FR2865203A1 - Process for forming carbon-carbon bonds by a coupling reaction between unsaturated compounds in the presence of a cobalt-based catalyst - Google Patents

Abstract

Formation of carbon-carbon bonds by a coupling reaction between a compound (I) with an unsaturation in alpha position to a separating group and an unsaturated compound (II) in a solvent and in the presence of a cobalt-based catalyst and a reducing agent. Independent claims are also included for compositions comprising the reaction medium and their use.

Description

The present invention relates to a method of forming a connection

  carbon-carbon according to a coupling reaction between a compound comprising unsaturation at the α-position of a leaving group and an unsaturated compound.

  The invention more particularly relates to the formation of a carbon-carbon bond according to a coupling reaction between a compound comprising unsaturation at the α position of a leaving group and an alkenic or alkynic compound.

  The addition to activated olefins is of great utility in organic synthesis due to the formation of carbon-carbon bonds (Perlmutter et al., Conjugated Addition Reactions in Organic Synthesis, Pergamon Press, Oxford, 1992). Most applications involve the reaction of organometallic reagents in the presence of cuprous salts and / or, in some cases, chlorotrimethylsilane or cuprate reagents (Rahman et al., J. Organomet Chem., 1980, 199, 9- 14). Therefore, these methods require the preliminary preparation of organometallic magnesium, lithium, zinc or manganese derivatives which are sensitive to air and / or moisture (Kharasch et al., J. Am Chem Soc. , 1941, 63, 2305-2307, Normant et al., Synthesis, 1972, 63-80, Klement et al., Tetrahedron Letters, 1994, 35, 1177-1180, Cahiez et al., Pure Appl. Chem., 1996 , 68, 53-60).

  Moreover, the preparation of these organometallic compounds from organic halides having a functional group such as -CO, COOR or -CN can be particularly difficult or impossible. As a result, other chemical or electrochemical processes have been designed to avoid this difficult step.

  These processes use a transition metal complex as a catalyst, and are carried out under mild reaction conditions. The transition metal may be, for example, nickel associated with various ligands such as those of the cyclam or salenic type (Hosaki et al., Chem Pharm Bull., 1991, 39, 31-33, Gosden et al. J. Organomet Chem, 1980, 186, 401-409) and excess zinc as a reducing agent (Boldrini et al., J. Organomet Chem, 1986, 301, C62-C64).

  Electrochemical processes using nickel salts or cobalt complexes as a catalyst have been described (Condon-Gueugnot et al., J. Org Chem 1995, 7684-7686, Scheffold et al Pure Appli Chem 1987 , 59, 363-372, Cannes et al., New J. Chem., 1999, 23, 489-494, Gomez et al., Synlett, 2002, 10, 1673-1676).

  However, these techniques have the drawbacks associated with any electrolysis. Thus, since it is relatively expensive to implement electrolytic techniques, they therefore apply only to expensive products.

  Another problem is the difficulty of producing large quantities in small volumes.

  Therefore, one of the aims of the present invention is to provide a novel process for addition to olefin derivatives, from easily accessible starting materials, with good yields, as well as reaction and transformation, and this without using an electrochemical technique.

  This has been made possible by the method according to the invention described below.

  According to a first subject, the present invention relates to a process for forming a carbon-carbon bond according to a coupling reaction between a compound comprising unsaturation at position a of a leaving group and an unsaturated compound characterized in that the reaction in a solvent medium, in the presence of an effective amount of a cobalt-based catalyst and in the presence of a reducing agent, in a medium comprising an organic solvent of aromatic type, the characteristic of which is to comprise at least one atom of nitrogen carrying a free doublet.

  More precisely, as organic solvent of aromatic type, the characteristic of which is to comprise at least one nitrogen atom carrying a free doublet, is meant any aromatic heterocyclic solvent containing a nitrogen atom carrying a free doublet, in particular chosen from: pyrrole, naphthyridine, quinoxaline, phthalazine, imidazole, indole, isoxazole, isoquinoline, oxadiazole, pyrazine, pyridazine, pyrazole, piridine, pyrimidine, purine, quinazone, quinoline, carbazole, pteridine, carboline, phenantridine, acridine, phenanthroline, phenazine.

  More specifically, said compound comprising an unsaturation at the α-position of a leaving group is a compound comprising a leaving group X symbolized by the formula (I): Ra X (I) in which formula: Ra represents a hydrocarbon group comprising from 2 to 20 carbon atoms and has a double bond or a triple bond located in position a of a leaving group X or a carbocyclic and / or heterocyclic, aromatic, monocyclic or polycyclic group.

  X represents a leaving group, preferably a halogen atom or a sulphonic ester group of formula - OSO2 - Rej in which Re is a hydrocarbon group, optionally perhalogenated.

  In the formula of the sulfonic ester group, Re is a hydrocarbon group of any kind. However, since X is a leaving group, it is interesting from an economic point of view that Re is of a simple nature, and more particularly represents a linear or branched alkyl group having from 1 to 4 carbon atoms, optionally perhalogen, preferably a methyl or ethyl group but it may also represent for example a phenyl or tolyl group or a trifluoromethyl group. Among the X groups, the preferred group is a triflate group, which corresponds to a Re group representing a trifluoromethyl group.

  As preferred leaving groups, a bromine or chlorine atom is preferably chosen.

