EP1509502A1 - Procede de formation d une liaison carbone-carbone ou carbone-heteroatome - Google Patents

Procede de formation d une liaison carbone-carbone ou carbone-heteroatome

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Publication number
EP1509502A1
EP1509502A1 EP03756038A EP03756038A EP1509502A1 EP 1509502 A1 EP1509502 A1 EP 1509502A1 EP 03756038 A EP03756038 A EP 03756038A EP 03756038 A EP03756038 A EP 03756038A EP 1509502 A1 EP1509502 A1 EP 1509502A1
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Prior art keywords
group
formula
groups
corresponds
ligand
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German (de)
English (en)
French (fr)
Inventor
Marc Taillefer
Henri-Jean Cristau
Pascal-Philippe Cellier
Jean-Francis Spindler
Armelle Ouali
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Rhodia Chimie SAS
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Rhodia Chimie SAS
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Priority claimed from FR0206717A external-priority patent/FR2840303B1/fr
Application filed by Rhodia Chimie SAS filed Critical Rhodia Chimie SAS
Publication of EP1509502A1 publication Critical patent/EP1509502A1/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • C07D213/64—One oxygen atom attached in position 2 or 6
    • C07D213/643—2-Phenoxypyridines; Derivatives thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/24—Oxygen or sulfur atoms
    • C07D207/26—2-Pyrrolidones
    • C07D207/263—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms
    • C07D207/267—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two 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
    • C07D207/323—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two 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 with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to the ring nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • C07D213/64—One oxygen atom attached in position 2 or 6
    • 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
    • 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
    • C07D233/58—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 with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring nitrogen 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
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D263/18—Oxygen atoms

Definitions

  • the present invention relates to a process for creating a carbon-carbon or carbon-heteroatom bond by reaction of an unsaturated compound carrying a leaving group and a nucleophilic compound.
  • the invention relates in particular to the creation of carbon-nitrogen bond according to a process for the arylation of organic nitrogen derivatives.
  • arylhydrazines which result from the arylation of a nucleophilic compound by creating a carbon-nitrogen bond.
  • a classic method of arylation consists in implementing the Ullmann reaction (Ullmann F. and Kipper H., Ber. Dtsch. Chem. Ges. 1905, 38, 2120-
  • Arylation reactions involve a catalyst and several types of catalysts have been described.
  • Palladium was used by Buchwald et al, in particular to conduct the arylation reaction of indoles (Org. Lett. 2000, 2, 1403-1406), in the presence of a base, in toluene at 80 ° C - 100 ° C. Generally, the yields are satisfactory but the reaction temperature remains high for this type of palladium-based catalyst, however.
  • the objective of the present invention is to provide a method which overcomes the aforementioned drawbacks and which makes it possible to address a very large number of nucleophilic compounds.
  • an arylation reaction is carried out by reacting an aromatic compound carrying a leaving group and a nucleophilic compound.
  • a vinylation or alkynation reaction is carried out by reacting respectively a compound having a double or triple bond in the ⁇ position of a leaving group and a nucleophilic compound.
  • arylation is used with an extensive meaning since it is contemplated the use of an unsaturated compound carrying a leaving group which is either of the unsaturated aliphatic type, either of aromatic carbocyclic or heterocyclic type.
  • nucleophilic compound is meant an organic hydrocarbon compound, both acyclic and cyclic and the characteristic of which is to comprise at least one atom carrying a free doublet which may or may not comprise a charge, and preferably a nitrogen atom. , oxygen, sulfur, phosphorus or carbon.
  • mine function is meant a functional group comprising a nitrogen atom linked by a double bond to a carbon atom.
  • “Other additional nitrogen atom” denotes a nitrogen atom capable of being provided by another imine function and / or by a functional group such as, in particular, amine, amide, urea, nitrile, guanidine, sulfonamide , phosphinamide and / or a nitrogen atom carrying a free doublet included in a saturated, unsaturated or aromatic cycle.
  • the nucleophilic compound comprises at least one atom carrying a free doublet which can be provided by a functional group and / or a carbanion.
  • a functional group comprising said atoms and / or carbanions, mention may be made in particular of the following atoms and groups:
  • NC- C— CN ooc- CN - N C " - N- ⁇ C " N 3 " N (CN) 2 " P (CN) 2 "
  • the nucleophilic compound comprises at least one nitrogen atom carrying a free doublet included in a saturated, unsaturated or aromatic cycle: the cycle generally comprising from 3 to 8 atoms.
  • the counterion is generally a metal cation such as an alkali metal, preferably sodium, lithium, an alkaline earth metal, preferably calcium or the remainder of an organometallic compound such as in particular magnesium or zinc.
  • a first advantage of the process of the invention is to carry out the reaction at moderate temperature.
  • Another advantage is to be able to use a wide range of nucleophilic arylating agents not only aryl iodides but also aryl bromides or chlorides.
  • Another advantage of the process of the invention is to use a catalysis with copper rather than palladium, which is very advantageous from an economic point of view.
  • a catalyst is combined with a ligand whose characteristic is to be polydentate, at least bidentate, tridentate or even tetradentate and to understand the atoms previously defined according to the invention.
  • ligands are illustrated below by formulas which are given by way of examples and without limitation.
  • the ligands comprise at least one imine function.
  • the imine function is not included in a cycle.
  • a first category of ligands suitable for implementing the invention are the hydrazone type ligands and more particularly those of formula:
  • one of the groups R a and Rb may comprise a nitrogen atom or a group comprising a nitrogen atom
  • R a and R independently of one another represent a hydrocarbon group having from 1 to 20 carbon atoms which may be a saturated or unsaturated, linear or branched acyclic aliphatic group; a saturated, unsaturated or aromatic, monocyclic or polycyclic carbocyclic or heterocyclic group; a sequence of the aforementioned groups,
  • R a and R b can be linked so as to constitute with the carbon atoms which carry them a carbocyclic or heterocyclic group having from 3 to 20 atoms, saturated, unsaturated, monocyclic or polycyclic,
  • R c identical or different, represent a hydrogen atom, an alkyl group preferably Ci to C 12 ; an alkenyl or alkynyl group, preferably C 2 to C 12; a C 3 to cycloalkyl group preferably
  • At least one of the groups R a and R b may comprise a nitrogen atom or a group comprising a nitrogen atom and mention may be made of groups such as amino, amido Among the various groups, the NH 2 group is preferred.
  • the different symbols can take more particularly the meaning given below.
  • R a and Rb can represent, independently of one another, an acyclic aliphatic group, saturated or unsaturated, linear or branched. More precisely, R a and R b preferably represent a linear or branched saturated acyclic aliphatic group, preferably in Ci to C ⁇ 2 , and even more preferably in Ci to C 4 .
  • the invention does not exclude the presence of an unsaturation on the hydrocarbon chain such as one or more double bonds which can be conjugated or not.
  • the hydrocarbon chain can optionally be interrupted by a heteroatom (for example, oxygen, sulfur, nitrogen or phosphorus) or by a functional group insofar as the latter does not react and mention may in particular be made of a group such as in particular -CO-.
  • the hydrocarbon chain may optionally carry one or more substituents (for example, halogen, ester, amino or alkyl and / or arylphosphine) insofar as they do not interfere.
  • acyclic, saturated or unsaturated, linear or branched aliphatic group may optionally carry a cyclic substituent.
  • cycle is meant a carbocyclic or heterocyclic, saturated, unsaturated or aromatic cycle.
  • the acyclic aliphatic group can be linked to the ring by a valential bond, a heteroatom or a functional group such as oxy, carbonyl, carboxyl, sulfonyl etc.
  • cyclic substituents it is possible to envisage cycloaliphatic, aromatic or heterocyclic, in particular cycloaliphatic substituents comprising 6 carbon atoms in the ring or benzenic, these cyclic substituents themselves being optionally carriers of any substituent insofar as they do not do not interfere with the reactions involved in the process of the invention.
  • alkyl, alkoxy C 4 There may be mentioned in particular, alkyl, alkoxy C 4.
  • cycloalkylalkyl groups for example, cyclohexylalkyl or arylkyl groups preferably C 7 to C 2 , in particular benzyl or phenylethyl.
  • the groups R a and R b can also represent, independently of one another, a carbocyclic group saturated or comprising 1 or 2 unsaturations in the ring, generally C 3 to C 8 , preferably 6 carbon atoms in the ring; said cycle can be substituted.
  • this type of group mention may be made of cyclohexyl groups optionally substituted in particular by linear or branched alkyl groups, having from 1 to 4 carbon atoms.
  • R a and R b may represent, independently of one another, an aromatic, and in particular benzene, hydrocarbon group corresponding to the general formula (F- [):
  • - Q represents a group selected from a linear or branched alkyl, Ci -C 6 alkoxy linear or branched Ci to Ce, alkylthio group linear or branched to C 6 , a group -N0 2 , a group -CN, a halogen atom, a group CF 3 .
  • the aromatic hydrocarbon group can therefore be substituted.
