Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
  • C07B37/00—Reactions without formation or introduction of functional groups containing hetero atoms, involving either the formation of a carbon-to-carbon bond between two carbon atoms not directly linked already or the disconnection of two directly linked carbon atoms
  • C07B37/04—Substitution
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
  • B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
  • B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
  • B01J31/22—Organic complexes
  • B01J31/2204—Organic complexes the ligands containing oxygen or sulfur as complexing atoms
  • B01J31/2208—Oxygen, e.g. acetylacetonates
  • B01J31/2226—Anionic ligands, i.e. the overall ligand carries at least one formal negative charge
  • B01J31/2243—At least one oxygen and one nitrogen atom present as complexing atoms in an at least bidentate or bridging ligand
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
  • B01J2231/00—Catalytic reactions performed with catalysts classified in B01J31/00
  • B01J2231/40—Substitution reactions at carbon centres, e.g. C-C or C-X, i.e. carbon-hetero atom, cross-coupling, C-H activation or ring-opening reactions
  • B01J2231/42—Catalytic cross-coupling, i.e. connection of previously not connected C-atoms or C- and X-atoms without rearrangement
  • B01J2231/4277—C-X Cross-coupling, e.g. nucleophilic aromatic amination, alkoxylation or analogues
  • B01J2231/4283—C-X Cross-coupling, e.g. nucleophilic aromatic amination, alkoxylation or analogues using N nucleophiles, e.g. Buchwald-Hartwig amination
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
  • B01J2531/00—Additional information regarding catalytic systems classified in B01J31/00
  • B01J2531/10—Complexes comprising metals of Group I (IA or IB) as the central metal
  • B01J2531/16—Copper

Definitions

• the present invention relates to a process for creating a carbon-carbon or carbon-heteroatom bond by reacting an unsaturated compound bearing a leaving group and a nucleophilic compound.
• the invention is aimed in particular at the creation of carbon-nitrogen bonding according to a process for the arylation of nitrogenous organic derivatives.
• arylhydrazines which result from the arylation of a nucleophilic compound by creating a carbon-nitrogen bond.
• a conventional method of arylation is to carry out the Ullmann reaction (Ullmann F. and Kipper H., Ber., Chem Chem., 1905, 38, 2120-
• the arylation reactions involve a catalyst and several types of catalysts have been described.
• Palladium was used by Buchwald et al., In particular to carry out 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.
• the disadvantage of this process is that the temperature remains high in the case of arylation carried out by aryl chlorides or even by aryl iodides.
• the objective of the present invention is to provide a method that overcomes the aforementioned drawbacks and makes it possible to address a very large number of nucleophiles.
• 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.
• arylation is used with an extensive meaning since the implementation of an unsaturated compound carrying a leaving group, which is either of aliphatic type, is contemplated. unsaturated, either aromatic carbocyclic or heterocyclic type.
• nucleophilic compound is meant a hydrocarbon organic compound that is both acyclic and cyclic and whose characteristic is to comprise at least one atom carrying a free doublet, which may or may not comprise a charge, preferably a nitrogen atom. , oxygen, sulfur, phosphorus or comprising a carbon atom capable of giving its electronic doublet.
• the nucleophilic compound comprises at least one free doublet bearing atom which may be provided by a functional group and / or a carbanion.
• the nucleophilic compound comprises at least one nitrogen atom carrying a free doublet included in a saturated, unsaturated or aromatic ring: the ring 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 arylation agents not only aryl iodides but also aryl bromides.
• Another advantage of the process of the invention is the possibility of using catalysis by copper rather than palladium, which is very advantageous from an economic point of view.
• a catalyst is associated with a ligand whose characteristic is to be polydentate, at least bidentate, tridentate or even tetradentate and to comprise at least two atoms of chelation which are oxygen and nitrogen.
• ligands are illustrated hereinafter by formulas which are given by way of example and without limitation.
• a first class of ligands suitable for the implementation of the invention are the ligands of oxime, dioxime or hydrazone type.
• At least one of the groups R a and R b comprises at least one oxygen atom or a group comprising an oxygen atom
• R a and R represent independently of one another a hydrocarbon group having 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 may be bonded 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,
• At most one of the groups R a and R represents a hydrogen atom
• R c represents a hydrogen atom, an alkyl group preferably C 1 to C 12 ; an alkenyl or alkynyl group preferably of C 2 to C 12; cycloalkyl preferably C 3 -C 12; an aryl or arylalkyl group preferably of C 6 to C ⁇ 2 .
• At least one of the groups R a and R comprises at least one oxygen atom or a group comprising an oxygen atom and there may be mentioned groups such as hydroxyl, ether, acyl, ester, sulfoxide, sulfone, phosphine oxide.
• groups such as hydroxyl, ether, acyl, ester, sulfoxide, sulfone, phosphine oxide.
• R a and R b may independently of each other represent an acyclic aliphatic group, saturated or unsaturated, linear or branched.
• R a and R b preferably represent a saturated acyclic aliphatic group, linear or branched, preferably C 1 to C 12 , and even more preferably C 1 to C 4 .
• the invention does not exclude the presence of unsaturation on the hydrocarbon chain such as one or more double bonds which can be conjugated or not.
• the hydrocarbon chain may be optionally interrupted by a heteroatom (for example, oxygen, sulfur, nitrogen or phosphorus) or by a functional group to the extent that it does not react, and a group such as in particular may be mentioned 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 aliphatic group saturated or unsaturated, linear or branched may optionally carry a cyclic substituent.
• ring is meant a carbocyclic or heterocyclic ring, saturated, unsaturated or aromatic.
• the acyclic aliphatic group may be linked to the ring by a valency 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 benzenes, these cyclic substituents being themselves optionally carrying any substituent insofar as they do not do not interfere with the reactions involved in the process of the invention.
• C 1 -C 4 alkyl, alkoxy groups may be mentioned.
• cycloalkylalkyl groups for example cyclohexylalkyl or arylkyl groups, preferably C 1 to C ⁇ 2 , in particular benzyl or phenylethyl, are more particularly targeted.
• the groups R a and Rb may also represent, independently of one another, a saturated carbocyclic group or group comprising 1 or 2 unsaturations in the ring, generally C 3 -C 8 , preferably 6 carbon atoms in the ring; said cycle being substitutable.
• Preferred examples of such groups are cyclohexyl groups optionally substituted with linear or branched alkyl groups having 1 to 4 carbon atoms.