  More precisely, Ra represents: an aliphatic hydrocarbon group comprising a double bond or a triple bond at the α position of the leaving group or a cyclic hydrocarbon group comprising an unsaturation bearing the leaving group, or a carbocyclic and / or heterocyclic aromatic group, monocyclic or polycyclic.

  The compound of formula (I) will be referred to hereinafter as "compound carrying a leaving group".

  The compounds of formula (I) particularly targeted according to the process of the invention can be classified in three groups: (1) those of aliphatic type bearing a double bond that can be represented by the formula (la): R; - C = C - X (la) R; R ;;; in said formula (la): - R ;, R ;; and R ;;;, identical or different, represent a hydrogen atom or a hydrocarbon group having from 1 to 20 carbon atoms which may be a linear or branched, saturated or unsaturated aliphatic group; a saturated, unsaturated or aromatic, monocyclic or polycyclic carbocyclic or heterocyclic group; a chain of aliphatic and / or carbocyclic and / or heterocyclic groups as mentioned above, - X symbolizes the leaving group as defined above, - (2) those of the aliphatic type carrying a triple bond and which can be represented by the formula (Ib): R; - C = C X (lb) in said formula (Ib): - R; has the meaning given in formula (Ia), - X represents a leaving group as defined above, the invention applies to unsaturated compounds of formulas (la) and (lb) wherein R; preferably represents a linear or branched acyclic aliphatic group having preferably 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 a halogen atom, a nitrile group or a trifluoromethyl group may be mentioned in particular.

  The acyclic aliphatic group, saturated or unsaturated, linear or branched may optionally carry a cyclic substituent. By ring is meant a carbocyclic or heterocyclic ring, saturated, unsaturated or aromatic.

  The acyclic aliphatic group may be linked to the ring by a valence bond, a heteroatom or a functional group such as oxy, carbonyl, carboxy, sulfonyl, etc. As examples of cyclic substituents, it is possible to envisage cycloaliphatic, aromatic or heterocyclic, in particular cycloaliphatic, substituents comprising 6 ring carbon atoms 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. In particular, alkyl or alkoxy groups having 1 to 4 carbon atoms may be mentioned.

  Among the aliphatic groups bearing a cyclic substituent, more particularly aralkyl groups having 7 to 12 carbon atoms, especially benzyl or phenylethyl.

  In the formulas (Ia) and (Ib), R; 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.

  As for R; and R ;;; 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 benzyl group.

  In formulas (la) and or (lb), R 1, R 2; and R ;;; more particularly represent a hydrogen atom or R ;, represents a phenyl group and R ;;, R ;;; represent a hydrogen atom.

  Examples of compounds of formulas (Ia) and (Ib) include chloride or vinyl bromide or R-bromo or [3-chlorostyrene or bromoalkyne, iodoalkyne, preferably bromostryrene.

  (3) those of aromatic type that can be represented by the formula (Ic): X (B) n in which: D represents the remainder of a cycle forming all or part of a carbocyclic system and / or heterocyclic, aromatic, monocyclic or polycyclic, - B, identical or different, represent substituents on the ring, - X represents a leaving group as defined above, - n represents the number of substituents on the ring.

  B represents any electro-donor or electron-withdrawing substituent not interfering with the reaction. An electroattractant group is particularly preferred. Among the electron-withdrawing groups, the groups of formula COR ', -CN, -SO 2 R, -COOR ", perhaloalkyl, -F, alkyl, -NO 2 where R represents an alkyl or cycloalkyl radical optionally substituted with one or more atoms are preferred. fluorine and R 'represents an alkyl radical, cycloalkyl, aryl, aralkyl, alkenyl.

  Preferably, R 'represents an alkyl or aralkyl radical, more preferably methyl or benzyl; R "represents a hydrogen atom or an alkyl, aryl or aralkyl radical, preferably an alkyl radical, and preferably B represents the radicals -CN, -perfluoroalkyl, -COR ', SO 2 R, -COOR" where R, R "R" are defined as above, and more particularly the radicals CN, -CF3, -COMe, -SO2Me, -COOMe, -COOEt.

  Preferably, when X represents a chlorine atom, B represents an electron-withdrawing group.

  The invention is particularly applicable to compounds of formula (Ic) 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 one one of the two rings is aromatic and forms between them ortho- or ortho- and peri-condensed systems or a compound consisting of at least one carbocycle and at least one heterocycle in which at least one of the rings is aromatic and forming between them ortho-systems. - or ortho- and peri-condensed.

  More particularly, 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.

  As particular examples, there may be mentioned 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 In the process of the invention, a compound of formula (Ic) in which D represents a aromatic ring, preferably a benzene or naphthalenic ring.

  Preferably, D represents a benzene ring.

  The aromatic compound of formula (Ic) may carry one or more substituents.

  In the present text, the term "several", generally, less than 4 substituents B on an aromatic ring.

  In the formula (Ic), n is an integer less than or equal to 4, preferably 1 or 2.

  Examples of compounds of formula (Ic) that may be mentioned include ethyl p-bromo-benzoate, 1-trifluoromethyl-4-bromophenyl, 1-cyano-4-bromo-phenyl, p-chlorotoluene, p-bromoanisole, pbromotrifluorobenzene, more preferentially ethyl p-bromo-benzoate, 1-trifluoromethyl-4-bromo-phenyl, 1-cyano-4-bromo-phenyl.