  • Q illustrates certain types of preferred substituents, but the listing is not limiting.
  • R a and Rb can also represent, independently of one another, a polycyclic aromatic hydrocarbon group with the cycles being able to form between them ortho-condensed, ortho- and pericondense systems. Mention may more particularly be made of a naphthyl group; said cycle can be substituted.
  • R a and R b can also represent, independently of one another, a polycyclic hydrocarbon group constituted by at least 2 saturated and / or unsaturated carbocycles or by at least 2 carbocycles of which only one of them is aromatic and forming between them ortho- or ortho- and pericondenses systems.
  • the cycles are in C 3 to C 8 , preferably in C 6 .
  • R a and R b can also represent, independently of one another, a heterocyclic group, saturated, unsaturated or aromatic, comprising in particular 5 or 6 atoms in the ring including one or two heteroatoms such as nitrogen atoms (unsubstituted by a hydrogen atom), sulfur and oxygen; the carbon atoms of this heterocycle can also be substituted.
  • R a and R can also represent a polycyclic heterocyclic group defined as being either a group consisting of at least two aromatic or non-aromatic heterocycles containing at least one heteroatom in each cycle and forming between them ortho- or ortho- and peri-condensed systems, or either a group consisting of at least one aromatic or non-aromatic hydrocarbon ring and at least one aromatic or non-heterocycle forming between them ortho- or ortho- and peri- condensed; the carbon atoms of said rings possibly being substituted.
  • groups R a and Rb of heterocyclic type mention may be made, among others, of furyl, thienyl, isoxazolyl, furazannyl, isothiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrannyl, phosphino and quinolyl, napthyridinyl, benzopyrannyl groups. , benzofurannyl.
  • the number of substituents present on each cycle depends on the carbon condensation of the cycle and on the presence or not of unsaturation on the cycle. The maximum number of substituents capable of being carried by a cycle is easily determined by a person skilled in the art.
  • R a and Rb can be linked so as to constitute, with the carbon atoms carrying them, a carbocyclic or heterocyclic group having from 3 to 20 atoms, saturated, unsaturated, monocyclic or polycyclic comprising two or three rings: the adjacent rings can be of aromatic nature.
  • the number of atoms in each cycle preferably varies between 3 and 6.
  • R a and Rb preferentially form a cyclohexane type cycle.
  • the radicals R c preferably represent a hydrogen atom or an alkyl group Ci - C 4, an amido group, an amido group substituted by an alkyl group Ci -C 4 .
  • the groups R a and R represents
  • R s representing a hydrogen atom, an alkyl group, preferably C 1 to C 4 alkoxy, or amino or amido substituted or not by preferably C 1 to C 4 alkyl group or a phosphino group substituted by identical groups or different, preferably alkyl to C 4 alkyl or phenyl.
  • R s representing a hydrogen atom, an alkyl group, preferably C 1 to C 4 alkoxy, or amino or amido substituted or not by preferably C 1 to C 4 alkyl group.
  • the bond is advantageously located in the ortho position relative to the nitrogen atom.
  • the hydrazone type ligands preferably chosen in the process of the invention are those which correspond to the formula (lai) or (la 2 ) in which the groups R c , identical or different, represent a hydrogen atom or a methyl group and R a represents one of the following groups of formula (F 0 ) preferably (F 4 ).
  • the preferred ligands of hydrazone type are those which correspond to the formula (lai).
  • the hydrazone type ligands result from the reaction: - of an aldehyde or of a ketone corresponding to the corresponding formulas:
  • R a and Rb have the meaning given in formulas (lai) or (la 2 ).
  • R c in said formula (Mas), R c , identical or different, have the meaning given in the formulas (lai) or (la 2 ).
  • the preferred ligands of hydrazone type used in the process of the invention contain a nitrogen atom provided by the pyridyl group of a residue of pyridylaldehyde. They preferably result from the reaction of a pyridylaldehyde with a hydrazine or an N-substituted or N, N-disubstituted hydrazine preferably by an alkyl group having from 1 to 4 carbon atoms.
  • ligands suitable for carrying out the invention are tetradentate ligands:
  • R a and / or R b can represent a hydrogen atom
  • R f and R g identical or different, independently of one another represent a hydrogen atom, a hydrocarbon group having from 1 to 20 carbon atoms which may be an acyclic aliphatic group saturated or unsaturated, linear or branched; a saturated, unsaturated or aromatic, monocyclic or polycyclic carbocyclic or heterocyclic group; a chain of the aforementioned groups;
  • Rf and R g can be linked so as to constitute with the carbon atoms which carry them a carbocyclic or heterocyclic group having from 3 to 20 atoms, saturated, unsaturated or aromatic, monocyclic or polycyclic,
  • An and Ar 2 symbolize, independently of one another, two aromatic cycles, carbocyclic or heterocyclic, substituted or not, condensed or not and if necessary carrying one or more heteroatoms,
  • - w is an integer varying from 0 to 3
  • - x and y respectively identify the two connections established between the skeleton symbolized by ⁇ and the imine groups.
  • the groups R a and R preferably represent one of the groups of formula (F 0 ).
  • R s representing a hydrogen atom, an alkyl group, preferably C 1 to C 4 alkoxy, or amino or amido substituted or not by preferably C 1 to C 4 alkyl group.
  • the preferred tetradentate ligands are those which correspond to the formula (Ibi).
  • R f and R g can take the meaning given for R a and R in the formulas (lai) and (la 2 ).
  • R f is identical to R g .
  • R f and R g can be linked so as to constitute with the carbon atoms which carry them a carbocyclic or heterocyclic group having from 3 to 20 atoms, saturated, unsaturated or aromatic, monocyclic or polycyclic.
  • Rf and R g preferably form a cyclohexane or benzene type ring.
  • R f and R g both represent a phenyl or naphthyl group, - R f and R g are linked together so as to constitute, with the carbon atoms which carry them, a ring such as cyclohexane or benzene.
  • An and Ar 2 together represent an aromatic group which may be a carbocycle having from 6 to 12 carbon atoms or a heterocycle having from 5 to 12 atoms.
  • aromatic means the conventional notion of aromaticity as defined in the literature, including J. March “Advanced Organic Chemistry", 4 th ed., John Wiley & Sons , 1992, pp 40 and following.
  • the aromatic group can be monocyclic or polycyclic.
  • a monocyclic group in the case of a monocyclic group, it can comprise, at the level of its cycle, one or more heteroatoms chosen from nitrogen, phosphorus, sulfur and oxygen atoms. According to a preferred mode, these are nitrogen atoms not substituted by a hydrogen atom.
  • the carbon atoms of the aromatic group can also be substituted.
  • Two vicinal substituents present on the aromatic ring can also form together with the carbon atoms which carry them a hydrocarbon ring, preferably aromatic and comprising, where appropriate, at least one heteroatom.
  • the aromatic group is then a polycyclic group.
  • the tetradentate type ligands preferably chosen in the process of the invention are those which correspond to the formula (Ibi) in which ⁇ represents a valential bond, a urea group or one of the groups (F ⁇ ) and (F 7 ) and R a represents one of the groups of formula (F 0 ) preferably (F 5 ).
  • the invention preferably does not envisage 1, 2-bis- (4-dimethylaminobenzylideneamino) ethane.
  • the ligands corresponding to formulas (Ibi) or (lb 2 ) are known products.
  • R a and Rb have the meaning given in formulas (lai) or (la 2 ).
  • ⁇ has the meaning given in the formulas (Ibi) or (lb 2 ) and symbolizes a valential bond, a urea group or a skeleton of general formula (F 2 ) or (F 3 ).
  • the preferred ligands of tetradentate type used in the process of the invention contain a nitrogen atom provided by the pyridyl group of a pyridylaldehyde residue. They preferably result from the reaction of a pyridylaldehyde with urea, 1, 2-cyclohexanediamine, 1, 2-diphenylethylenediamine.
  • Another category of ligands suitable for implementing the invention are the bidentate ligands of formula:
  • R c , Rd identical or different, represent:. a hydrogen atom
  • the preferred groups R a represent one of the following groups one of the groups of formula (F 0 ).
  • those which are preferred are one of the groups of formula (F 0 ).
  • R s representing a hydrogen atom, an alkyl group, preferably C1 to C alkoxy, or amino substituted or not by preferably C1 to C alkyl group.
  • ⁇ represents a valential bond, a methylene or ethylene group, a divalent cyclic group such as:
  • the bidental type ligands preferably chosen in the process of the invention are those which correspond to the formula (here) in which ⁇ represents a valential bond, a methylene or ethylene group, one of the groups (F 9 ) and R a represents one of the groups of formula (F 8 ).
  • the ligands of formula (Here) result from the reaction:
  • R a has the meaning given in the formula
  • the preferred ligands of formula (Here) used in the process of the invention contain two nitrogen atoms provided by two imine functions. They preferably result from the reaction of a carbonyl ⁇ or ⁇ compound, for example glyoxal with an amine, preferably cyclohexylamine.