• the groups R a and R b may independently of one another represent an aromatic hydrocarbon group, and in particular a benzene group corresponding to the general formula
• q represents an integer of 0 to 5
• R a and R b may also independently of one another represent a polycyclic aromatic hydrocarbon group with rings capable of forming between them ortho- condensed, ortho- and peri-condensed systems. There may be mentioned more particularly a naphthyl group; said cycle being substitutable.
• R a and R may also independently of one another represent a polycyclic hydrocarbon group consisting of at least 2 saturated and / or unsaturated carbocycles or at least 2 carbocycles of which only one of them is aromatic and forming between they are ortho- or ortho- and peri-condensed systems.
• the rings are C 3 to C 8 , preferably C 6 . More specific examples include the bornyl group or the tetrahydronaphthalene group.
• R a and R b may also independently of one another represent a saturated, unsaturated or aromatic heterocyclic group, in particular having 5 or 6 atoms in the ring, one or two of which are heteroatoms such as nitrogen atoms (unsubstituted by a hydrogen atom), sulfur and oxygen; the carbon atoms of this heterocycle may also be substituted.
• R a and R b may 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 ring and forming between them ortho- or ortho- and peri- condensed, or is a group consisting of at least one aromatic or non-aromatic hydrocarbon ring and at least one aromatic or non-aromatic heterocycle forming between them ortho- or ortho- and peri-condensed systems; the carbon atoms of said rings can optionally be substituted.
• heterocyclic groups R a and R are, for example, furyl, thienyl, isoxazolyl, furazanyl, isothiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyranyl, phosphino and quinolyl, naphthyridinyl and benzopyranyl groups. , benzofuranyl.
• the number of substituents present on each ring depends on the carbon condensation of the ring and the presence or absence of unsaturation on the ring. The maximum number of substituents which can be carried on a ring is readily determined by those skilled in the art.
• R a and Rb may be linked so as to form, 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 comprising two or three ortho-condensed rings; which means that at least two rings have two carbon atoms in common.
• the number of atoms in each ring preferably varies between 3 and 6.
• R a and Rb preferably form a cyclohexane or fluorenone type ring.
• R c preferably represents a hydrogen atom or a C 1 -C 4 alkyl group.
• the preferred oxime ligands have the formula (la-i) wherein R c represents a hydrogen atom and R a represents one of the following groups:
• R s represents an alkyl group, preferably C 1 -C 4 alkoxy, or amino substituted or unsubstituted by C 1 -C 4 alkyl groups.
• the ligands corresponding to the formulas (lai) or (la 2 ) are known products, described in particular by Hach, C. C; Banks, CV; Diehl, H .; (Org Synth, Vol IV, John Wiley and Sons, Inc. 1963, 230-232.)
• R a and R b have the meaning given in formulas (lai) or (la 2 ). with the hydroxylamine or derivative corresponding to the formula (IIa 3 ):
• R c represents a hydrogen atom or has the meaning given in formulas (lai) or (la 2 ).
• the preferred oxime type ligands used in the process of the invention contain an oxygen atom provided by the hydroxyl group of a salicylic aldehyde residue. They result preferentially from the reaction of salicylic aldehyde with hydroxylamine or O-methylhydroxylamine.
• R a - and or Rb ' may represent a hydrogen atom, - R a > and R 'can form a carbocyclic or heterocyclic ring, substituted or unsubstituted, having from 5 to 6 atoms,
• R c represents a hydrogen atom, an alkyl group preferably Ci to C ⁇ 2 ; an alkenyl or alkynyl group preferably of C 2 to C ⁇ 2 ; a cycloalkyl group preferably of C 3 to C ⁇ 2 ; an aryl or arylalkyl group preferably of C 6 to C ⁇ 2 .
• R d , R e identical or different, represent:. a hydrogen atom
• a linear or branched alkyl group having from 1 to 12 carbon atoms, optionally carrying a halogen atom, preferably from 1 to 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl or isobutyl; sec-butyl, tert-butyl, a halogen atom,
• n 0.1, 2 or 3, preferably equal to 0 or 1.
• the preferred dioxime ligands correspond to the formula (Ib 1) in which R c represents a hydrogen atom, m is equal to And R a 'and Rb - represent a methyl group or form a cyclohexane ring.
• the ligands corresponding to formulas (Ibi) result from the reaction of: a diketone, preferably - or ⁇ -diketone corresponding to the formula:
• R a 'and R b ', R d and R e> and m have the meaning given in formula (Ibi), with hydroxylamine or a derivative corresponding to formula (IIa 3 ).
• the preferred dioxime ligands result from the reaction of 2,3-butanedione or 1,2-cyclohexanedione and hydroxylamine. They are described in particular by Hach, C. C; Banks, C.V .; Diehl, H .; (Org Synth, Vol IV, John Wiley and Sons, Inc. 1963, 230-232).
• R a and Rb identical or different, have the meaning given in formulas (lai) and (la 2 ),
• At least one of the groups R a and Rb comprises at least one oxygen atom or a group comprising an oxygen atom
• - R a and / or Rb may represent a hydrogen atom
• - R c identical or different, represents a hydrogen atom, have the meanings given in formulas (lai) and (la 2 ) and also represent a group -CO-NH 2 .
• the preferred ligands of the hydrazone type correspond to the formulas (Here) or
• R s represents an alkyl group, preferably a C 1 -C 4 alkoxy, or an amino substituted or unsubstituted by C 1 -C 4 alkyl groups.
• Hydrazone type ligands result from the reaction:
• R a and Rb have the meaning given in the formulas (Here) or (Ic 2 ).
• a hydrazine or derivative corresponding to the formula (IIC3) preferably O-methylhydroxylamine.
• R c identical or different, have the meaning given in the formulas (Here) or (Ic 2 ).
• the preferred hydrazone ligands used in the process of the invention contain an oxygen atom provided by the hydroxyl group of a salicylic aldehyde residue. They result preferentially from the reaction of the salicylic aldehyde with a hydrazine or an N-substituted hydrazine or N, N-disubstituted preferably by an alkyl group having from 1 to 4 carbon atoms.
• a second category of ligands suitable for the implementation of the invention are tridentate ligands:
• R AA represents the residue of an amino acid, preferably a hydrogen atom, a linear or branched alkyl group in Ci C ⁇ 2 optionally bearing a functional group, aryl or arylalkyl C 6 -C 12 or a functional group, preferably a hydroxyl group,
• R a and / or R may represent a hydrogen atom
• R AA represents an alkyl group capable of carrying a functional group and there may be mentioned, inter alia, a group -OH, -NH 2 , -CO-NH 2 , -NH -C (NH) -NH 2 (guanidine), -COOH, -SH, -S-CH 3 or an imidazole group.