  According to a preferred aspect, the compounds of formula (I) correspond to formula (Ic) as defined above.

  Said unsaturated compound may be represented by the formula: Rb-Y (II) in which formula Rb represents a hydrocarbon group comprising from 2 to 20 carbon atoms and has a double bond or a triple bond located in position a of the group Y; Y represents an electron-withdrawing group.

  Preferably, Rb represents an aliphatic hydrocarbon group comprising a double bond or a triple bond at the α position of the Y group; Y represents an electron-withdrawing group. Preferably, Y is chosen from groups of formula -COR ', -CN, -SO 2 R, -COOR ", perhaloalkyl, -NO 2 where R is defined as above, R' represents an alkyl, cycloalkyl, aryl, aralkyl or alkenyl radical. .

  Preferably, R 'represents an alkyl or aralkyl radical, more preferably methyl or benzyl; R "represents a hydrogen atom or an alkyl, aryl or aralkyl radical, preferably an alkyl radical, and preferably Y represents the radicals COR ', -COOR", -CN and more particularly -CN, -COMe, - COOalkyl.

  According to the invention, the compounds of formula (II) are preferably represented by formula (II '): in which formula (II'): represents a double or a triple bond.

  It goes without saying that when represents a triple bond, R1 or R3 forms with R2 a bond.

  R1, R2, R3, which may be identical or different, 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 or aromatic, monocyclic or polycyclic carbocyclic or heterocyclic group; a chain of aliphatic and / or carbocyclic and / or heterocyclic groups as mentioned above, optionally substituted, preferably unsubstituted or R1 or R3 form with R2 a bond.

  Preferably, R1, R2 and R3 represent a hydrogen atom.

  Y is as defined above. The compounds of formula (II) particularly targeted according to the process of the invention may be: (1) those of aliphatic type carrying a double bond which may be represented by the formula ( II 'a): R 1 - C = C - Y (II' a) 1 1 R 3 R 2 in said formula (II 'a): - R 1, R 2 and R 3, which are identical or different, 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 or aromatic, monocyclic or polycyclic carbocyclic or heterocyclic group; a chain of aliphatic and / or carbocyclic and / or heterocyclic groups as mentioned above, - Y symbolizes the electron-attracting group as defined above, - (2) those of the aliphatic type carrying a triple bond and which can be represented by formula (II'b): R - CCY (II'b) In said formula (Wb): - RI has the meaning given in formula (II'a), - Y represents an electron-withdrawing group as defined above .

  The invention applies preferentially to unsaturated compounds corresponding to formulas (II'a) and (Wb) in which R1 preferably represents a hydrogen atom or a linear or branched acyclic aliphatic group preferably having from 1 to 12 carbon atoms , saturated, and even more preferably to the compounds of formula (II'a) for which R1, R2, R3 represent a hydrogen atom. . 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 a halogen atom, a nitrile group or a trifluoromethyl group may be mentioned in particular.

  The acyclic aliphatic group, saturated or unsaturated, linear or branched may optionally carry a cyclic substituent. By ring is meant a carbocyclic or heterocyclic ring, saturated, unsaturated or aromatic.

  The acyclic aliphatic group may be linked to the ring by a valence bond, a heteroatom or a functional group such as oxy, carbonyl, carboxy, sulfonyl, etc. As examples of cyclic substituents, it is possible to envisage cycloaliphatic, aromatic or heterocyclic, in particular cycloaliphatic, substituents comprising 6 ring carbon atoms 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. In particular, alkyl or alkoxy groups having 1 to 4 carbon atoms may be mentioned.

  Among the aliphatic groups bearing a cyclic substituent, more particularly aralkyl groups having 7 to 12 carbon atoms, especially benzyl or phenylethyl.

  In the formulas (II 'a) and (II' b), R 1 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.

  As for R2 and R3, 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 benzyl group.

  In formulas (IIa) and or (IIb), R1, R2 and R3 are more particularly hydrogen or R1, is phenyl and R2, R3 are hydrogen.

  Examples of compounds corresponding to formula (II 'a) and (II' b) include, in particular, ethyl or methyl acrylate.

  More specifically, the process according to the present invention can be illustrated by the following reaction (1): R 2 + Ra Ra-X (I) Y (II ') where in formulas (I), (II'), ( III), Ra, R1, R2, R3, X, Y and are defined as above and ---- represents a single or a double bond.

  Of course, in the foregoing and the following, the preferred embodiments stand alone or in combination with each other.

  According to the present invention, the alkyl radicals represent straight or branched chain saturated hydrocarbon radicals of 1 to 20 carbon atoms, preferably 1 to 5 carbon atoms.

  Mention may in particular be made, when they are linear, the methyl, ethyl, propyl, butyl, pentyl, hexyl, octyl, nonyl, decyl, dodecyl, hexadecyl and octadecyl radicals.

  When they are branched or substituted by one or more alkyl radicals, mention may be made especially of the isopropyl, tert-butyl, 2-ethylhexyl, 2-methylbutyl, 2-methylpentyl, 1-methylpentyl and 3-methylheptyl radicals.

