer catalyst may also serve as a counterion to the anion.

Cesium fluoride is the compound that most particularly exemplifies this variation of the invention. That leads to very satisfying results.

Phase transfer catalysts different from those mentioned above may be used, provided that these phase transfer catalysts are positively charged. From this, they may be cryptand cations, for example crown ethers, cryptand cations. However, the latter is not preferred due to their cost and chemical instability.

During the work leading up to the present invention, the effect of microwaves on onium in the presence of high concentrations of fluoride was shown to be extremely detrimental to the survival of this phase transfer catalyst.

In accordance with the present invention, the presence of anions that are less aggressive than onium, such as chloride, has been shown to help stabilize the anion.

Thus, for example, during the chlorine / fluorine exchange reaction, this reaction releases the chloride anion, so that the progress of the reaction increases the stability of onium.

During the reaction, the anion different from fluoride is present in an amount of more than 1 time, advantageously more than 2 times, preferably more than 3 times the equivalent amount of the labile onium. It is preferable to arrange the arrangement.

As mentioned above, chloride ions are good candidates for reducing onium degradation during the reaction.

According to a preferred embodiment of the present invention, when the phase transfer catalyst is an onium labile in the presence of fluoride, the reaction is carried out in an amount of 1 equivalent to the labile onium.
Carried out in the presence of more than double the amount of chloride.

When the present invention is used to carry out a chlorine / fluorine exchange reaction, it is common to use a dipolar aprotic solvent, a solid phase consisting at least in part of an alkali metal fluoride and a reaction-promoting cation. The cation is an agent for transferring a heavy alkali metal or cationic organic phase.

When an alkali metal cation is used as a promoter, its content is usually more than 0.5%, calculated as the moles of the nucleophile used, of from 1 to 5%. Is preferred, with 2-3% being preferred. These ranges are closed ranges, ie they include their limits.

The reactants may include a phase transfer agent that is onium (organic cation ending in “onium”) as a promoter. Onium is 1 to in terms of moles of the aromatic base.
It usually corresponds to 10%, preferably to 2-5%; it does not matter what the counterion is, but it is usually halogenated.

Among the onium, suitable reactants are carbon atoms 4-28, preferably carbon atoms 4-28.
It is a tetraalkylammonium containing 16. The tetraalkylammonium is usually tetramethylammonium.

Also to be mentioned are phosphoniums, especially phenylphosphoniums, which have the advantage of being stable and relatively not very hygroscopic, but they are relatively expensive.

Halex type aprotic solvents advantageously have a significant dipole efficiency. That is, its relative dielectric constant ε is advantageously equal to at least 10, preferably equal to or less than 100 and equal to or greater than 25.

It has been shown that the best results are obtained when using a dipolar aprotic solvent with a donor index of 10 to 50, the donor index being the antimony pentachloride of the dipolar aprotic solvent. Is the ΔH (change in enthalpy) expressed in kilocalories of the meeting.

Onium, Bulletin de la Societ, January 1966
selected from the group of cations formed by the VB and VIB columns as defined in the Periodic Table of the Elements published in the e Chiquique de France addendum, each having a hydrocarbon chain 4 or 3.

It is generally known that fine particle size has an influence on kinetics. From this it follows that the solids in suspension have a particle size whose d ₉₀ (defined as the size of the sieve through which 90% by weight of the solids passes) of at most 100 μm, preferably at most 50 μm.
m, preferably at most 200 μm. The lower limit is advantageously characterized in that the d ₁₀ of the solid in suspension is at least 0.1 μm, preferably at least 1 μm.

The ratio of the nucleophile, preferably the alkali metal fluoride and the base is usually 1 to 1.5, preferably around 5/4, with respect to the exchange stoichiometry. .

The mass content of solid substances present in the reaction medium is advantageously at least ⅕, advantageously ¼ and preferably ⅓.

It is advantageous to carry out the stirring so that at least 80%, preferably at least 90% of the solids are kept in suspension by stirring.

The following examples are given by way of illustration of the invention and are not intended to limit the invention.

Example 1 Experiments were performed on ortho-nitrochlorobenzene (ONCB). KF and ONCB were pre-weighed into glass bottles. KF (and catalyst if necessary) and then ONCB were introduced into the reactor and a stream of argon was passed through. The reactor wall was then rinsed with sulfolane added using a syringe. After the reactor was closed, the reaction mixture was irradiated with microwaves and, when possible, the irradiation was opened immediately after which the reactor was opened. The cooling rate was increased by using an ice bath. After returning to room temperature, the reaction mixture was entrained with dichloromethane and filtered on sintered glass to separate the solids, which were washed with dichloromethane. Dichloromethane was distilled from the organic phase using a rotavapor. The residual phase was then analyzed by HPLC.