• the preferred tridentate ligands have the formulas (Idi) or (ld 2 ) in which RAA represents a hydrogen atom or a methyl group and R a represents one of the following groups:
• R s represents an alkyl group, preferably a C 1 -C 4 alkoxy, or an amino substituted or unsubstituted by C 1 -C 4 alkyl groups.
• the ligands of formula (Idi) and (ld 2 ) result from the reaction of: an aldehyde or a ketone corresponding to the corresponding formulas:
• R a and R b have the meaning given in formulas (Id) or (ld),
• amino acid and more particularly glycine, cysteine, aspartic acid, glutamic acid, histidine.
• amino acids can be used in salified form, preferably in the form of a sodium salt or in the form of ammonium-carboxylate of the "zwitterion" type.
• An example of a preferred ligand is given below:
• a third category of ligands suitable for the implementation of the invention are tetradentate ligands:
• R a and / or R b may represent a hydrogen atom
• R f and R g represent, independently of one another, a hydrogen atom, a hydrocarbon group having 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 f and R g may be bonded so as to constitute, with the carbon atoms which carry them, a saturated, unsaturated, monocyclic or polycyclic carbocyclic or heterocyclic group having from 3 to 20 atoms,
• the tetradentated preferred ligands have the formula (lei) or ( 2 ) wherein Rb represents a hydrogen atom and R a represents one of the following groups:
• R s represents an alkyl group, preferably C 1 -C 4 alkoxy, or amino substituted or unsubstituted by C 1 -C 4 alkyl groups.
• R f and R g may have the meaning given for R a and R b in the formulas (lai) and (la 2 ).
• R f is identical to R g .
• R f and R g can also be linked to represent carbocyclic or heterocyclic, mono- or polycyclic, saturated, unsaturated or aromatic, preferably bicyclic, groups which means that at least two rings have two carbon atoms in common.
• the number of carbon atoms in each cycle preferably varies between 3 and 6.
• 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, monocyclic or polycyclic.
• R f and R g preferably form a cyclohexane type cycle.
• R f and R g both represent a phenyl or naphthyl group
• R f and R g are linked together so as to form with the carbon atoms which carry them a cycle such as cyclohexane.
• An and Ar 2 together represent an aromatic group which may be a carbocycle having 6 to 12 carbon atoms or a heterocycle having 5 to 12 atoms.
• aromatic means the conventional notion of aromaticity as defined in the literature, including J. March “Advanced Organic Chemistry", 4th ed., John Wiley & Sons , 1992, pp 40 et seq.
• the aromatic derivative may be monocyclic or polycyclic.
• a monocyclic derivative in the case of a monocyclic derivative, it may comprise at its ring level one or more heteroatoms chosen from nitrogen atoms, phosphorus, sulfur and oxygen. According to a preferred mode, it is nitrogen atoms not substituted by a hydrogen atom.
• the carbon atoms of the aromatic derivative can also be substituted.
• Two vicinal substituents present on the aromatic ring may also form together with the carbon atoms which carry them a hydrocarbon ring, preferably aromatic, and optionally comprising at least one heteroatom.
• the aromatic derivative is then a polycyclic derivative.
• the ligands corresponding to the formulas (lei) or ( 2 ) are known products.
• R a and R b have the meaning given in formulas (lai) or (la).
• ⁇ has the meaning given in formulas (lei) or (2) and symbolizes a -HN-CO-NH- group or a skeleton of the general formula (F 2) or (F 3 ).
• the preferred tetradentate type ligands used in the process of the invention contain an oxygen atom provided by the hydroxyl group of a salicylic aldehyde residue. They result preferentially from the reaction of salicylic aldehyde with urea, 1,2-cyclohexanediamine, 1,2-diphenylethylenediamine and ethylenediamine.
• those which are preferred contain a salicylic aldehyde residue.
• They are more particularly of the oxime or hydrazone type.
• the ligand can be introduced concomitantly with the compound supplying the catalytic metal element.
• the invention also includes the case where a metal complex is previously prepared by reaction of the compound providing the catalytic metal element M and the ligand. then isolated.
• reaction of this liganded metal complex also makes it possible to catalyze the reactions according to the invention and more particularly the arylation reaction.
• a first category of substrates to which the process of the invention applies are the nitrogenous organic derivatives and more particularly the primary or secondary amines; hydrazine or hydrazone derivatives; amides; sulfonamides; urea derivatives, heterocyclic derivatives preferably nitrogen and / or sulfur. More specifically, the primary or secondary amines can be represented by a general formula:
• R 1, R 2 which are identical or different, represent a hydrogen atom or have the meaning given for R a and R in the formulas (lai) and (la 2 ),
• R 1 and R 2 represents a hydrogen atom.
• the amines used preferentially correspond to the formula (IIIa) in which R 1, R 2 , which may be identical or different, represent an alkyl group of C 1 to C 15 , preferably of C 1 to C ⁇ 0 , a cycloalkyl group of C 3 to C 8 preferably C 5 or C 6 , an aryl or arylalkyl group of C 6 to C ⁇ 2 .
• R 1 and R 2 groups C 1 -C 4 alkyl, phenyl, naphthyl or benzyl may be mentioned.
• amines of 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. Examples of such compounds include sodium or potassium amide.
• Other nucleophilic compounds that can be used in the process of the invention are the hydrazine derivatives corresponding to the various formulas (IIIb), (IIIc) or (IIId):
• R 3 , R 4 , R, R 6 identical or different, have the meaning given for R 1 and R 2 in the formula (IIIa).
• the groups R 3 , R 4 , R 5 and R 6 more particularly represent an alkyl group of C 1 to C 15, preferably of C 1 to C 10 , a cycloalkyl group of C 3 to C 8 , preferably C 5 or Ce, an aryl or arylalkyl group of C 6 to C ⁇ 2 .
• R 3 is preferably tert-butyl, R is methyl or phenyl, and R 5 , R 6 is phenyl.
• the invention also relates to compounds of amide type more particularly corresponding to formula (IIle):
• R 7 - NH - CO - R 8 (IIe) in said formula (IIle), R 7 and R 8 have the meaning given for R 1 and R 2 in formula (IIIa).
• Examples of compounds of formula (III) are: oxazolidin-2-one, benzamide, acetamide.
• the invention is also applicable to sulfonamide compounds. They can answer the following formula:
• R 9 - SO 2 - NH - R 10 (IIIf) in said formula (IIIf), R 9 and Rio have the meaning given for R 1 and R 2 in formula (IIIa).
• Examples of compounds of formula (IIIf) include tosylhydrazide.
• nucleophilic substrates that may be mentioned are urea derivatives such as guanidines and which can be represented by formula (IIIg):
• Examples of compounds of formula (IIIg) include N, N, N ', N'-tetramethylguanidine.