  The alkenyl radicals represent hydrocarbon radicals, in straight or linear chain, and comprise one or more ethylenic unsaturations. Among the alkenyl radicals, mention may especially be made of allyl or vinyl radicals.

  The cycloalkyl radical is a saturated or partially unsaturated, non-aromatic mono-, bi- or tricyclic hydrocarbon radical of 3 to 10 carbon atoms, such as, in particular, cyclopropyl, cyclopentyl, cyclohexyl or adamantyl, and the corresponding rings containing one or several unsaturations.

  The term aryl or aromatic carbocycle denotes a hydrocarbon aromatic system, mono or bicyclic of 6 to 12 carbon atoms.

  Among the hydrocarbon aryl radicals, mention may especially be made of the phenyl or naphthyl radical, more particularly substituted by at least one halogen atom.

  Among the aralkyl radicals, mention may be made especially of the benzyl or phenethyl radical.

  Aromatic heterocycles denote the radicals of aromatic systems comprising one or more heteroatoms chosen from nitrogen, oxygen or sulfur, mono or bicyclic, of 5 to 10 carbon atoms. Among the heteroaryl radicals, mention may be made of pyrazinyl, thienyl, oxazolyl, furazanyl, pyrrolyl, 1,2,4-thiadiazolyl, naphthyridinyl, pyridazinyl, quinoxalinyl, phthalazinyl, imidazo [1 , 2-a] pyridine, imidazo [2,1-b] thiazolyl, triazinyl, benzofurazanyl, azaindolyl, benzimidazolyl, benzothienyl, thienopyridyl, thienopyrimidinyl, pyrrolopyridyl, imidazopyridyl, benzoazaindole 1,2,4-triazinyl, benzothiazolyl, furanyl, imidazolyl, indolyl, triazolyl, tetrazolyl, indolizinyl, isoxazolyl, isoquinolinyl, isothiazolyl, oxadiazolyl, pyrazinyl, pyridazinyl, pyrazolyl, pyridine, pyrimidinyl, purinyl, quinazolinyl, quinolinyl, isoquinolyl, 1,3,4-thiadiazolyl, thiazolyl, triazinyl, isothiazolyl, carbazolyl, as well as the corresponding groups resulting from their fusion or from the fusion with the phenyl nucleus. Preferred aromatic heterocycle groups include thienyl, pyrrolyl, quinoxalinyl, furanyl, imidazolyl, indolyl, isoxazolyl, isothiazolyl, pyrazinyl, pyridazinyl, pyrazolyl, pyridyl, pyrimidinyl, quinazolinyl, quinolinyl, thiazolyl, carbazolyl, thiadiazolyl, and groups derived from the fusion with a phenyl ring.

  As preferred aromatic heterocycle group according to the present invention, there may be mentioned furanyl, pyrrolyl, imidazolyl, pirazolyl, thienyl, pyridyl, pyrazinyl, pyrimidinyl, indolyl, purinyl or quinolyl radical; more particularly, the thienyl or pyridyl radical is preferred.

  Preferably, the reaction (1) is carried out in a solvent or solvent mixture, preferably comprising pyridine or quinoline, more preferably pyridine. As cosolvent (s), mention may be made in particular of aprotic polar solvents, alone or as a mixture, such as: oxygenated solvents, in particular ethers, preferably polyethers such as dimethoxy-1,2-ethane or ethers; cyclic such as THF or dioxane; amides or ureas (DMF, N-methylpyrrolidone-2, imidazolidone, tetramethylurea, dimethoxypropylene, etc.); sulfones (for example sulfolane) or sulfoxides (such as DMSO). In these cases, however, it will be necessary to verify that zinc is not capable, in the reaction reactions, of reducing these solvents; nitrile-functional compounds, in particular acetonitrile or adiponitrile.

  Preferably, the reaction is carried out in a DMF / pyridine mixture.

  Preferably, the solvent mixture contains between 10% and 60% by volume of pyridine, more particularly in a proportion of 10% to 15% by volume of pyridine, still more preferably 12%.

  The concentration of compound of formula (I) is preferably between 10-2 and 2 mol / liter, preferably between 2 x 10-2 mol / liter and 1.5 mol / liter.

  The concentration of the compound (II) is greater than or equal to that of the compound (I), preferably equal.

  The reaction (1) is carried out in the presence of cobalt or its derivatives.

  The cobalt or its derivatives can be introduced into the reaction medium in different ways and in different forms, but it is preferable that it be introduced in the form of a salt, preferably a cobaltous salt. CoBr2 is especially preferred. The cobaltous salt may be optionally in coordinated form. Bipyridine-based complexes, in particular 2,2'-bipyridine, or phosphine-based complexes, and more particularly the (CoBr 2) (2,2'-bipyridine) complex, are preferred.

  Preferably, one operates using CoBr2 (2,2'-bipyridine).

  To be effective, it is desirable that the cobalt be present in a minimum concentration of at least 10 -3 mol / liter. To be economical, it is preferable that the cobalt is not too concentrated, so it is preferable that the cobalt content is at most equal to 0.2 mol / liter The bipyridine-cobalt-based complex is preferably formed in situ in the presence of between 0.5 and 2 equivalents of bipyridine relative to cobalt. preferably, an equivalent of 2,2'-bipyridine with respect to cobalt is used.