Finally, the reaction mixture was irradiated without catalyst in the following stoichiometry (3
Min / 300 W): ONCB 1 eq; KF 1.13 eq; TMSO ₂ 1.05 eq.

In a second series of experiments irradiation was carried out in the presence of 4 moles Me ₄ NCl 4 in lean or non-lean media.

Microwave irradiation time was increased by adding a 3 min / 300 W sequence and allowed to come to room temperature between each sequence unless otherwise indicated.

[0086]   Table 1 listed below shows the results obtained.   The observed results are as follows: In the absence of catalyst, the selectivity is poor (RT = 10%) (experiment 1).

In the presence of Me ₄ NCl in non-diluted media, on the other hand, the selectivity is better (RT = 75-80%) for the same degree of conversion (experiments 2a and 2b).

Experiments performed in a more dilute medium (having 3-4 equivalents of sulfolane) (Experiment 4
For), multiply the RR and TT by a factor of 1.5-2 for a medium with 1 equivalent of sulfolane. This beneficial effect of dilution is due to the absence of stirring of the reaction mixture. Similarly, it should be noted that RR and TT increase with total irradiation time (experiments 5 and 6). The best results are obtained after irradiation for 15 minutes with 4.2 mol of Me ₄ NCl and 3 equivalents of sulfolane: RR = 45%; TT = 56%; RT = 79%; RR (2-2 ′-( PhNO ₂ ) ₂ O) <1%

[0089]

[Table 1]

Example 2 The reactants were the same as used in Example 1.

The reaction mixture was irradiated without catalyst in the following stoichiometric amount (3 min / 30
0W): ONCB 1 equivalent; KF 1.13 equivalent; TMSO ₂ 1.05 equivalent. For this type of experiment (Experiment A), the temperature recorded when opening the reactor was 15
It was in the range of 0 ° to 160 ° C.

For comparison, thermal activation of the same mixture was carried out at two different temperatures, 170 ° C.
And at 230 ° C.

The results obtained are listed in Table 2 below. The table also shows the results obtained by microwave irradiation carried out in the presence of the catalyst (experiment B).

When present, this catalyst is obtained by conventional heating at 170 ° C. for 5 hours.
It should be noted that a conversion yield of about 79% is obtained in 15 minutes compared to%.

[0095]

[Table 2]

Example 3 Experiment with 2,4-dichloronitrobenzene. The conditions used for ONCB (ortho) were applied to DNCB (dichloronitrobenzene). The results obtained are listed in Table 3 below.

[0097]

[Table 3]

Example 4 Experiment with 2,4-dichloronitrobenzene. The experiment was carried out under similar operating conditions as described in Example 1, but using CsF instead of KF. The working conditions and results are listed in Table 4 below.

[0099]

[Table 4]

It should be noted that with microwave activation, the kinetics are twice as fast as with thermal activation.

─────────────────────────────────────────────────── ─── Continued front page    (81) Designated countries EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, I T, LU, MC, NL, PT, SE), OA (BF, BJ , CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, GM, K E, LS, MW, SD, SL, SZ, TZ, UG, ZW ), EA (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), AE, AG, AL, AM, AT, AU, AZ, BA, BB, BG, BR, BY, CA, CH, C N, CR, CU, CZ, DE, DK, DM, DZ, EE , ES, FI, GB, GD, GE, GH, GM, HR, HU, ID, IL, IN, IS, JP, KE, KG, K P, KR, KZ, LC, LK, LR, LS, LT, LU , LV, MA, MD, MG, MK, MN, MW, MX, NO, NZ, PL, PT, RO, RU, SD, SE, S G, SI, SK, SL, TJ, TM, TR, TT, TZ , UA, UG, US, UZ, VN, YU, ZA, ZW (72) Inventor Natalie Loren             French country F 69540 Irini, Ryu             Dravisina, 31 F term (reference) 4H006 AA02 AC30 BA51 BA95 BB22                       BB23 BE61                 4H039 CA51 CD20

Claims (20)