• Nucleophilic subtrates quite well adapted to the implementation of the process of the invention are heterocyclic derivatives comprising at least one nucleophilic atom such as a nitrogen, sulfur or phosphorus atom. More precisely, they answer to the general formula (lllh): "
• A symbolizes the remainder of a cycle forming all or part of a heterocyclic system, aromatic or otherwise, monocyclic or polycyclic, one of the carbon atoms is replaced by at least one nucleophilic atom such as a nitrogen atom , sulfur or phosphorus,
• n the number of substituents on the cycle.
• the invention is particularly applicable to monocyclic heterocyclic compounds corresponding to formula (IIIh) in which A represents a heterocycle, saturated or unsaturated, or aromatic, in particular having 5 or 6 atoms in the ring, which may comprise 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 being constituted by at least 2 aromatic heterocycles or not containing at least one heteroatom in each ring and forming between them ortho- or ortho- and peri-condensed systems or is a group consisting of 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 is preferably meant a cycloaliphatic or aromatic ring having 3 to 8 carbon atoms, preferably 6.
• the carbon atoms of the heterocycle may optionally be substituted, in whole or in part only with R ⁇ 2 groups.
• the number of substituents present on the ring depends on the number of atoms in the ring and the presence or absence of unsaturations on the ring.
• n is a number less than or equal to 4, preferably equal to 0 or 1. Examples of substituents are given below but this list is not limiting in nature.
• 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 from C 1 to C 6
• C 4 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl,
• 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 is particularly applicable to compounds of formula (IIIh) in which the R ⁇ 2 group or groups 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:
• a bicycle comprising a carbocycle and a heterocycle comprising one or more heteroatoms:
• a tricycle comprising at least one carbocycle or a heterocycle comprising one or more heteroatoms:
• heterocyclic compounds it is preferred to use those which have 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 that may also be used in the process of the invention, mention may also be made of alcohol or thiol type compounds which may be represented by the following formula:
• R 13 represents a hydrocarbon group having from 1 to 20 atoms and has the meaning given for R 1 or R 2 in 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 13 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 or unsaturated carbocyclic or heterocyclic group aromatic, monocyclic or polycyclic; a sequence 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 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 bearing one or more substituents.
• R ⁇ 3 can also represent a saturated or unsaturated carbocyclic group preferably having 5 or 6 carbon atoms in the ring; a heterocyclic group, saturated or unsaturated, in particular containing 5 or 6 atoms in the ring, including 1 or 2 heteroatoms such as nitrogen, sulfur, oxygen or phosphorus atoms; an aromatic or monocyclic aromatic carbocyclic or heterocyclic group, preferably phenyl, pyridyl, furyl, pyranyl, thiofenyl, thienyl, phospholyl, pyrazolyl, imidazolyl, pyrolyl or polycyclic fused or unsubstituted, preferably naphthyl.
• R ⁇ 3 includes a cycle, it can also be substituted.
• the nature of the substituent can be any as long as it does not interfere with the main reaction.
• the number of substituents is generally at most 4 per cycle but most often equal to 1 or 2.
• the invention also relates to the case where R ⁇ 3 comprises a chain of aliphatic and / or cyclic, carbocyclic and / or heterocyclic groups.
• An acyclic aliphatic group may be linked to a ring by a valency bond, a heteroatom or a functional group such as oxy, carbonyl, carboxy, sulfonyl, etc. More particularly, cycloalkylalkyl groups, for example cyclohexylalkyl or aralkyl groups having from 7 to 12 carbon atoms, especially benzyl or phenylethyl.
• the invention also contemplates a chain of carbocyclic and / or heterocyclic groups and more particularly a chain of phenyl groups separated by a valence bond or an atom or functional group G such as: oxygen, sulfur, sulpho, sulphonyl, carbonyl, carbonyloxy, imino , carbonylimino, hydrazo, alkylene (C ⁇ -C ⁇ 0 , preferably C ⁇ ) -diimino.
• the acyclic aliphatic group, saturated or unsaturated, linear or branched may optionally carry a cyclic substituent.
• ring is meant a carbocyclic or heterocyclic ring, saturated, unsaturated or aromatic.
• B represents the remainder of an aromatic, monocyclic or polycyclic carbocyclic group or a divalent group consisting of a chain of two or more monocyclic aromatic carbocyclic groups
• R 14 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.
• substituents R14 one can refer to those of formula R ⁇ 2 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 constituted by a sequence of two or more aromatic carbocyclic groups monocyclic compounds having the formula (F 5 ): in said formula (F 5 ), the symbols R ⁇ 4 and n 'which are identical or different have the meaning given above, p is a number equal to 0, 1, 2 or 3 and w represents a valency bond, an alkylene or alkylidene group of Ci -C 4 preferably methylene or isopropylidene, or a functional group such as G.
• compounds of formula (LLLI) used preferably correspond to the formulas (F 4) and (F 5) in which:
• Ru represents a hydrogen atom, a hydroxyl group, a CHO group, a -NO p group or a linear or branched alkyl or alkoxy group containing from 1 to 6 carbon atoms, preferably from 1 to 4 carbon atoms; , and more preferably methyl, ethyl, methoxy or ethoxy,
• w represents a valency bond, an alkylene or alkylidene group having 1 to 4 carbon atoms or an oxygen atom, m is 0 or 1,
• p 0 or 1.
• residue B corresponds to the formula (F 4 ) in which m is equal to 0 and n 'is equal to 1, such as hydroquinone, pyrocatechol, resorcinol, alkylphenols, alkylthiophenols and alkoxyphenols; salicylic aldehyde, p-hydroxybenzaldehyde, methyl salicylate, p-hydroxybenzoic acid methyl ester, chlorophenols, nitrophenols, p-acetamidophenol,
• residue B corresponds to the formula (F 4 ) in which m is equal to O and n 'is equal to 2, such as dialkylphenols, vanillin, isovanillin, 2-hydroxy-5-acetamido; benzaldehyde, 2-hydroxypropionamido-5-benzaldehyde, 4-allyloxybenzaldehyde, dichlorophenols, methylhydroquinone, chlorohydroquinone,
• residue B corresponds to the formula (F 4 ) in which m is equal to 0 and n 'is equal to 3, such as 4-bromo-vanillin, 4-hydroxy vanillin, trialkylphenols, trinitro; -2,4,6 phenol, 2,6-dichloro-4-nitro phenol, trichlorophenols, dichlorohydroquinones, 3,5-dimethoxy-4-hydroxybenzaldehyde,
• residue B corresponds to the formula (F) in which m is equal to 1 and n 'is greater than or equal to 1, such as dihydroxynaphthalene, 4-methoxy-1-naphthol, 6-bromo-naphthol- 2
• nucleophilic compounds capable of being used in the process of the invention are hydrocarbon derivatives comprising a nucleophilic carbon. Mention may more particularly be made of malonate anions comprising a group - OOC - HC - COO -.