  Generally, the reaction is carried out in the presence of from 0.05 to 0.5 molar equivalents of Co relative to the starting compound (I), preferably from 0.1 to 0.33 equivalent, and more advantageously from 0.10 to 0, 15 equivalent.

  The reaction (1) is carried out in the presence of a reducing agent. Preferably, zinc or manganese, more particularly manganese, is used. Preferably, zinc or manganese are used in finely divided form, for example in powder form.

  The reducing agent is preferably between 2 and 10 molar equivalents relative to the compound of formula (I) starting. Advantageously, one operates in the presence of 3 to 7 equivalents of manganese powder.

  It is preferred to carry out the reaction in the presence of acid. Without being bound by theory, the present inventors hypothesized that the acid could activate the reductant. Suitable acids include organosoluble acids, especially carboxylic acids, fatty acids or halogenated or perhalogenated acids. Perfluorinated acids are of particular interest because of their solubility in the organic phase and their high acidity. Trifluoroacetic acid or acetic acid is particularly preferred. The acid concentration is advantageously between 10 -3 mol / l and 10 -2 mol / l, preferably 5 x 10 -3 mol / l. The higher value is essentially limited by the amount of reductant in the medium. The amount of acid must be less than that necessary to dissolve the entire reductant and leave enough reductant for the reaction.

  According to the present invention, it has also been possible to replace the acid in equivalent amounts (expressed in moles) with iodine (12). In general, whether it is iodine or acids, it is preferable to set a relatively low level to avoid parasitic reactions, especially the formation of the hydrocarbon in place of the desired organozinc. Also, generally used amounts of acid or iodine less than 10% of the compound of formula (I) expressed in moles, preferably at most equal to 5%.

  Preferentially, the reaction (I) is carried out in the presence of salts. Without being bound by theory, the present inventors hypothesized that the presence of salts would stabilize the intermediately formed hope. As suitable salts, there may be mentioned LiCl, LiBr, NaBr, KBr, NaCl, NaI, FeBr2, ZnBr2. It is preferred to use LiBr or FeBr 2, more preferably LiBr.

  The amount of salts used does not have a particular maximum, but it is preferable to arrange for the salts, after the end of the reaction, not to exceed the solubility of said salt in the media. It is thus preferable to have a salt concentration of between 103 mol / liter and 10 -2 mol / liter. Preferably, 0.1 to 0.2 equivalents of salts are used relative to the compound of formula (I) starting.

  The reaction (1) can be carried out at room temperature or up to a temperature below the boiling point of the solvent.

  Preferably, the reaction is carried out at a temperature of between 20 ° C. and 60 ° C., preferably at about 50 ° C.

  Preferably, when operating with a cobalt derivative in free form, it operates by mixing all the ingredients.

  The progress of the reaction may be followed by any method known per se, for example by chromatography, such as gas chromatography.

  For this, a gas chromatographic control agent such as dodecane may be added to the reaction mixture. The presence of an organometallic may in particular be demonstrated by identifying the iodinated compound on the iodolyzed sample chromatograms by methods known per se.

  According to the invention, conversions as high as 100% can be achieved.

  The reaction is carried out for a period of time such that a satisfactory degree of progress is achieved. Preferably, the reaction is carried out for a period of 5 minutes to 24 hours, preferably 15 minutes to 5 hours.

  Optionally, said method may also include the step of isolating the product obtained.

  The compound thus prepared can be recovered from the reaction mixture by conventional means. For example, the compounds can be recovered by distilling the solvent from the reaction mixture or if necessary after distilling the solvent from the solution mixture, pouring the remainder into water followed by extraction with an organic solvent immiscible in the reaction mixture. water, and distilling the solvent from the extract. In addition, the product may, if desired, be further purified by various techniques, such as recrystallization, reprecipitation or various chromatography techniques, including column chromatography or preparative thin layer chromatography.

  In the reactions described below, it may be necessary to protect the reactive functional groups, for example the hydroxy, amino, imino, thio, carboxy groups, when desired in the final product, to avoid their undesirable participation in the reactions. Traditional protection groups can be used according to standard practice, for examples see T.W. Green and P.G.M. Wuts in Protective Groups in Organic Chemistry, John Wiley and Sons, 1991; J. F. W. McOmie in Protective Groups in Organic Chemistry, Plenum Press, 1973.

  Compounds of formula (I) and / or (II) are commercially available or can be prepared by the application or adaptation of known methods, for example methods as described by Larock in Comprehensive Organic Transformations.

  According to another object, the present application also relates to a composition comprising a cobalt derivative, a reducing agent, a solvent medium comprising an aromatic-type organic solvent and optionally a salt, as previously defined. Preferably, the composition may also contain a cobalt complexing agent and, optionally, the compounds of formula (I) and (II) as previously defined.

  Said composition may also contain an acid or molecular iodine. According to another object, the present invention also relates to the use of said composition for preparing a derivative of formula (III) as defined above.

  The following examples are given by way of non-limiting illustration of the present invention.