  • ligands suitable for implementing the invention are tridentate ligands:
  • R a and / or Rb can represent a hydrogen atom
  • Rc identical or different, have the meaning given in the formulas (lai) and (la 2 ); at most one of the groups R c represents a hydrogen atom,
  • R a and Rb preferentially represent one of the groups of formula one of the groups of formula (F 0 ).
  • R s representing a hydrogen atom, an alkyl group, preferably C 1 to C 4 alkoxy, or amino substituted or not by preferably C 1 to C alkyl group.
  • the group ⁇ is preferably a methylene or ethylene group.
  • the groups R c identical or different, preferably represent an alkyl group having from 1 to 4 carbon atoms, preferably a methyl group
  • the preferred ligands of the tridentate type are those which correspond to the formula
  • the ligands of the tridentate type preferably chosen in the process of the invention are those which correspond to the formula (Idi) in which the groups R c , identical or different, represent an alkyl group having from 1 to 4 carbon atoms, preferably a methyl group and R a represents one of the following groups of formula (F ⁇ 0 ) and the group ⁇ , a methylene or ethylene group.
  • the tridentate ligands result from the reaction: - of an aldehyde or of correspondents:
  • R a and R have the meaning given in formulas (lai) or (la 2 ).
  • R c in said formula (lld 3 ), R c , identical or different, have the meaning given in the formulas (lai) or (la 2 ); at most one of the groups R c represents a hydrogen atom.
  • the preferred ligands of tridentate type used in the process of the invention contain a nitrogen atom provided by the pyridyl group of a residue of pyridylaldehyde. They preferably result from the reaction of a pyridylaldehyde with an N-substituted or N, N-disubstituted diamine preferably by an alkyl group having from 1 to 4 carbon atoms.
  • DAPAE the following ligand
  • a nitrogen type ligand is used.
  • the ligands advantageously do not include as chelating atoms an oxygen atom or a group comprising an oxygen atom.
  • the presence of an oxygen atom is possible in a functional group without a chelating function.
  • Chxn-Py-AI Chxn-Py-AI
  • Carbo-Py-AI Py-semizone
  • Chxn-Thio-AI Chxn-Thio-AI
  • DAPAE DAPAE
  • ligands which are used in the process of the invention can be used in an optically pure form or else in the form of a racemic mixture.
  • the ligands involved in the process of the invention are known products.
  • the ratio between the number of moles of ligand and the number of moles of copper varies between 20 and 0.9, preferably between 2 and 1.
  • the ligand can be introduced concomitantly with the compound providing the catalytic metallic element.
  • the invention also includes the case where a metal complex is prepared beforehand by reaction of the compound providing the copper and of the ligand, then isolated.
  • This complex can be prepared extemporaneously, or in situ before or during the reaction, by separately adding the ligand and the compound providing the copper at the start of the reaction.
  • Another object of the invention resides in copper complexes and its optically active forms obtained from a tetradentate ligand. More specifically, the complex meets the formula:
  • - X represents a halogen atom
  • - U represents a ligand corresponding to the formula (Ibi) or (lb 2 ) in which
  • R represents a hydrogen atom or a methyl group and R a represents a pyridyl group of formula:
  • R s has the meaning given in the formulas (F 0 ).
  • the preferred complexes correspond to formula (C) in which: - U represents a ligand corresponding to the formula (Ibi) in which ( ⁇ ) represents a urea group or one of the groups (F 6 ) and (F 7 ) and R a represents a pyridyl group as previously defined in which R s has the meaning given in the formulas (F 5 ),
  • - X represents a chlorine, bromine or iodine atom.
  • the invention relates more particularly to the following complex:
  • the complexes of formula (C), preferably are obtained by bringing the ligand generally dissolved in an adequate solvent, for example of the ether type, preferably ethyl ether and copper halide, also dissolved in an organic solvent , for example acetonitrile or any other solvent suitable for dissolving it.
  • an adequate solvent for example of the ether type, preferably ethyl ether and copper halide
  • an organic solvent for example acetonitrile or any other solvent suitable for dissolving it.
  • the precipitating complex is separated according to conventional techniques of solid / liquid separation, for example, by filtration.
  • reaction of this liganded metal complex also makes it possible to catalyze the reactions according to the invention and more particularly the arylation reaction.
  • the process of the invention concerns a large number of nucleophilic compounds and examples are given below, by way of illustration and without any limiting character.
  • a first category of substrates to which the process of the invention applies are nitrogenous organic derivatives and more particularly, primary or secondary amines; hydrazine or hydrazone derivatives; amides; sulfonamides; urea derivatives, heterocyclic derivatives preferably nitrogen and / or sulfur.
  • the primary or secondary amines can be represented by a general formula: R ⁇ R 2 NH (llla) in said formula (llla):
  • R ⁇ R 2 identical or different, represent a hydrogen atom or have the meaning given for R a and Rb in the formulas (lai) and (la 2 ), - At most one of Ri and R 2 represents a hydrogen atom.
  • the amines preferably used correspond to the formula (IIIa) in which Ri, R 2 , identical or different, represent an alkyl group of Ci to C ⁇ 5 , preferably of Ci to C 1 0, a cycloalkyl group of C 3 to C 8 , preferably C 5 or C 6 , an aryl or arylalkyl group from C 6 to C ⁇ 2 .
  • groups R 1 and R 2 mention may be made of C 1 to C 4 alkyl, phenyl, naphthyl or benzyl groups.
  • amines corresponding to the formula (IIIa) there may be mentioned aniline, N-methylaniline, diphenylamine, benzylamine, dibenzylamine.
  • the amino group can be in the form of anions.
  • the counterion is then a metal cation, preferably an alkali metal cation and more preferably soduim or potassium.
  • a metal cation preferably an alkali metal cation and more preferably soduim or potassium.
  • alkali metal cation preferably an alkali metal cation and more preferably soduim or potassium.
  • soduim or potassium mention may be made of sodium or potassium amide.
  • Other nucleophilic compounds capable of being used in the process of the invention are the hydrazine derivatives corresponding to the different formulas (IIIb), (IIIc) or (IIId):
  • the groups R 3 , R 4 , R 5 , R ⁇ represent more particularly an alkyl group of Ci to C ⁇ 5 , preferably of Ci to C ⁇ 0 , a cycloalkyl group of C 3 to C 8 , preferably of C 5 or C 6 , an aryl or arylalkyl group from C 6 to C ⁇ 2 .
  • R 3 preferably represents a tert-butyl group, R 4 a methyl or phenyl group and R 5 , R ⁇ . a phenyl group.
  • the invention also relates to the amide type compounds corresponding more particularly to the formula (IIe):
  • R 7 - NH - CO - R 8 (llle) in said formula (llle), R 7 and R 8 have the meaning given for Ri and R 2 in formula (llla).
  • compounds of formula (IIe) there may be mentioned: oxazolidine-2-one, benzamide, acetamide.
  • the invention also applies to compounds of the sulfonamide type. They can answer the following formula: R 9 - S0 2 - NH - R ⁇ o (lllf) in said formula (lllf), R 9 and Rio have the meaning given for Ri and R 2 in formula (llla).
  • urea derivatives such as guanidines and which can be represented by the formula (IIIg):
  • Nucleophilic subtrates quite well suited to the implementation of the method of the invention are heterocyclic derivatives comprising at least one nucleophilic atom such as a nitrogen, sulfur or phosphorus atom. More precisely, they correspond to the general formula (lllh):
  • the invention applies in particular to monocyclic heterocyclic compounds corresponding to the formula (IIIh) in which A symbolizes a heterocycle, saturated or unsaturated, or aromatic comprising in particular 5 or 6 atoms in the cycle which may include 1 or 3 heteroatoms such as nitrogen, sulfur and oxygen atoms and at least one of which is a nucleophilic atom such as NH or S.
  • A may also represent a polycyclic heterocyclic compound defined as consisting of at least 2 aromatic or non-aromatic heterocycles containing at least one heteroatom in each cycle and forming between them ortho- or ortho- and per-condensed systems or either a group constituted by at at least one aromatic or non-aromatic carbocycle and at least one aromatic or non-aromatic heterocycle forming between them ortho- or ortho- and peri-condensed systems.
  • Carbocycle preferably means a ring of cycloaliphatic or aromatic type having from 3 to 8 carbon atoms, preferably 6.
  • carbon atoms of the heterocycle can optionally be substituted, in their entirety or for a part of them only by R ⁇ 2 groups.
  • the number of substituents present on the cycle depends on the number of atoms in the cycle and on the presence or not of unsaturations on the cycle.
  • n is a number less than or equal to 4, preferably equal to 0 or 1.