• alkyl malonates anions or alkyl cyanomalonate formulas respectively (lllj ⁇ ) and (lllj 2):
• R 1 and R 5 ' identical or different, represent an alkyl group having from 1 to 12 atoms in the alkyl group, preferably from 1 to 4 atoms,
• R 15 "represents: a hydrogen atom
• an alkyl group having 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 phenyl group substituted with one or more alkyl radicals having 1 to 4 carbon atoms or alkoxy having 1 to 4 carbon atoms or with one or more halogen atoms a phenylalkyl group whose aliphatic part contains from 1 to 6 carbon atoms.
• malodinitrile anions comprising a group NC - C (R 15 ") - CN in which R 15 " has the meaning given above.
• Nitrile compounds which can be represented by the formula (IIIk) are also suitable: in said formula, R ⁇ 6 is of any type and has the meaning given for R 1 and also represents a metal cation, preferably an alkaline cation, and even more preferably lithium, sodium or potassium.
• R ⁇ 6 is of any type and has the meaning given for R 1 and also represents a metal cation, preferably an alkaline cation, and even more preferably lithium, sodium or potassium.
• Rie we can refer in particular to the meanings of Ri.
• nitriles mention may be made of acetonitrile, cyanobenzene optionally bearing one or more substituents on the benzene ring or ethanal cyanohydrin CH 3 CH (OH) CN.
• acetylenide compounds can also be used in the process of the invention.
• R 17 - c ⁇ c " 17 (IIIm) in said formula R 1 is of any kind and the counterion is a metal cation, preferably a sodium or potassium atom.
• R17 we can refer to the meanings of Ri.
• acetylide or diacetylide of sodium or potassium there may be mentioned acetylide or diacetylide of sodium or potassium.
• nucleophilic compounds As other classes of nucleophilic compounds that can be used in the process of the invention, mention may be made of the compounds of the profene type and derivatives that can be represented by the following formula:
• R 1 f - R ⁇ 8 has the meaning given for R 1 f - R 19 represents an alkyl group having from 1 to 12 atoms in the alkyl group, preferably from 1 to 4 atoms.
• R 1 represents an alkyl group having 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 that can be used in the process of the invention are amino acids and their derivatives:
• - AA represents the residue of an amino acid, preferably a hydrogen atom, a linear or branched alkyl group in Ci C ⁇ 2 optionally bearing a functional group, aryl or arylalkyl C 6 C ⁇ 2 or a group functional, preferably a hydroxyl group,
• R 20 and R 2 ⁇ have the meaning given for H and R 2 in formula (IIIa),
• R h represents a hydrogen atom, a metal cation, preferably an alkali metal cation or a hydrocarbon group having 1 to 12 carbon atoms, preferably an alkyl group Ci-C ⁇ 2.
• RAA represents an alkyl group capable of carrying a functional group and there may be mentioned, inter alia, a group -OH, -NH 2 , -CO-NH 2 , -NH-CNH-, -HN -C (O) -NH 2 -, -COOH, -SH, -S-CH 3 or an imidazole, pyrole or pyrazole group.
• amino acids examples include glycine, cysteine, aspartic acid, glutamic acid, histidine.
• nucleophilic compounds those comprising a carbanion and whose counterion is a metal and corresponding to the following formulas:
• an alkyl group having 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 whose aliphatic part contains from 1 to 6 carbon atoms
• 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. . a saturated, unsaturated or aromatic heterocyclic group, preferably comprising 5 or 6 atoms and comprising, as heteroatom, sulfur, oxygen or nitrogen,
• the groups R 22 'and R 22 "represent a hydrogen atom or a group such as R 1, two of the groups R 22 , R 22 ' and R 22 - may be linked together to form a saturated carbocycle or heterocycle unsaturated or aromatic, preferably having 5 or 6 carbon atoms,
• - M 2 represents a metallic element of group (IA) of the periodic table of elements
• - M 3 represents a metallic element of groups (MA), (MB) of the periodic table of elements
• - Xi represents a chlorine or bromine atom
• those which are preferred include, as metals, lithium, sodium, magnesium or zinc and Xi represents a chlorine atom.
• the groups R 22 , R 22 - and R 22 - are advantageously a C 1 -C 4 alkyl group, a cyclohexyl or phenyl group; or said groups can form a benzene or pyridine or thiofenic ring.
• ethylzinc As 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:
• the groups R 23 which are identical or different, and the group R 24 represent: an alkyl group having 1 to 12 carbon atoms,
• a cycloalkyl group having 5 or 6 carbon atoms a cycloalkyl group having 5 or 6 carbon atoms, substituted with one or more alkyl radicals having 1 to 4 carbon atoms, alkoxy having 1 or 4 carbon atoms, a phenylalkyl group whose aliphatic part 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 include tricyclohexylphosphine, trimethylphosphine, triethylphosphine, tri- ⁇ -butylphosphine, triisobutylphosphine, tri-tert-butylphosphine, tribenzylphosphine, dicyclohexylphenylphosphine, triphenylphosphine, dimethylphenylphosphine, diethylphenylphosphine, di-te / t-butylphenylphosphine.
• nucleophilic compounds that may be used may be boronic or derivative acids and more particularly those having the following formula:
• R 5 represents a carbocyclic or heterocyclic, aromatic, monocyclic or polycyclic group
• Q 1 , Q 2 which may be identical or different, represent a hydrogen atom, a linear or branched, saturated or unsaturated aliphatic group having from 1 to 20 carbon atoms or an R 2 group;
• the boronic acid has the formula (Iu) in which the group R 25 represents a carbocyclic or aromatic heterocyclic group.
• R 25 can take the meanings given above for B in the formula (IIIi).
• R 2 is more particularly a carbocyclic group such as a phenyl, naphthyl group or a heterocyclic group such as pyrrolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, 1, 3-thiazolyl, 1, 3,4- thiadiazolyl or thienyl.
• the aromatic ring 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 1 2 of 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 2 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.
• Q 1 , Q 2 preferably represent an alkyl group having 1 to 10 carbon atoms, preferably 1 to 4 or an alkenyl group having 2 to 10 carbon atoms, preferably a vinyl or 1-methylvinyl group,
• Q 2 may take the meanings given for R 25 and in particular any ring may also carry a substituent as previously described.