  EXAMPLES The reaction according to the invention Ra-X (I) + was carried out under the following reaction conditions A and B from various compounds (I) and (II): A. In the presence of Mn and ZnBr2 50 ml flask, 15 ml of DMF, 2 ml of pyridine, 0.75 mmol of CoBr 2, 0.75 mmol of 2,2'-bipyridine, 7 mmol of ZnBr 2, 7.5 mmol of aromatic bromide, 8 mmol of acrylate are introduced. a CPG control (dodecane) and 40 mmol of manganese powder which is activated by the addition of 50 μl of trifluoroacetic acid. The reaction is carried out at 50 ° C. and its evolution is followed by GC analysis after iodolysis of the samples taken at regular intervals of time. The reaction is continued until the total consumption of the aromatic halide. At the end of the reaction, the medium is hydrolysed with 40 ml of HCl (2N). Then, it is extracted with diethyl ether (3 × 40 mL). The combined organic phases are dried over anhydrous MgSO 4 and the solvent is evaporated under vacuum. The crude product is chromatographed on silica gel with a pentanelether eluent.

B. In the presence of Mn and LiBr.

  In a 50 ml flask 15 mL of DMF, 2 mL of pyridine, 0.75 mmol of CoBr2, 0.75 mmol of 2,2'-bipyridine, 7 mmol of LiBr, 7.5 mmol of aromatic bromide, 8 mmol acrylate, a control CPG (dodecane) and 40 mmol of manganese powder which is activated by the addition of 50 μl of trifluoroacetic acid. The reaction is carried out at 50 ° C. and its evolution is followed by GC analysis after iodolysis of the samples taken at regular intervals of time. The reaction is continued until the total consumption of the aromatic halide. At the end of the reaction, the medium is hydrolysed with 40 ml of HCl (2N). Then, it is extracted with diethyl ether (3 × 40 mL). The combined organic phases are dried over anhydrous MgSO 4 and the solvent is evaporated under vacuum. The crude product is chromatographed on silica gel with a pentane / ether eluent.

Example 1

  1. The compound is prepared according to ethyl 4- [2- (ethoxycarbonyl) ethyl] benzoate from compounds (I) and (II) for which X = Br, A = phenyl, n = 1, B = -COOEt, R1 = R2 = R3 = H and Y = COOEt.

  according to the conditions A and B. The purification is carried out by chromatography using an eluent: pentane / ether 85/15.

  The yields are respectively 26% according to conditions A and 72% according to conditions B. 2. The characteristics of the product obtained are as follows.

  C14H18O4 M = 250 g.mor1; 1 H NMR (200 MHz) bppm: 7.88 (He, 2H, d, JHeHf = 8.3Hz), 7.19 (Hf, 2H, d, 30 JHfHe = 8.3Hz), 4.27 (Hb, 2H, q, JHbHa = 7.2Hz ), 4.03 (Hk, 2H, q, JHkH1 = 7.2Hz), 2.91 (H ", 2H, t, JH" H '= 7.7Hz), 2.54 (H', 2H, t, JH'H "= 7.7Hz ), 1.29 and 1. 13 (Ha and Hh, 6H, 2t, JHaHb = JHkHi = 7.1 Hz) 13C NMR bppm: 172.2 (Ci), 166. 2 (C), 145.6 (C9), 129.7-129.4 (Cd, e) 128.4 (Cf), 60.4 (Ch), 35.1 (C '), 30.6 (C "), 14.0 (Ca'I) Mass (%): 250 (M, 34), 205 (36), 179 (23); ), 177 (29), 176 (100), 149 (17), 148 (66), 133 (17), 131 (45), 107 (11), 103 (10), 79 (11), 77 (13). ) IR (v cm-1): 2980, 1730, 1640

Example 2

  1. The following compound is prepared, ethyl 4- [2- (Methoxycarbonyl) ethyl] benzoate from compounds (I) and (II) for which X = Br, A = Phenyl, n = 1, B = p-COOEt, R, = R2 = R3 = H, and Y = -COOMe. k

  according to the conditions B. The purification is carried out by chromatography using an eluent: pentanelether 90110.

The yield obtained is 82%.

  2. The characteristics of the product obtained are as follows.

  C13H1604 M = 236 gmol -1, 1 H NMR (200 MHz) bppm: 7.90 (He, 2H, d, JHeHf = 8.1 Hz), 7.19 (Hf, 2H, d, JHfHe = 8.1 Hz), 4.29 (Nb , 2H, q, JH) Ha = 7.1Hz), 3.58 (Hk, 3H, s), 2.93 (H ", 2H, t, JH'H" = 7.6Hz), 2.57 (H ', 3H, t, JH). "H" = 7.1 Hz), 1.31 (Ha, 3H, t, JHaHb = 7.1 Hz) 13 C NMR bp: 172.7 (C 1), 166.2 (C), 145.7 (C), 129.7-128.0 (Cd, e, f) 128.1 (C9), 60.5 (Cb), 51.4 (Ck), 34.9 (C 1), 30.6 (C "), 14.0 (Ca) Mass (%): 237 (M + 1, 11), 236 (M, 33) , 208 (15), 191 (56), 177 (19), 176 (100), 149 (22), 148 (79), 133 (18), 132 (11), 131 (61), 121 (10) IR (cm-1): 2980, 1730, 1620

Example 3

  1. The following compound is prepared, ethyl 3- [4- (trifluoromethylphenyl)] propanoate from compounds (I) and (II) for which X = Br, A = Phenyl, n = 1, B = p- CF3, R1 = R2 = R3 = H, Y = -COOEt.

  according to the conditions A. The purification is carried out by chromatography using an eluent: pentane / ether 90/10.