  • the group or groups R ⁇ 2 which may be identical or different, preferably represent one of the following groups:
  • a linear or branched alkyl group of C 1 to C 6 preferably of C 1 to C 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl,
  • a linear or branched alkenyl or alkynyl group of C 2 to C 6 preferably of C 2 to C 4 , such as vinyl, allyl,
  • a linear or branched alkoxy or thioether group from C 1 to C 6 , preferably from C 1 to C 4 such as methoxy, ethoxy, propoxy, isopropoxy, butoxy groups, an alkenyloxy group, preferably an allyloxy group or a phenoxy group ,. a cyclohexyl, phenyl or benzyl group,
  • a group or function such as: hydroxyl, thiol, carboxylic, ester, amide, formyl, acyl, aroyl, amide, urea, isocyanate, thioisocyanate, nitrile, azide, nitro, sulfone, sulfonic, halogen, pseudohalogen, trifluoromethyl.
  • the present invention applies very particularly to the compounds corresponding to the formula (IIIll) in which the group or groups R ⁇ 2 more particularly represent an alkyl or alkoxy group.
  • the optionally substituted residue A represents one of the following cycles: a monocyclic heterocycle comprising one or more heteroatoms:
  • heterocyclic compounds it is preferred to use those which correspond to the formula (IIIh) in which A represents a ring such as: imidazole, pyrazole, triazole, pyrazine, oxadiazole, oxazole, tetrazole, indole, pyrole, phthalazine, pyridazine, oxazolidine.
  • nucleophilic compounds capable of also being used in the process of the invention, mention may also be made of compounds of alcohol type or of thiol type which can be represented by the following formula: in said formula (llli):
  • R ⁇ 3 represents a hydrocarbon group having from 1 to 20 atoms and has the meaning given for Ri or R 2 in the formula (IIIa),
  • - Z represents a group of OMi or SMi type in which Mi represents a hydrogen atom or a metal cation, preferably an alkali metal cation.
  • R ⁇ 3 represents a hydrocarbon group having from 1 to 20 carbon atoms which may be a saturated or unsaturated, linear or branched acyclic aliphatic group; a saturated, unsaturated or aromatic, monocyclic or polycyclic carbocyclic or heterocyclic group; a chain of the aforementioned groups.
  • R ⁇ 3 preferably represents a linear or branched saturated acyclic aliphatic group preferably having from 1 to 12 carbon atoms, and even more preferably from 1 to 4 carbon atoms.
  • the invention does not exclude the presence of an unsaturation on the hydrocarbon chain such as one or more double bonds which may or may not be conjugated, or a triple bond.
  • the hydrocarbon chain may be optionally interrupted by a heteroatom, a functional group or may carry one or more substituents.
  • R13 may also represent a carbocyclic group, saturated or unsaturated, preferably having 5 or 6 carbon atoms in the ring; a heterocyclic group, saturated or not, comprising in particular 5 or 6 atoms in the ring including 1 or 2 heteroatoms such as nitrogen, sulfur, oxygen or phosphorus atoms; a carbocyclic or heterocyclic aromatic, monocyclic group, preferably phenyl, pyridyl, furyl, pyrannyl, thiofenyl, thienyl, phospholyl, pyrazolyl, imidazolyl, pyrolyl or polycyclic condensed or not, preferably naphthyl.
  • R ⁇ 3 includes a cycle, it can also be substituted.
  • the nature of the substituent can be arbitrary as long as it does not interfere with the main reaction.
  • the number of substituents is generally at more than 4 per cycle but most often equal to 1 or 2. We can refer to the definition of R ⁇ 2 in the formula (lllh).
  • R ⁇ 3 comprises a chain of aliphatic and / or cyclic, carbocyclic and / or heterocyclic groups.
  • An acyclic aliphatic group can be linked to a ring by a valential bond, a heteroatom or a functional group such as oxy, carbonyl, carboxy, sulfonyl etc.
  • cycloalkylalkyl groups for example cyclohexylalkyl or aralkyl groups having from 7 to 12 carbon atoms, in particular benzyl or phenylethyl, are targeted.
  • the invention also envisages a chain of carbocyclic and / or heterocyclic groups and more particularly a chain of phenyl groups separated by a valential bond or an atom or functional group G such as: oxygen, sulfur, sulfo, sulfonyl, carbonyl, carbonyloxy, imino , carbonylimino, hydrazo, alkylene (C ⁇ -C ⁇ 0 , preferably C ⁇ ) -diimino.
  • G such as: oxygen, sulfur, sulfo, sulfonyl, carbonyl, carbonyloxy, imino , carbonylimino, hydrazo, alkylene (C ⁇ -C ⁇ 0 , preferably C ⁇ ) -diimino.
  • acyclic, saturated or unsaturated, linear or branched aliphatic group may optionally carry a cyclic substituent.
  • cycle is meant a carbocyclic or heterocyclic, saturated, unsaturated or aromatic cycle.
  • - R represents one or more substituents, identical or different
  • - Z represents a group of OMi or SMi type in which Mi represents a hydrogen atom or a metal cation, preferably an alkali metal cation.
  • - n ' is a number less than or equal to 5.
  • Ru substituents reference may be made to those of formula R 12 defined in formula (IIIh).
  • m represents a number equal to 0, 1 or 2 and the symbols R 4 and n 'identical or different having the meaning given above, - a group consisting of a chain of two or more monocyclic aromatic carbocyclic groups corresponding to the formula (F i2 ):
  • - R14 represents a hydrogen atom, a hydroxyl group, a _CHO group, a -N0 2 group, a linear or branched alkyl or alkoxy group having from 1 to 6 carbon atoms, preferably from 1 to 4 carbon atoms , and more preferably methyl, ethyl, methoxy or ethoxy,
  • - w symbolizes a valence bond, an alkylene or alkylidene group having from 1 to 4 carbon atoms or an oxygen atom,
  • - m is equal to 0 or 1
  • - p is 0 or 1.
  • n ′ those in which the remainder B corresponds to the formula (Fn) in which m is equal to 0 and n ′ is equal to 1, such as hydroquinone, pyrocatechin, resorcinol, alkylphenols, alkylthiophenols, alkoxyphenols, salicylic aldehyde, p-hydroxybenzaldehyde, methyl salicylate, methyl ester of p-hydroxybenzoic acid, chlorophenols, nitrophenols, p-acetamidophenol,
  • nucleophilic compounds which can be used in the process of the invention are hydrocarbon derivatives comprising a nucleophilic carbon.
  • Mention may more particularly be made of anions of the malonate type comprising a group - OOC - HC - COO -.
  • R 15 and Ris' identical or different, represent an alkyl group having from 1 to 12 atoms in the alkyl group, preferably from 1 to 4 atoms, - R 1 5 "represents:
  • a cycloalkyl group having 5 or 6 carbon atoms .
  • a cycloalkyl group having 5 or 6 carbon atoms substituted by one or more alkyl radicals having 1 to 4 carbon atoms, alkoxy having 1 or 4 carbon atoms,.
  • a phenylalkyl group the aliphatic part of which contains from 1 to 6 carbon atoms.
  • R ⁇ 6 is of any kind and has the meaning given for Ri and also represents a metal cation, preferably an alkaline cation, and even more preferably lithium, sodium or potassium.
  • a metal cation preferably an alkaline cation, and even more preferably lithium, sodium or potassium.
  • R ⁇ 6 one can refer in particular to the meanings of Ri.
  • nitriles mention may be made of acetonitrile, cyanobenzene optionally carrying one or more substituents on the benzene ring or ethanolic cyanhydrin CH 3 CH (OH) CN.
  • the acetylenide type compounds are also capable of being used in the process of the invention.
  • R17 is of any kind and the counterion is a metal cation preferably a sodium or potassium atom.
  • the counterion is a metal cation preferably a sodium or potassium atom.
  • nucleophilic compounds which can be used in the process of the invention, mention may be made of compounds of the profene type and derivatives which can be represented by the following formula:
  • Rig represents an alkyl group having from 1 to 12 atoms in the alkyl group. preferably from 1 to 4 atoms.
  • the preferred compounds are those which correspond to the formula (II In) in which Ris represents an alkyl group having from 1 to 12 carbon atoms, a cycloalkyl group having 5 or 6 carbon atoms and an aryl group having 6 or 12 carbon atoms. carbon, or a nitrogen heterocycle having 5 or 6 atoms.
  • nucleophiles capable of being used in the process of the invention are amino acids and their derivatives:
  • R AA represents the remainder of an amino acid, preferably a hydrogen atom, a linear or branched alkyl group Ci to C 2 optionally carrying a functional group, an aryl or arylalkyl group C 6 to C ⁇ 2 or a functional group, preferably a hydroxyl group,
  • R h represents a hydrogen atom, a metal cation, preferably an alkali metal cation or a hydrocarbon group having from 1 to 12 carbon atoms, preferably a Ci to C ⁇ 2 alkyl group.