• R 25 preferably represents a phenyl group. It will not be departing 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 examples include: benzeneboronic acid, 2-thiopheneboronic acid, 3-thiopheneboronic acid, 4-methylbenzeneboronic acid, 3-methylthiophene-2-boronic acid, 3-aminobenzeneboronic acid, 3-aminobenzeneboronic hemisulfate acid, 3-fluorobenzeneboronic acid, 4-fluorobenzeneboronic acid, 2-formylbenzeneboronic acid, 3- formylbenzeneboronic acid, 4-formylbenzeneboronic acid, 2-methoxybenzeneboronic acid, 3-methoxybenzeneboronic acid, 4-methoxybenzeneboronic acid, 4-chlorobenzeneboronic acid, 5-chlorothiophene-2-boronic acid, benzo [b] furan-2-boronic acid, 4-carboxybenzeneboronic acid, 2,4,6-trimethylbenzeneboronic acid, 3-nitrobenzeneboronic acid, 4- (methylthio)
• nucleophilic compounds which are in no way limiting and any type of nucleophilic compound can be envisaged.
• the creation of a - C - C - or - C - Nu - bond is carried out by reacting a nucleophilic compound with a compound comprising ⁇ -unsaturation of a leaving group.
• formula Ro represents a hydrocarbon group comprising from 2 to 20 carbon atoms and has a double bond or a triple bond situated in the position of a leaving group Y or a carbocyclic and or heterocyclic, aromatic, mocyclic or polycyclic group.
• - Ro represents an aliphatic hydrocarbon group comprising a double bond or a triple bond in the ⁇ position of the leaving group or a cyclic hydrocarbon group comprising an unsaturation bearing the leaving group
• - Ro represents a carbocyclic and / or heterocyclic, aromatic, mocyclic or polycyclic group
• Y represents a leaving group, preferably a halogen atom or a sulphonic ester group of formula - OSO 2 - R ⁇ , in which R e is a hydrocarbon group.
• R e is a hydrocarbon group of any kind.
• Y is a leaving group, it is interesting 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 may 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) particularly targeted according to the method of the invention can be classified into three groups:
• R 26 - C C - Y (IVa)
• R 26 has the meaning given in formula (IVa),
• Y represents a leaving group as defined above, - (3) those of aromatic type which are hereafter designated “haloaromatic compound” and which can be represented by formula (IVc):
• D represents the remainder of a ring forming all or part of a carbocyclic and / or heterocyclic, aromatic, monocyclic or polycyclic system
• R 29 which may be identical or different, represent substituents on the ring
• Y represents a leaving group as defined above, n represents the number of substituents on the ring.
• 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 the presence of another unsaturation on the hydrocarbon chain such as another triple bond or one or more double bonds that can be conjugated or not.
• the hydrocarbon chain may be optionally interrupted by a heteroatom (for example, oxygen or sulfur) or by a functional group to the extent that it does not react and there may be mentioned in particular 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 may be mentioned in particular a halogen atom, a nitrile group or a trifluoromethyl group.
• the acyclic aliphatic group, saturated or unsaturated, linear or branched may optionally carry a cyclic substituent.
• ring is meant a carbocyclic or heterocyclic ring, saturated, unsaturated or aromatic.
• the acyclic aliphatic group may be linked to the ring by a valency 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 benzenes, these cyclic substituents being themselves optionally carriers of any substituent to the extent that they do not interfere with the reactions involved in the process of the invention.
• alkyl or alkoxy groups having 1 to 4 carbon atoms may be mentioned.
• aliphatic groups bearing a cyclic substituent more particularly aralkyl groups having 7 to 12 carbon atoms, especially benzyl or phenylethyl.
• R 2 ⁇ may also represent a saturated or unsaturated carbocyclic group preferably having 5 or 6 carbon atoms in the ring, preferably cyclohexyl; a heterocyclic group, saturated or unsaturated, in particular containing 5 or 6 atoms in the ring, including 1 or 2 heteroatoms such as nitrogen, sulfur and oxygen atoms; a carbocylic aromatic 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 1 to 12 carbon atoms, a phenyl group or an aralkyl group having 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.
• Examples of compounds corresponding to formulas (IVa) and (IVb) include chloride or vinyl bromide or ⁇ -bromo or ⁇ -chlorostyrene or bromoalcyne, iodoalkyne.
• 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 carbocycle, monocyclic or polycyclic that is to say a compound consisting of at least 2 aromatic carbocycles and forming between them ortho- or ortho- and peri-condensed systems or a compound consisting of at least 2 carbocycles of which only one of them is aromatic and forming between them ortho- or ortho- and peri-condensed systems.
• a monocyclic aromatic 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 ring of which at least 1 one of the two rings is aromatic and forming between them ortho- or ortho- and pericondensates 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 ortho- or ortho- and peri-condensed systems.
• the optionally substituted residue D preferably represents the residue of an aromatic carbocycle such as benzene, an aromatic bicycle comprising two aromatic carbocycles such as naphthalene; a partially aromatic bicycle comprising two carbocycles, one of which is aromatic such as 1,2,3,4-tetrahydro-naphthalene.
• D may represent the remainder of a heterocycle to the extent that it is more electrophilic than the compound of 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 5,6,7,8-tetrahydroquinoline
• haloaromatic compound of formula (IVc) in which D represents an aromatic nucleus, preferably a benzene or naphthalenic nucleus.
• the aromatic compound of formula (IVc) may carry one or more substituents.
• R 29 also represents a saturated, unsaturated or aromatic heterocycle comprising 5 or 6 atoms and comprising, as heteroatom, sulfur, oxygen or nitrogen.
• n is a number less than or equal to 4, preferably equal to 1 or 2.
• Examples of compounds corresponding to formula (IVc) that may be mentioned include p-chlorotoluene, p-bromoanisole and p-bromotrifluorobenzene.
• the amount of the compound carrying a leaving group of formula (IV), preferably of formula (IVa) or (IVb) or (IVc), used is generally expressed with respect to the amount of nucleophilic compound close to stoichiometry. .
• the ratio between the number of moles of the leaving group carrying compound and the number of moles of the nucleophilic compound varies most often between 0.9 and 1.2.
• the nucleophilic compound preferably corresponding to formulas (IIIa) to (III) is reacted with a compound bearing a leaving group corresponding to formula (IV), preferably of formula ( IVa) or (IVb) or (IVc) in the presence of an effective amount of a catalyst based on a metal element M selected from group (VIII), (IB) and (MB) and a ligand such that defined according to the invention.
• the different metals M can be used in a mixture, especially in a mixture with copper.
• a mixture comprising palladium and copper is used.