The yield obtained is 42%.

  2. The characteristics of the product obtained are as follows. C12H1302F3; M = 246 g.mol_1; 1H NMR liquid (200 MHz) bp: 7.45 (Hh, 2H, d, JHhHg = 8.1Hz), 7.22 (Hg, 2H, d, JHgHh = 8.1Hz), 4.02 (Hb, 2H, q, JHbHa = 7.2Hz ), 2.92 (He, 2H, t, JHeHd = 7.6Hz), 2.54 (Hd, 2H, t, JHdHe = 7.6Hz), 1.35 (Ha, 3H, t, JHaHb = 7.2Hz) 13C NMR bppm: 172.4 (C), 144.7 (Cf), 128.7 (Cl 5, 125.3 (Ch), 121.6 (C1), 60.5 (Ch), 35.4 (Cd), 30.7 (Ce), 14.1 (Ce) 19 F NMR bppm: -62.8 ( 3F, s) Mass (%): 246 (M, 25), 175 (19), 173 (33), 172 (100), 159 (19), 153 (19), 133 (16) IR (νcm) 1): 2980, 1720, 1620

Example 4

  1. The following compound is prepared, ethyl 3- [3- (cyanophenyl)] propanoate from the compounds (I) and (II) for which X = Br, A = Phenyl, n = 1, B = m- CN, R1 = R2 = R3 = H and Y = -COOEt. F3C

  according to the conditions A. The purification is carried out by chromatography using a pentane / ether 85/15 eluent.

The yield obtained is 32%.

  2. The characteristics of the product obtained are as follows.

  C12H1302N; M = 203 gmol-1; 1H NMR liquid (200 MHz) δppm: 7.39-7.31 (H₂H'₁H₁HH, m), 4.01 (Hb, 2H, q, JHbHa = 7.0Hz), 2.87 (He, 2H, t, JHeHd = 7.5Hz), 2.52 (Hd, 2H, t, JHdHe = 7.5Hz), 1.10 (Ha, 3H, t, JHaHb = 7.0Hz) 13C NMR ompm: 171.8 (C), 141.8 (Cf), 132.6-129.0 (Cg) h), 118.5 (C), 112. 4 (C 1), 60.4 (Cb), 34.9 (Cd), 30.0 (Ce), 13.8 (Ca) Mass (%): 203 (M, 44), 175 ( 10), 158 (22), 157 (22), 132 (13), 131 (14), 130 (95), 129 (100), 116 (19), 103 (18) IR (νcm-1): 2980, 2210, 1730

Example 5

  1. The following compound is prepared, ethyl 3- [4- (cyanophenyl)] propanoate from compounds (I) and (II) for which X = Br, A = Phenyl, n = 1, B = p- CN, R1 = R2 = R3 = H and Y = -COOEt.

  according to the conditions A and B. The purification is carried out by chromatography using an eluent: pentane / ether 85/15.

  The yields are respectively 39% according to conditions A and 62% according to conditions B. 2. The characteristics of the product obtained are as follows.

  C12H1302N; M = 203 gmol -1, 1 H NMR (200 MHz) 5 ppm: 7.58 (H +, 2H, m), 7.28 (Hg, 2H, d, JHgH + = 8.2 Hz), 4.06 (Hb, 2H, q). , JHbHa = 7.1Hz), 2.96 (He, 2H, t, JHeHd = 7.5Hz), 2.59 (Hd, 2H, t, JHdHe = 7.5Hz), 1.17 (Ha, 3H, t, JHaHb = 7.1Hz) NMR13C bppm : 171.8 (Cc), 145.9 (Cf), 132.0-128.9 (Cg '' '), 118.6 (C1), 109.8 (C'), 60.1 (Cb), 34.7 (Cd) 330.7 (Ce), 13.8 (Ca) Mass (%): 203 (M, 44), 175 (10), 158 (22), 157 (22), 132 (13), 131 (14), 130 (95), 129 (100), 116 (20) , 104 (10), 103 (18), 77 (10) IR (νcm-1): 2980, 2210, 1730

Claims (41)