  • RA A represents an alkyl group capable of carrying a functional group and mention may be made, inter alia, of an —OH group,
  • amino acids examples include glycine, cysteine, aspartic acid, glutamic acid, histidine. Mention may also be made, as nucleophilic compounds, of those comprising a carbanion and the counterion of which is a metal and corresponding to the following formulas: in which :
  • R 22 'and R 22 represent a hydrogen atom or a group such as R 22 ,
  • R 22 , R 22 'and R 22 - can be linked together to form a saturated, unsaturated or aromatic carbocycle or heterocycle preferably having 5 or 6 carbon atoms,
  • - M 2 represents a metallic element from group (IA) of the periodic table
  • - M 3 represents a metallic element from groups (IIA), (IIB) of the periodic table,
  • - Xi represents a chlorine or bromine atom
  • the groups R 22 , R 22 > and R 22 - are advantageously a CC 4 alkyl group, a cyclohexyl or phenyl group; or said groups can form a benzene, cyclopentadienic, pyridine or thiofenic ring.
  • nucleophilic compounds of any other nature mention may also be made of phosphorus or phosphorus and nitrogen compounds and more particularly those corresponding to the following formulas:
  • an alkyl group having from 1 to 12 carbon atoms a cycloalkyl group having 5 or 6 carbon atoms,. a cycloalkyl group having 5 or 6 carbon atoms, substituted by one or more alkyl radicals having 1 to 4 carbon atoms, alkoxy having 1 or 4 carbon atoms,
  • a phenylalkyl group the aliphatic part of which contains from 1 to 6 carbon atoms,. a phenyl group,
  • a phenyl group substituted by one or more alkyl radicals having 1 to 4 carbon atoms or alkoxy having 1 to 4 carbon atoms or by one or more halogen atoms.
  • phosphorus compounds mention may in particular be made of tricyclohexylphosphine, trimethylphosphine, triethylphosphine, tri-n-butylphosphine, triisobutylphosphine, tri-fe / ⁇ -butylphosphine, tribenzylphosphine, dicyclohexylphenylphosphine, triphine dimethylphenylphosphine, diethylphenylphosphine, di-ferf-butylphenylphosphine.
  • tricyclohexylphosphine trimethylphosphine
  • triethylphosphine tri-n-butylphosphine
  • triisobutylphosphine tri-fe / ⁇ -butylphosphine
  • tribenzylphosphine dicyclohexylphenylphosphine
  • triphine dimethylphenylphosphine dieth
  • nucleophilic compounds capable of being used, use may be made of boronic acids or derivatives and more particularly those corresponding to the following formula:
  • R 5 represents a carbocyclic or heterocyclic, aromatic, monocyclic or polycyclic group
  • Qi, Q 2 identical or different, represent a hydrogen atom, a saturated or unsaturated, linear or branched aliphatic group, having from 1 to 20 carbon atoms or an R 25 group
  • boronic acid corresponds to the formula (III) in which the group R 25 represents an aromatic carbocyclic or heterocyclic group.
  • R 2 can take the meanings given above for B in the formula (IIIh).
  • R 25 more particularly represents a carbocyclic group such as a phenyl, naphthyl group or a heterocyclic group such as a pyrrolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, 1, 3-thiazolyl, 1, 3,4-thiadiazolyl group. or thienyl.
  • the aromatic cycle can also be substituted.
  • the number of substituents is generally at most 4 per cycle but most often equal to 1 or 2. Reference may be made to the definition of R ⁇ 2 of the formula (IIIh) for examples of substituents.
  • Preferred substituents are alkyl or alkoxy groups having 1 to 4 carbon atoms, an amino group, a nitro group, a cyano group, a halogen atom or a trifluoromethyl group.
  • Q, Q 2 identical or different, they more particularly represent a hydrogen atom or an acyclic aliphatic group, linear or branched, having from 1 to 20 carbon atoms, saturated or comprising one or more unsaturations on the chain, preferably 1 to 3 unsaturations which are preferably single or conjugated double bonds.
  • QL Q 2 preferably represent an alkyl group having from 1 to 10 carbon atoms, preferably from 1 to 4 or an alkenyl group having from 2 to 10 carbon atoms, preferably a vinyl or 1-methylvinyl group, Q, Q 2 can take the meanings given for R 25 and in particular any cycle can also carry a substituent as described above.
  • R 5 preferably represents a phenyl group. It will not depart from the scope of the present invention to use derivatives of boronic acids such as anhydrides and esters and more particularly alkyl esters having from 1 to 4 carbon atoms.
  • arylboronic acids there may be mentioned in particular: benzeneboronic acid, 2-thiopheneboronic acid, 3-thiopheneboronic acid, 4-methylbenzeneboronic acid, 3-methylthiophene-2-boronic acid, l 3-aminobenzeneboronic acid, 3-aminobenzeneboronic hemisulfate acid, 3-fluorobenzeneboronic acid, acid
  • nucleophilic compounds are given which are in no way limiting and any type of nucleophilic compound can be envisaged.
  • - R 0 represents an aliphatic hydrocarbon group comprising a double bond or a triple bond in position ⁇ of the leaving group or a cyclic hydrocarbon group comprising an unsaturation carrying the leaving group, - R 0 represents a carbocyclic and / or heterocyclic, aromatic, moncyclic group or polycyclic,
  • - Y represents a leaving group, preferably, a halogen atom or a sulphonic ester group of formula - OS0 2 - R e , in which R e is a hydrocarbon group.
  • the compound of formula (IV) will be designated subsequently by "compound carrying a leaving group”.
  • R e is a hydrocarbon group of any kind.
  • Y is a leaving group, it is advantageous from an economic point of view that R e is of a simple nature, and more particularly represents a linear or branched alkyl group having from 1 to 4 carbon atoms, preferably a methyl or ethyl group, but it can also represent, for example, a phenyl or tolyl group or a trifluoromethyl group.
  • the preferred group is a triflate group which corresponds to a group R e representing a trifluoromethyl group.
  • a bromine or chlorine atom is preferably chosen.
  • the compounds of formula (IV) targeted very particularly according to the process of the invention can be classified into three groups: - (1) those of aliphatic type carrying a double bond which can be represented by the formula (IVa):
  • R 27 and R 28 represent a hydrogen atom or a hydrocarbon group having from 1 to 20 carbon atoms which may be a saturated or unsaturated, linear or branched aliphatic group; a saturated, unsaturated carbocyclic or heterocyclic group or aromatic, monocyclic or polycyclic; a chain of aliphatic and / or carbocyclic and / or heterocyclic groups as mentioned above,
  • - Y represents a leaving group as defined above, - (3) those of aromatic type which are designated subsequently by "haloaromatic compound” and which can be represented by the formula (IVc):
  • the invention applies to unsaturated compounds corresponding to formulas (IVa) and (IVb) in which R 26 preferably represents a linear or branched acyclic aliphatic group preferably having from 1 to 12 carbon atoms, saturated
  • R 26 preferably represents a linear or branched acyclic aliphatic group preferably having from 1 to 12 carbon atoms, saturated
  • the invention does not exclude not the presence of another unsaturation on the hydrocarbon chain such as another triple bond or one or more double bonds which can be conjugated or not.
  • the hydrocarbon chain can optionally be interrupted by a heteroatom (for example, oxygen or sulfur) or by a functional group insofar as the latter does not react and mention may in particular be made of a group such as in particular -CO-.
  • a heteroatom for example, oxygen or sulfur
  • a functional group insofar as the latter does not react and mention may in particular be made of a group such as in particular -CO-.
  • the hydrocarbon chain may optionally carry one or more substituents insofar as they do not react under the reaction conditions and there may be mentioned in particular a halogen atom, a nitrile group or a trifluoromethyl group.
  • the acyclic, saturated or unsaturated, linear or branched aliphatic group may optionally carry a cyclic substituent.
  • cycle is meant a carbocyclic or heterocyclic, saturated, unsaturated or aromatic cycle.
  • the acyclic aliphatic group can be linked to the ring by a valential bond, a heteroatom or a functional group such as oxy, carbonyl, carboxy, sulfonyl etc.
  • cyclic substituents it is possible to envisage cycloaliphatic, aromatic or heterocyclic, in particular cycloaliphatic substituents comprising 6 carbon atoms in the ring or benzenic, these cyclic substituents themselves being optionally carriers of any substituent insofar as they do not do not interfere with the reactions involved in the process of the invention. Mention may in particular be made of alkyl or alkoxy groups having from 1 to 4 carbon atoms.
  • aliphatic groups carrying a cyclic substituent more particularly are targeted the aralkyl groups having from 7 to 12 carbon atoms, in particular benzyl or phenylethyl.
  • R 26 may also represent a carbocyclic group, saturated or unsaturated, preferably having 5 or 6 carbon atoms in the ring, preferably cyclohexyl; a heterocyclic group, saturated or unsaturated, comprising in particular 5 or 6 atoms in the ring including 1 or 2 heteroatoms such as nitrogen, sulfur and oxygen atoms; an aromatic carbocylic group, monocyclic, preferably phenyl or polycyclic condensed or not, preferably naphthyl.
  • R 27 and R 28 they preferably represent a hydrogen atom or an alkyl group having from 1 to 12 carbon atoms, a phenyl group or an aralkyl group having from 7 to 12 carbon atoms, preferably a group benzyl.