• metals M include copper, silver, palladium, cobalt, nickel, iron and / or zinc.
• copper or palladium is preferably chosen.
• catalysts examples include copper metal or 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 mention may be made especially, as copper compounds, cuprous bromide, cupric bromide, cuprous iodide, cuprous chloride, cupric chloride, basic copper (II) carbonate , cuprous nitrate, cupric nitrate, cuprous sulphate, cupric sulphate, cuprous sulphite, cuprous oxide, cuprous acetate, cupric acetate, cupric trifluoromethylsulfonate, cupric hydroxide, copper methoxide ( I), the methoxide of copper (II), the chlorocuivic methoxide of formula CICuOCH.
• a palladium catalyst is involved.
• Palladium can be supplied in the form of a finely divided metal or form of an inorganic derivative such as an oxide or hydroxide. It is possible to use a mineral salt preferably, nitrate, sulfate, oxysulfate, halide, oxyhalide, silicate, carbonate, or an organic derivative, preferably cyanide, oxalate, acetylacetonate; alkoxide and even more preferably methylate or ethylate; carboxylate and even more preferably acetate. Can also be used complexes, especially chlorinated or cyanized palladium and / or alkali metals, preferably sodium, potassium or ammonium
• nickel (II) halides such as chloride, bromide or nickel iodide (II); nickel sulphate (II); nickel carbonate (II); salts of organic acids comprising from 1 to 18 carbon atoms such as in particular acetate, propionate; nickel (M) complexes such as nickel (II) acetylacetonate, nickel (II) dibromo-bis- (triphenylphosphine), nickel (II) dibromo-bis (bipyridine); nickel (0) complexes such as nickel bis (cycloocta-1,5-diene) (0), nickel bis-diphenylphosphinoethane (0). It is also possible to use catalysts based on iron or zinc, generally in the form of oxide, hydroxides or salts such as halides, preferably chloride, nitrates and sulphates.
• Cupric chloride or bromide and cuprous oxide are preferably chosen.
• the amount of catalyst used expressed as the molar ratio between the number of moles of catalyst and the number of moles of compound of formula (IV) generally varies between 0.01 and 0.1. Also involved in the method of the invention, a base whose 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 2, preferably between 4 and 30.
• the pKa is defined as the ionic dissociation constant of the acid / base pair, when the water is used. as a solvent.
• a base having a pKa as defined by the invention reference may be made, among others, the Handbook of Chemistry and Physics, 66 th Edition, p. D-161 AND D-162.
• mineral bases such as carbonates, hydrogenocarbonates or hydroxides of alkali metals, preferably of sodium, of potassium, of cesium or of alkaline earth metals, preferably of calcium, barium or magnesium.
• alkali metal hydrides preferably sodium hydride or alkali metal alkoxides, preferably sodium or potassium, and more preferably sodium methoxide, ethylate or tert-butoxide.
• Organic bases such as tertiary amines and more particularly triethylamine, tri-n-propylamine, tri-n-butylamine, methyldibutylamine, methyldicyclohexylamine, ethyldiisopropylamine and N, N-diethylcyclohexylamine are also suitable.
• pyridine 4-dimethylaminopyridine, N-methylpiperidine, N-ethylpiperidine, Nn-butylpiperidine, 1,2-dimethylpiperidine, N-methylpyrrolidine, 1,2-dimethylpyrrolidine.
• the alkali metal carbonates 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.
• 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 conditions of the reaction.
• types of solvents used it is preferable to use a polar organic solvent and preferably aprotic.
• linear or cyclic carboxamides such as N, N-dimethylacetamide (DMAC), N, N-diethylacetamide, dimethylformamide (DMF), diethylformamide or 1-methyl-2-pyrrolidinone (NMP);
• DMSO dimethylsulfoxide
• HMPT hexamethylphosphotriamide
• nitro compounds such as nitromethane, nitroethane, 1-nitropropane, 2-nitropropane or their mixtures, nitrobenzene;
• alpha or aromatic nitrites such as acetonitrile, propionitrile, butanenitrile, isobutanenitrile, pentanenitrile, 2-methylglutaronitrile, adiponitrile;
• organic carbonates such as dimethylcarbonate, diisopropylcarbonate, di-n-butylcarbonate;
• alkyl esters such as ethyl acetate or isopropyl acetate.
• halogenated or non-halogenated aromatic hydrocarbons such as chlorobenzene or toluene;
• ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone, cyclopentanone, cyclohexanone,
• nitrogen heterocycles such as pyridine, picoline and quinolines. It is also possible to use a mixture of solvents.
• the amount of organic solvent to be used is determined according to the nature of the organic solvent chosen.
• the concentration of the leaving group carrying compound 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 85 ° C.
• the arylation or vinylation or alkynation reaction is generally carried out at atmospheric pressure, but higher pressures of up to 10 bar, for example, may also be used. From a practical point of view, the reaction is simple to implement.
• the order of implementation of the reagents is not critical.
• the catalyst is preferably loaded with copper, the ligand, the nucleophilic compound of formula (III), the base, the leaving group bearing compound of formula (IV) and the organic solvent.
• a metal complex comprising the metal element and the ligand.
• the reaction medium is brought to the desired temperature.
• the progress of the reaction is monitored by following the disappearance of the carrier group leaving group.
• R representing the remainder of the nucleophilic compound, and more particularly an aryl product comprising the remainder of the nucleophilic compound and the remainder of the electrophilic compound which preferentially corresponds to the formula ( V) following:
• the compound obtained is recovered according to the standard techniques used, in particular by crystallization in 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, dimethylformamide and acetonitrile.
• the transformation ratio (TT) corresponds to the ratio between the number of transformed substrates and the number of moles of substrate involved.
• the yield (RR) corresponds to the ratio between the number of moles of product formed and the number of moles of substrate engaged.
• the selectivity (RT) corresponds to the ratio between the number of moles of product formed and the number of moles of substrate transformed.
• the mixture is placed in an oil bath at 50 ° C and stirred for 90 hours.
• a sample is taken from the reaction medium, which is subjected to filtration on celite (or filtering ground), eluting with ether or dichloromethane according to the solubility.
• the aryl compound obtained is extracted with ethyl ether or dichloromethane and then with distilled water, and the product obtained is determined by gas chromatography with respect to 1,3-dimethoxybenzene as internal standard.
• the ligand is prepared according to the procedure described by Hach, C.C; Banks, C.V .; Diehl, H .; (Org Synth, Vol IV, John Wiley and Sons, Inc. 1963, 230-232.) To a solution of 16.73 g of hydroxylamine hydrochloride (240.8 mmol) dissolved in 30 mL of distilled water cooled by an ice bath is added a solution also cooled by an ice bath of 13.51 g of potassium hydroxide (240.8 mmol) in 30 ml of distilled water.