[Claims] 1. An aromatic base of the following general formula I: ## STR1 ## Wherein A is the residue of a monocyclic aromatic unit or polycyclic aromatic unit, optionally containing one or more heteroatoms, or two or more monocyclic aromatic units. Represents a divalent group consisting of a bond, X is a substituent that can be exchanged by an ArNS reaction and is different from a nitro group or a quaternary ammonium, and R is the same or different. , At least one of them represents one or more capable of at least partially reducing the aromatic base, n represents 0 or an integer in the range of 1 to 4, and p represents Represents an integer in the range 1-3, preferably 1 or 2, where n + p represents an integer which cannot be greater than the number of carbon atoms which can be substituted in the ring symbolized by A. ) In an organic medium Microwave action in the presence of at least one nucleophile and at least one cationic phase transfer catalyst which can be exchanged with a substituent X or at least one of the substituents X. A useful method for making ArNS-type nucleophilic substitutions on aromatic substrates. 2. The aromatic base has the following general formula Ia: A method according to claim 1, characterized in that m represents an integer equal to 0 or 1 and the symbols X, R, p and n are as defined in claim 1. . 3. The base has the following general formula Ib: Wherein X, R, p and n are as defined in claim 1). 4. The method according to claim 1, wherein X represents at least one halogen atom selected from chlorine, bromine and iodine, or a pseudohalogen group. 5. Process according to one of the preceding claims, characterized in that X represents at least one halogen atom, preferably a chlorine atom. 6. Method according to one of the preceding claims, characterized in that at least one R group is an electron-withdrawing and non-leaving substituent, more preferably different from a carbon-containing substituent. . 7. R representing an electron-withdrawing group is a halogen atom or the following radical.
Le:   NO_Two   SO_TwoAlk and SO_ThreeAlk   Rf   CN   COAlk   COOH   COOAlk   Phosphon and phosphonate (Where the symbol Alk is a linear or branched alkyl group, preferably C₁~ C _Four Represents an alkyl group) 7. The method of claim 6, wherein the method is selected from: 8. A process according to claim 6 or 7, characterized in that R represents a chlorine atom and / or a nitro group. 9. The nucleophile is as follows:   Phosphine, arsine, ammonia;   Phosphines, arsines, amines bearing at least one hydrogen atom;   water;   Alcohols and alkoxides;   A hydrazine having at least one hydrogen atom, a semicarbazide;   Salts of weak acids such as carboxylates, thiolates, thiols, carbonates;   Cyanide;   Malonic acid derivatives; and   Imine Method according to one of the preceding claims, characterized in that 10. Method according to one of the preceding claims, characterized in that the nucleophile is a fluoride. 11. The method of claim 10 wherein said fluoride is an alkali metal fluoride whose atomic number is at least equal to that of sodium. 12. The microwave effect is applied to the aromatic base in the presence of a phase transfer catalyst selected from onium type compounds, cesium or rubidium cations and mixtures thereof. The method described in one of the above. 13. The phase transfer catalyst is onium.
the method of. 14. When the phase transfer catalyst is an onium which is unstable in the presence of fluoride, the reaction is more than 1 times the equivalent amount of said unstable onium.
14. Process according to claim 12 or 13, characterized in that it is carried out in the presence of anion different from fluoride which is advantageously greater than doubled, preferably greater than tripled. 15. The aromatic base material is subjected to an exchange reaction between fluorine and a halogen atom having a larger atomic number than that of fluorine, preferably a chlorine atom. The method described. 16. The reaction is carried out in a solvent and at least 10 ° C., advantageously 20 ° C. lower, preferably 40 ° C. below the normally accepted limit temperature for the solvent used.
16. Process according to one of claims 1 to 15, characterized in that it is carried out at a temperature lower by ° C. 17. Microwaves are emitted for a short period of time alternating with the cooling step, and the microwave emission time and the cooling period are each timed at a temperature at the end of each microwave time below the temperature initially set. Method according to one of claims 1 to 16, characterized in that it is chosen to be low. 18. The reaction mixture is microwaved at the same time as it is cooled and the power generated by the microwaves, which is about the initial temperature determined, is
17. Method according to one of the claims 1 to 16, characterized in that it is chosen to correspond to the range of energy extracted by the cooling system, heat released or absorbed. 19. The method according to claim 1, wherein the power generated by microwaves is 1 to 50 watts per milliequivalent of aromatic base. 20. The method according to claim 1, wherein the power generated by microwaves is from 2 to 100 watts per gram of reaction mixture.