  • R 26 , R 27 and R 28 more particularly represent a hydrogen atom or R 26 represents a phenyl group and R 27 , R 28 represent a hydrogen atom.
  • the invention is particularly applicable to haloaromatic compounds corresponding to formula (IVc) in which D is the residue of a cyclic compound, preferably having at least 4 atoms in the ring, preferably 5 or 6, optionally substituted , and representing at least one of the following cycles: .
  • an aromatic, monocyclic or polycyclic carbocycle that is to say a compound constituted by at least 2 aromatic carbocycles and forming between them ortho- or ortho- and pericondenses systems or a compound constituted by at least 2 carbocycles of which only one of them is aromatic and forms between them ortho- or ortho- and pericondenses systems.
  • an aromatic, monocyclic heterocycle comprising at least one of the heteroatoms P, O, N and S or a polycyclic aromatic heterocycle, that is to say a compound consisting of at least 2 heterocycles containing at least one heteroatom in each cycle of which at least l one of the two rings is aromatic and forming between them ortho- or ortho- and pericondenses systems or a compound consisting of at least one carbocycle and at least one heterocycle of which at least one of the rings is aromatic and forming between them systems ortho- or ortho- and pericondenses.
  • the optionally substituted residue D preferably represents the remainder of an aromatic carbocycle such as benzene, of an aromatic bicycle comprising two aromatic carbocycles such as naphthalene; a partially aromatic bicycle comprising two carbocycles, one of which is aromatic such as tetrahydro-1, 2,3,4-naphthalene.
  • D can represent the remainder of a heterocycle insofar as it is more electrophilic than the compound corresponding to the formula (IIIh).
  • an aromatic heterocycle such as furan, pyridine
  • an aromatic bicycle comprising an aromatic carbocycle and an aromatic heterocycle benzofuran, benzopyridine
  • a partially aromatic bicycle comprising an aromatic carbocycle and a heterocycle such as methylenedioxybenzene
  • an aromatic bicycle comprising two aromatic heterocycles such as 1, 8-naphthypyridine
  • a partially aromatic bicycle comprising a carbocycle and an aromatic heterocycle such as tetrahydro-5,6,7,8-quinoline
  • haloaromatic compound of formula (IVc) in which D represents an aromatic ring, preferably a benzene or naphthalene ring.
  • the aromatic compound of formula (IVc) can carry one or more substituents.
  • n is a number less than or equal to 4, preferably equal to 1 or 2.
  • R 29 also represents a saturated, unsaturated or aromatic heterocycle, comprising 5 or 6 atoms and comprising as heteroatom, sulfur, oxygen or nitrogen. Mention may in particular be made of pyrazolyl or imidazolyl groups.
  • n is a number less than or equal to 4, preferably equal to 1 or 2.
  • the amount of the compound carrying a leaving group of formula (IV), preferably of formula (IVa) or (IVb) or (IVc), used is generally expressed relative to the amount of the nucleophilic compound close to the stoichiometry .
  • the ratio between the number of moles of the compound carrying the leaving group and the number of moles of the nucleophilic compound generally varies between 0.5 and 1.5, preferably between 0.9 and 1.2, and more preferably around 1.
  • the nucleophilic compound preferably corresponding to the formulas (IIIa) to (IIIII) is reacted with a compound carrying a leaving group corresponding to the formula (IV), preferably of formula (IVa) ) or (IVb) or (IVc) in the presence of an effective amount of a copper-based catalyst and of a ligand as defined according to the invention.
  • catalysts capable of being used mention may be made of copper metal or the organic or inorganic compounds of copper (I) or copper (II).
  • the catalysts used in the process of the invention are known products.
  • catalysts of the invention there may be mentioned in particular as copper compounds, cuprous bromide, cupric bromide, cuprous iodide, cuprous chloride, cupric chloride, basic copper (II) carbonate , cuprous nitrate, cupric nitrate, cuprous sulfate, cupric sulfate, cuprous sulfite, cuprous oxide, cupric oxide, cupric acetate, cupric acetate, cupric trifluoromethylsulfonate, Hydroxide copper, copper methylate (I), copper methylate (II), chloro-copper methylate of formula CICuOCHg.
  • copper or cupric chloride or bromide and cuprous or cupric oxide are chosen.
  • the amount of catalyst used expressed by the molar ratio between the number of moles of copper catalyst expressed as copper and the number of moles of compound of formula (IV) generally varies between 0.001 and 0.2, preferably between 0, 01 and 0.1.
  • the invention does not exclude that the copper is associated with a small amount of another metallic element designated by M.
  • the metallic element M is chosen from group (VIII), (IB) and (MB) of the periodic table.
  • metals M which may be mentioned are silver, palladium, cobalt, nickel, iron and / or zinc.
  • a mixture comprising palladium and copper is used.
  • Palladium can be provided in the form of a finely divided metal or in the form of an inorganic derivative such as an oxide or a hydroxide. It is possible to use a mineral salt preferably, nitrate, sulfate, oxysulfate, halide, oxyhalogenide, silicate, carbonate, or an organic derivative preferably, cyanide, oxalate, acetylacetonate; alcoholate and even more preferably methylate or ethylate; carboxylate and even more preferably acetate. Can also be used complexes, in particular chlorinated or cyanated palladium and / or alkali metals, preferably sodium, potassium or ammonium
  • Examples of compounds which can be used for the preparation of the catalysts of the invention there may be mentioned in particular palladium (II) bromide, palladium (II) chloride, palladium iodide ( II), palladium (II) cyanide, hydrated palladium (II) nitrate, palladium (II) oxide, palladium (II) sulfate dihydrate, palladium (II) acetate, propionate palladium (II), palladium (II) butyrate, palladium (II) benzoate, palladium (II) acetylacetonate, ammonium tetrachloropalladate (ll), potassium hexachloropalladate (IV), palladium (II) tetramine nitrate, palladium (II) dichlorobis (acetonitrile), palladium (II) dichlorobis (benzonitrile), palladium (II) dichloro
  • nickel (II) halides such as nickel (II) chloride, bromide or iodide
  • nickel (II) sulfate nickel (II) carbonate
  • salts of organic acids comprising from 1 to 18 carbon atoms such as in particular acetate, propionate
  • nickel (II) complexes such as nickel (II) acetylacetonate, nickel (II) dibromo-bis- (triphenylphosphine), nickel (II) dibromo-bis (bipyridine); nickel complexes (0) such as bis- (cycloocta-1,5-diene) nickel (0), bis-diphenylphosphinoethane nickel (0).
  • derivatives based on iron or zinc generally in the form of oxide, hydroxides or salts such as halides, preferably chloride, nitrates and sulfates.
  • the amount of the metallic element M represents less than 50%, preferably less than 10% in moles of copper.
  • a catalyst comprising only copper is used.
  • a base which function is to trap the leaving group.
  • the characteristic of the base is that it is a pka at least greater than or equal to 4, preferably between 6 and 30.
  • PKa is defined as the ionic dissociation constant of the acid / base couple, when water is used as a solvent.
  • inorganic bases such as carbonates, hydrogencarbonates or hydroxides of alkali metals, preferably sodium, potassium, cesium or alkaline earth metals, preferably calcium, barium or magnesium. It is also possible to use alkali metal hydrides, preferably sodium hydride or alkali metal alcoholates, preferably sodium or potassium. And more preferably sodium methylate, ethylate or tert-butylate.
  • Organic bases such as tertiary amines are also suitable, and triethylamine, tri-n-propylamine, tri- ⁇ -butylamine, methyldibutylamine, methyldicyclohexylamine, ethyldiisopropylamine, N, N-diethylcyclohexylamine may be mentioned more particularly.
  • pyridine 4-dimethylamino pyridine, N-methylpiperidine, N-ethylpiperidine, -n- butylpiperidine, 1, 2-dimethylpiperidine, N-methylpyrrolidine, 1, 2-dimethylpyrrolidine.
  • the carbonates of alkali metals are preferably chosen.
  • the amount of base used is such that the ratio between the number of moles of base and the number of moles of the aromatic compound carrying the leaving group preferably varies between 1 and 4, preferably around 2.
  • the arylation or vinylation or alkynation reaction carried out according to the invention is most often carried out in the presence of an organic solvent.
  • An organic solvent is used, which does not react under the reaction conditions.
  • solvents used use is preferably made of a polar and preferably aprotic organic solvent.
  • N N-dimethylacetamide
  • DMAC N-dimethylacetamide
  • DMF dimethylformamide
  • NMP 1-methyl-2-pyrrolidinone
  • DMSO dimethyl sulfoxide
  • HMPT hexamethylphosphotriamide
  • nitro compounds such as nitromethane, nitroethane, 1 - nitropropane, 2-nitropropane or their mixtures, nitrobenzene;
  • - alphatic or aromatic nitriles such as acetonitrile, propionitrile, butanenitrile, isobutanenitrile, pentanenitrile, 2-methylglutaronitrile, adiponitrile;
  • organic carbonates such as dimethylcarbonate, diisopropylcarbonate, di-n-butylcarbonate; - alkyl esters such as ethyl or isopropyl acetate.
  • ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone, cyclopentanone, cyclohexanone, - nitrogen heterocycles such as pyridine, picoline and quinolines.
  • the amount of organic solvent to be used is determined according to the nature of the organic solvent chosen. It is determined so that the concentration of the compound carrying the leaving group in the organic solvent is preferably between 5 and 40% by weight.
  • the arylation or vinylation or alkynation reaction of the nucleophilic compound takes place at a temperature which is advantageously between 0 ° C and 120 ° C, preferably between 20 ° C and 100 ° C, and even more preferably between 25 ° C and 80 ° C.
  • the arylation or vinylation or alkynation reaction is generally carried out under atmospheric pressure, but higher pressures of up to, for example, 10 Bar can also be used.
  • the order of implementation of the reagents is not critical.
  • the catalyst is loaded in preference to copper, the ligand, the nucleophilic compound of formula (III), the base, the compound carrying the leaving group of formula (IV) and the organic solvent.
  • the reaction medium is brought to the desired temperature.
  • the progress of the reaction is monitored by following the disappearance of the compound carrying the leaving group.
  • R representing the remainder of the nucleophilic compound, and more particularly an arylated product comprising the remainder of the nucleophilic compound and the remainder of the electrophilic compound which preferably corresponds to the formula ( V) following:
  • the compound obtained is recovered according to the conventional techniques used, in particular by crystallization from an organic solvent.
  • organic solvents there may be mentioned in particular aliphatic or aromatic hydrocarbons, halogenated or not, carboxamides, nitriles. Mention may in particular be made of cyclohexane, toluene, dim ⁇ thyiformamide, acetonitrile. Examples of the invention are given below. These examples are given for information, without limitation.
  • the transformation rate (TT) corresponds to the ratio between the number of transformed substrates and the number of moles of substrate engaged.
  • the yield (RR) corresponds to the ratio between the number of moles of product formed and the number of moles of substrate used.
  • the transformation yield (RT) or selectivity corresponds to the ratio between the number of moles of product formed and the number of moles of substrate transformed.
  • the mixture is diluted with ethyl ether or dichloromethane.
  • the arylated compound obtained is extracted with ethyl ether or dichloromethane then with distilled water and the product obtained is assayed by gas chromatography with respect to 1,3-dimethoxybenzene as internal standard.
  • the ligand is prepared according to the procedure described by Gao, J. -X .; Zhang, H .; Yi, X. -D .; Xu, P. -P .; Tang, C. -L; Wan, H. -L .; Tsai, K. -R .; Ikariya, T .; (Chirality 2000, 12, 383-388).
  • the reaction mixture is stirred for 20 hours at room temperature (the solution turns yellow after three hours of stirring), heated for 2.5 hours at reflux and then filtered through a frit.
  • the isolated solid is washed with dichloromethane.
  • the overall filtrate is concentrated completely under reduced pressure, which makes it possible to isolate an ocher solid, recrystallized from ethanol.
  • the ligand is prepared according to the procedure described by Exner, O .; Kliegman, J. M .; J. Org. Chem. 1971, 36, 2014-2015.
  • reaction mixture is heated for 4 hours at reflux then filtered through a frit (the disappearance of 2-pyridylaldehyde was monitored by gas chromatography).
  • the filtrate is concentrated, which makes it possible to isolate a colorless solid, dried in an oven at 100 ° C. and then recrystallized from methanol.
  • the ligand is prepared according to the procedure described by Exner, O .; Kliegman, J. M .; J. Org. Chem. 1971, 36, 2014-2015.
  • reaction mixture is stirred for 30 minutes at room temperature, heated for 20 hours at reflux and then filtered through a frit.
  • the isolated sodium sulphate is washed with diethyl ether.
  • the overall filtrate is completely concentrated under reduced pressure.
  • the orange oil obtained is subjected to the usual treatment (diethyl ether / water extraction).
  • the crystals thus obtained are washed abundantly with petroleum ether in order to make them colorless.
  • the solution is heated to 50 ° C. and then 5 ml of 2-pyridylaldehyde are quickly added.
  • the mixture is brought to reflux for two hours, cooled to 20 ° C. and filtered through a frit.
  • the isolated solid is washed with dichloromethane.
  • the overall filtrate is concentrated completely under reduced pressure, which makes it possible to isolate a brown solid, recrystallized from ethanol.
  • the reaction mixture is stirred 72 hours at room temperature then filtered through a frit.
  • the isolated solid is washed with dichloromethane.
  • the overall filtrate is concentrated completely under reduced pressure, which makes it possible to isolate a brown oil.
  • the catalysts used are commercial products with the exception of activated Cu (A) and activated Cu (B). A procedure is also given below for the preparation of said catalysts which are then used in the examples.
  • a - Activated Cu prepared by purification of the metallic copper: A few grams of copper powder are triturated for 15 minutes in a solution composed of 2 g of iodine dissolved in 100 ml of acetone. The mixture is filtered on a frit, washed with 150 ml of a solution composed of concentrated hydrochloric acid (75 ml) and acetone (75 ml), with 100 ml of acetonitrile and then with 100 ml of acetone.
  • the copper thus activated is dried in a vacuum desiccator in the presence of P 2 0 5 .
  • the mixture is stirred at room temperature for two hours, then filtered through a frit, which allows a black powder to be isolated, washed with acetonitrile and petroleum ether and then dried in a desiccator under vacuum in the presence of anhydride phosphoric.
  • v (cm "1 ) 2935 and 2858 (f), 2192 (f), 1593 (F), 1471 and 1439 (f), 1384 (FF), 1291, 1223 and 1156 (f) , 771 (FF), 746 (f).
  • Example 1 N-arylation and N-vinylation of azoles. Several procedures are given below, chosen according to the physical form of the nucleophile and of the arylating agent.
  • Operating protocol A case of a solid nucleophile and a liquid arylating agent.
  • the reactor is placed in an oil bath at a temperature of 82 ° C. and stirred for a period varying from one to five days.
  • Operating protocol B case of a solid nucleophilic compound and a solid arylating agent.
  • a Schlenk tube of 35 mL previously dried in an oven at 100 ° C, fitted with a magnetic bar (12 x 4.5 mm) and placed under a nitrogen atmosphere are successively introduced 14.4 mg of cuprous oxide (0.1 mmol), 116.8 mg of Chxn-Py-AI or of another ligand meeting the general definition of the patent (0.4 mmol), 3 mmol of a nucleophilic compound, 2 mmol of arylating agent and 1.303 g of cesium carbonate (4 mmol).
  • the Schlenk tube is purged under vacuum and then refilled with nitrogen.
  • the reactor is placed in an oil bath at a temperature of 82 ° C. and stirred for a period varying from one to five days.
  • Operative protocol C case of a nucleophilic compound and a liquid arylating agent
  • cuprous oxide 0.1 mmol
  • the Schlenk tube is purged under vacuum and then refilled with nitrogen.
  • the Schlenk tube is purged under vacuum and then refilled with nitrogen. 3 mmol of a nucleophilic compound and 1.2 ml of acetonitrile or DMF are then added to it by means of syringes.
  • the reactor is placed in an oil bath at a temperature of 82 ° C. and stirred for a period varying from one to five days. Whatever the operating protocol implemented A, B, C or D, the rest of the treatment is strictly the same Determination of the isolated yield:
  • reaction mixture is diluted with 25 ml of dichloromethane, filtered through celite, completely concentrated under reduced pressure (approximately 20 mm of mercury) then taken up in 50 ml of dichloromethane.
  • This organic phase is extracted with distilled water (2 x 20 mL).
  • the aqueous phase is reextracted with 20 ml of dichloromethane.
  • the overall organic phase is washed with a saturated aqueous solution of sodium chloride (2 x 20 mL), dried over MgSO, filtered and concentrated under reduced pressure.
  • the residue obtained is purified by chromatography on silica gel (35 - 70 ⁇ m).
  • Example 1.6 Preparation of 1 - (o-tolyl) -1 H-pyrazole.
  • Example 1.8 is repeated, replacing 1- (4'-bromophenyl) -1 H-imidazole with 1- (4'-bromophenyl) -1 H-pyrazole (2.4 mmol; 535 mg)
  • the isolated training and performance rates are 100%.
  • the value of the coupling constant 3 JHIH2 proves that the phenyl and pyrazolyl substituents of the ethylenic bond are located in the trans position.
  • the coupling constants 4 JH 3 H S , 3 JH3H4 and 3 JH4H5 could not be calculated, the signals being disturbed by a coupling with the proton H1.
  • - NMR 13 C / CDCI 3 ⁇ 141, 13 (C3), 135.09 (C6), 128.89 (C8 and C10), 128.14 (C1), 127.60 (C9), 126.48 ( C5), 126.26 (C7 and C11), 116.88 (C2), 107.34 (C4).
  • the yellow oil obtained at the end of the treatment was purified by chromatography on silica gel (eluent: dichloromethane / ethyl acetate 100/0 to 50/50).