• reaction mixture is then placed a few hours in the refrigerator which has the effect of precipitating a brown solid, isolated by filtration on frit, washed extensively with water and with petroleum ether and then dried in a desiccator.
• Salicylaldoxime is purified by recrystallization from a petroleum ether / chloroform mixture. 9.91 g of white-orange crystals are obtained, which corresponds to a yield of 81%.
• nioxime (cyclohexane-1,2-dionedioxime):
• the ligand is prepared according to the procedure described by Hach, C.C .; Banks, C.V .; Diehl, H .; (Org Synth, Vol IV, John Wiley and Sons, Inc. 1963, 230-232).
• the nioxime is purified by recrystallization from an acetone / water mixture 98/2.
• catalysts used are commercial products with the exception of activated Cu (A) and activated Cu (B). Also given below is a procedure for the preparation of said catalysts which are then used in the examples.
• a few grams of copper powder are triturated for 15 minutes in a solution consisting of 2 g of iodine dissolved in 100 ml of acetone.
• the mixture is filtered on frit, washed with 150 ml of a solution composed of concentrated hydrochloric acid (75 ml) and acetone (75 ml), with 100 ml of acetonitrile then with 100 ml of acetone.
• cuprous iodide is ensured by washing with acetonitrile, solvent in which it is very soluble (27.51 g / l).
• the activated copper is dried in a vacuum desiccator in the presence of P 2 0 5 . It is used immediately after its preparation.
• the precipitated copper is isolated by filtration on frit, washed with distilled water and then with acetone and dried in a desiccator in the presence of P 2 0 5 .
• the solvent is concentrated in part by a nitrogen sweep.
• the filtrate is immediately put back to -5 ° C. After a week, small translucent needles were deposited at the bottom of the balloon.
• the characteristics of the crystals obtained are as follows: An aliquot of the crystals is taken and analyzed immediately in mass: 2 peaks were identified at 336 and 335 showing the presence of complexes ⁇ Cu [salox] 2 -
• the amount of ligand is two molar equivalents relative to copper.
• Acetonitrile is used in an amount such as bromobenzene at a concentration of 1.67 M.
• the reaction takes place at 50 ° C for 90 hours.
• the various copper catalysts are used in the arylation reaction, according to the invention, in the presence of the ligands defined according to the invention and mentioned in Table (I).
• Example 1 is repeated but replacing bromobenzene with iodobenzene.
• the catalyst used is activated Cu (A) at a rate of 10%.
• Example 2 is repeated but replacing bromobenzene with iodobenzene.
• the catalyst used and the cuprous oxide at a rate of 5%.
• the reaction takes place at 20 ° C.
• Acetonitrile is used in an amount such as bromobenzene at a concentration of 1.67 M.
• the reaction takes place at 82 ° C for 24 hours.
• pyrazole (51 mg) and bromobenzene are reacted in the presence of cuprous oxide (5%), a Salox ligand, DMG or 2-Py-Aldox (20%), carbonate of cesium or potassium tert-butoxide (112 mg, 1 mmol) in the presence of acetonitrile.
• Acetonitrile is used in an amount such as bromobenzene at a concentration of 1.67 M.
• the reaction takes place at 82 ° C for 24 hours.
• the acetonitrile is used in an amount such as bromobenzene at a concentration of 1.67 M.
• the reaction takes place at 82 ° C. for 24 hours.
• a metal complex prepared extemporaneously is used. Its preparation is described previously from cuprous iodide and
• the complex crystals are recovered by spatula and dried on filter paper.
• the Schlenk tube is purged under vacuum and then refilled with nitrogen. Using syringes, 56 ⁇ L of arylating agent (0.5 mmol) and then 300 ⁇ L of anhydrous acetonitrile are added.
• the reactor is placed in an oil bath at a temperature of 50 ° C and stirred for 24 hours.
• the selectivity is 100%.
• the pyrazole (51 mg) is reacted with different substituted aryl bromides, the nature of which is specified in Table (V), in the presence of cuprous oxide (5%) and of Salox (20%). ), cesium carbonate (2 equivalents), in the presence of acetonitrile
• the acetonitrile is used in an amount such that bromobenzene at a concentration of 1.67 M.
• the reaction takes place at 82 ° C for 24 hours.
• the reaction takes place at 82 ° C for 24 hours.
• the temperature is 82 ° C and the reaction time is 24 hours.
• the yield of N-phenylimidazole obtained is specified in the table
• f-butyl carbazate H 2 N -NH-Boc
• iodobenzene iodobenzene
• CuBr cesium carbonate
• DMG dimethylglyoxime
• the piperidine (56 mg, 0.75 mmol) was arylated by reacting it with iodobenzene in the presence of cuprous oxide (3.6 mg, 0.025 mmol, 5%), a Salox ligand ( 20%), cesium carbonate (0.325 g, 1 mmol, 2 equivalents) in the presence of acetonitrile.
• the temperature is 82 ° C and the reaction time is 24 hours.
• N-phenylpiperidine is obtained with a yield of 17.7%.
• the arylation of 4-f-butylphenol (112.5 mg, 0.75 mmol) is carried out by reacting it with iodobenzene in the presence of cuprous oxide (5%), a Salox ligand, cesium in the presence of acetonitrile.
• the temperature is 82 ° C and the reaction time is 24 hours.
• the 4-t-butylphenyl ether is obtained in a yield of 80.5%.
• Example 49 The arylation of oxazolidin-2-one (65.3 mg) is carried out by reacting it with iodobenzene in the presence of cuprous oxide, a saline ligand, cesium carbonate, in the presence of acetonitrile.
• the temperature is 82 ° C and the reaction time is 24 hours.
• the corresponding 3-phenyloxazolidin-2-one is obtained with a yield of 54.2%.
• indole 87.9 mg, 0.75 mmol
• iodobenzene iodobenzene
• cuprous oxide a Salox ligand, cesium carbonate, in acetonitrile
• the temperature is 82 ° C and the reaction time is 24 hours.
• the arylation of the benzophenone hydrazone (147.2 mg) is carried out with iodobenzene.
• the temperature is 82 ° C and the reaction time is 24 hours.
• the Schlenk tube is purged under vacuum and then refilled with nitrogen. Using syringes, 56 ⁇ L of arylating agent (0.5 mmol) and then 300 ⁇ L of anhydrous DMF are added.
• the reactor is placed in an oil bath at a temperature of 110 ° C and stirred for 48 hours.

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