  • the rate of formation and selectivity to 1-phenyl-1 H-indole is 99.5%.
  • the red oil obtained at the end of the treatment was purified by chromatography on silica gel (eluent: hexane / dichloromethane 100/0 to 50/50).
  • the compound obtained has:
  • Light yellow needles can be obtained after recrystallization from chloroform.
  • Example 1.18 is reproduced by working at 50 ° C (72 hours). The formation rate and the selectivity for 1-phenyl-1 H- [1,2,4] triazole are respectively
  • the rate of formation of 1-phenyl-1 H-pyrrole is 70%.
  • the brown oil obtained at the end of the filtration step was directly purified by chromatography on alumina (eluent: hexane / dichloromethane 100/0 to 50/50).
  • Treatment and analyzes were carried out as quickly as possible and protected from light, due to the risks of decomposition of the compound.
  • the above-mentioned compound is obtained according to a process for the arylation of 3-trifluoromethyl-5- (p-tolyl) -1 H-pyrazole with iodobenzene.
  • Example 1.24 the abovementioned compound is obtained according to a process for the arylation of 5- (3-chlorosulfonyl-4-methyl-phenyl) -3-trifluoromethyl-1 H-pyrazole by iodobenzene.
  • the Schlenk tube is purged under vacuum and then refilled with nitrogen.
  • the reactor is placed in an oil bath at a temperature of 50 ° C. and stirred for a period of 24 hours.
  • the residue obtained is directly purified by chromatography on a silica column (eluent: dichloromethane / hexane 70/30).
  • the residue obtained is purified by chromatography on silica gel (35 - 70 ⁇ m).
  • the Schlenk tube is purged under vacuum and then refilled with nitrogen. 224 ⁇ L of iodobenzene (2 mmol), then 1.2 ml of DMF are then added using syringes.
  • the reactor is placed in an oil bath at a temperature of 82 ° C. and stirred for a period of 24 hours.
  • the 3-phenyloxazolidin-2-one formation rate is then 99.7% and the selectivity reaches 100%.
  • reaction mixture is diluted with 25 ml of dichloromethane, filtered through celite, completely concentrated under reduced pressure and then taken up in 50 ml of dichloromethane.
  • This organic phase is extracted with distilled water (2 x 20 mL).
  • the aqueous phase is reextracted with 20 ml of dichloromethane.
  • the overall organic phase is washed with a saturated aqueous solution of sodium chloride (2 x 20 mL), dried over MgSO, filtered and concentrated under reduced pressure.
  • Example 2.1 Preparation of 3-phenyloxazolidin-2-one.
  • Example 2.1 is repeated by heating 96 h at 50 ° C.
  • the 3-phenyloxazolidin-2-one formation rate is then 99.6% and the selectivity reaches 100%.
  • the 1-phenyl-1 H-pyridin-2-one formation rate is 98%.
  • the residue obtained was purified by chromatography on silica gel (eluent: hexane / dichloromethane / ethyl acetate 100/0/0 to 0/100/0 then 0/100/0 to 0/80/20).
  • Example 2.1 is repeated, replacing the oxazolidin-2-one with 363 mg of benzamide (3 mmol) and bringing the reaction time to 48 h.
  • the N-phenylbenzamide formation rate is 96% and the selectivity reaches 100%.
  • Example 2.1 is repeated, replacing Poxazolidin-2-one with 152 ⁇ L of pyrrolidin-2-one (2 mmol) and working with 336 ⁇ L of iodobenzene (3 mmol), the latter being added at the same time as pyrrolidin. -2-one.
  • the reaction time is increased to 40 h.
  • the compound can also be isolated by recrystallization from ethanol of the residue obtained at the end of the solvent extraction steps, rather than by chromatography on silica gel.
  • Example 2.1 is reproduced using 14.4 mg of cuprous oxide (0.1 mmol), 117 mg of Chxn-Py-Al (0.4 mmol), 472 mg of benzenesulfonamide (3 mmol), 224 ⁇ L d 'iodobenzene (2 mmol), 1.04 g of cesium carbonate (3.2 mmol), 600 mg of crushed and activated 3 ⁇ molecular sieve and 1.6 ml of DMF.
  • reaction time is brought to 48 h.
  • the N-phenylbenzenesulfonamide formation rate is then 95%.
  • reaction mixture was diluted with 25 ml of dichloromethane / methanol before being filtered through celite.
  • reaction mixture is diluted with 25 ml of dichloromethane, filtered through celite, completely concentrated under reduced pressure and then taken up in 50 ml of dichloromethane.
  • This organic phase is extracted with distilled water (2 x 20 mL).
  • the aqueous phase is reextracted with 20 ml of dichloromethane.
  • the overall organic phase is washed with a saturated aqueous sodium chloride solution (2 x 20 mL), dried over MgSO 4 , filtered and concentrated under reduced pressure.
  • the residue obtained is purified by chromatography on silica gel (35 - 70 ⁇ m).
  • the formation rate and the selectivity for diphenyl ether are 100%.
  • reaction mixture is diluted with 25 ml of dichloromethane, filtered through celite, completely concentrated under reduced pressure and then taken up in 50 ml of dichloromethane.
  • the aqueous phase is reextracted with 20 ml of dichloromethane.
  • the oily residue obtained at the end of the treatment was purified by chromatography on silica gel (eluent: hexane).
  • Example 3.2 Preparation of 4-methoxyphenyl ether and phenyl ether.
  • Example 3.1 is repeated, replacing the phenol with 248 mg of 4-methoxyphenol (2 mmol), and heating for 28 h at 82 ° C.
  • the rate of formation and the selectivity in ether of 4-methoxyphenyl and phenyl are 100%.
  • the orange oil obtained at the end of the treatment was purified by chromatography on silica gel (eluent: hexane / dichloromethane 100/0 to 95/5).
  • Example 3.1 is repeated, replacing the phenol with 300 mg of 4-f-butylphenol (2 mmol).
  • the 4-f-butylphenyl and phenyl ether formation rate and selectivity are 100%.
  • the oily residue obtained at the end of the treatment was purified by chromatography on silica gel (eluent: hexane).
  • Example 3.1 is repeated, replacing the phenol with 244 mg of 3,5-dimethylphenol (2 mmol).
  • the 4-f-butylphenyl and phenyl ether formation rate and selectivity are 100%.
  • the brown oil obtained at the end of the treatment was purified by chromatography on silica gel (eluent: hexane).
  • Example 3.3 is reproduced by replacing the iodobenzene with bromobenzene (316 ⁇ L, 3 mmol), the acetonitrile with DMF, and by heating for 24 h at 110 ° C.
  • the rate of formation of 3,5-dimethylphenyl ether is 70%.
  • the formation rate of 3,5-dimethylphenyl ether is 100% after 72 h of heating under these conditions.
  • Example 3.1 is repeated, replacing the phenol with 244 mg of 3,5-dimethylphenol (2 mmol) and the iodobenzene with 294 ⁇ L of 4-iodotrifluoromethylbenzene (2.6 mmol).
  • Example 3.7 Preparation of 3,5-dimethylphenyl ether of 2-methylphenyl ether
  • Example 3.1 is reproduced by replacing the phenol with 244 mg of 3,5-dimethylphenol (2 mmol), the iodobenzene with 383 ⁇ L of 2-iodotoluene (3 mmol), and increasing the reaction time to 118 hours.
  • the oily residue obtained at the end of the treatment was purified by chromatography on silica gel (eluent: hexane).
  • Example 3.1 is repeated, replacing the phenol with 244 mg of 3,5-dimethylphenol (2 mmol), the iodobenzene with 595 mg of 4-iodobenzonitrile (2.6 mmol), the latter being added at the same time as 3 , 5-dimethylphenol.
  • Example 3.1 is repeated, replacing phenol with 206 ⁇ L of ocresol (2 mmol), iodobenzene with 383 ⁇ L of 2-iodotoluene (3 mmol), acetonitrile with DMF, the nucleophilic compound and the agent. arylation being added at the same time as the solvent.
  • the reaction time is brought to 35 h and the temperature to 110 ° C.
  • the oily residue obtained at the end of the treatment was purified by chromatography on silica gel (eluent: hexane).
  • the reaction time is increased to 40 h.
  • the formation rate and the selectivity for phenyl ether and 2-methylphenyl ether are 100%.
  • the oily residue obtained at the end of the treatment was purified by chromatography on silica gel (eluent: hexane).
  • the oil obtained at the end of the filtration step was dried for two hours in an oven at 100 ° C. in order to evaporate the 2-pyridylaldehyde and then purified by chromatography on silica gel (eluent: hexane / dichloromethane 100 / 0 to 85/15).

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  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
  • Indole Compounds (AREA)
  • Heterocyclic Compounds Containing Sulfur Atoms (AREA)
  • Pyridine Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
  • Pyrrole Compounds (AREA)
  • Catalysts (AREA)
  • Plural Heterocyclic Compounds (AREA)
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