  1. A process for forming a carbon-carbon bond according to a coupling reaction between a compound (I) comprising an unsaturation at position a of a leaving group and an unsaturated compound (II), characterized in that the reaction takes place in a solvent medium, in the presence of an effective amount of a cobalt-based catalyst and in the presence of a reducing agent, in a medium comprising an aromatic-type organic solvent whose characteristic is to comprise at least one nitrogen atom bearer of a free doublet.   2. Method according to claim 1, characterized in that the solvent is pyridine or a mixture of solvents comprising pyridine.   3. Method according to claim 1 or 2, characterized in that the solvent is a DMF / pyridine mixture.   4. Process according to any one of the preceding claims, characterized in that the cobalt is used in the form of an optionally coordinated cobaltous salt.   5. Method according to any one of the preceding claims, characterized in that the cobalt is used in CoBr2 form (2,2'-bipyridine).   6. Method according to any one of the preceding claims, characterized in that the reducing agent is manganese.   7. Method according to claim 6, characterized in that the manganese is in powder form.   8. Process according to any one of the preceding claims, characterized in that the said reaction is carried out in the presence of salts.   9. Method according to claim 8, characterized in that said salts are selected from LiCl, LiBr, NaBr, KBr, NaCl, NaI, FeBr2, ZnBr2.   10. Process according to any one of claims 8 or 9, characterized in that the salts are selected from LiBr or FeBr2.   11. Process according to any one of the preceding claims, characterized in that the said reaction is carried out in the presence of acid or molecular iodine.   12. Process according to any one of the preceding claims, characterized in that the reaction is carried out in the presence of 1 molar equivalent of the compound (II) relative to the compound (I).   13. Method according to any one of the preceding claims, characterized in that one operates in the presence of 0.05 to 0.5 molar equivalents of cobalt relative to the compound (I).   14. Method according to any one of the preceding claims, characterized in that one operates in the presence of 0.1 to 0.33 molar equivalents of cobalt relative to the compound (I).   15. Process according to any one of the preceding claims, characterized in that the reducing agent is present between 2 and 10 molar equivalents relative to the compound of formula (I).   16. Process according to any one of the preceding claims, characterized in that the reaction is carried out in the presence of 3 to 7 molar equivalents of reducing agent relative to the compound of formula (I).   17. Method according to any one of claims 9 to 11, characterized in that one operates in the presence of 0.1 to 0.2 equivalent of salts relative to the compound of formula (I).   18. Process according to any one of the preceding claims, characterized in that the acid or iodine is present at a concentration of less than 10% of that of the product (I).   19. Process according to any one of the preceding claims, characterized in that the reaction is carried out at a temperature of between 20 and 60 ° C.   20. Process according to any one of the preceding claims, characterized in that the said compound comprising an unsaturation in position a of a leaving group is a compound comprising a leaving group X symbolized by the formula (I): Ra X (I in which formula: Ra represents a hydrocarbon group comprising from 2 to 20 carbon atoms and has a double bond or a triple bond located in position a of a leaving group X or a carbocyclic and / or heterocyclic, aromatic, monocyclic or polycyclic, and X represents a leaving group.   21. Process according to claim 20, characterized in that X represents a halogen atom or a sulphonic ester group of formula -OSO2-Re, in which Re is a hydrocarbon group, optionally perhalogenated.   22. The method of claim 21, characterized in that Re represents a linear or branched alkyl group having 1 to 4 carbon atoms optionally perfluorinated.   23. The method of claim 21 or 22, characterized in that Re represents a methyl group, ethyl, phenyl, tolyl or trifluoromethyl.   24. Process according to any one of Claims 20 to 23, characterized in that X represents a bromine or chlorine atom.   25. Process according to any one of claims 20 to 24, characterized in that Ra represents: an aliphatic hydrocarbon group comprising a double bond or a triple bond at the α-position of the leaving group or a cyclic hydrocarbon group comprising an unsaturation bearing the leaving group, or - a carbocyclic and / or heterocyclic, aromatic, monocyclic or polycyclic group.   26. Process according to any one of claims 20 to 25, characterized in that Ra is chosen from the aliphatic type groups bearing a double bond which can be represented by the formula (la): R; - C = C - X (la) 1 1 R; R ;;; in said formula (la): - R ;, R ;; and R ;;;, identical or different, represent a hydrogen atom or a hydrocarbon group having from 1 to 20 carbon atoms which may be a linear or branched, saturated or unsaturated aliphatic group; a saturated, unsaturated or aromatic, monocyclic or polycyclic carbocyclic or heterocyclic group; a chain of aliphatic and / or carbocyclic and / or heterocyclic groups as mentioned above, - X symbolizes the leaving group as defined according to any one of the claims 20 to 24.   27. Process according to any one of claims 20 to 25, characterized in that Ra is chosen from aliphatic groups bearing a triple bond and which can be represented by formula (Ib): R; - CC X (lb) in said formula (lb): - R; has the meaning given in formula (la) according to claim 25, X represents a leaving group as defined according to any one of claims 20 to 24.   28. Process according to any one of Claims 20 to 25, characterized in that Ra is chosen from carbocyclic and / or heterocyclic, aromatic, monocyclic or polycyclic type groups that can be represented by the formula (Ic). : X (B) n (Ic) in which: D represents the remainder of a ring forming all or part of a carbocyclic and / or heterocyclic, aromatic, monocyclic or polycyclic system; B, which are identical or different, represent any electro-donating or electron-withdrawing substituent not interfering with the reaction; X represents a leaving group as previously defined according to any one of claims 120 to 24, n represents the number of substituents on the ring.   29. The method of claim 28, characterized in that B represents an electro-attractor group.   30. Process according to claim 28 or 29, characterized in that B 30 is chosen from the groups of formula -COR ', -CN, -SO2R, -COOR ", perhaloalkyl, -F, alkyl, -NO2, where R represents an alkyl, cycloalkyl radical optionally substituted by one or more fluorine atoms, R 'represents an alkyl, cycloalkyl, aryl, aralkyl or alkenyl radical, and R "represents a hydrogen atom or an alkyl, aryl or aralkyl radical of preferably an alkyl radical.   31. Process according to any one of claims 28 to 30, characterized in that B represents the CN, perfluoroalkyl, -COR ', -SO2R, -COOR "radicals where R, R', R" are defined as above.   32. Process according to any one of claims 28 to 31, characterized in that D is the residue of a cyclic compound, 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 orthoetheric 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 constituted by at least 2 heterocycles containing at least one heteroatom in each ring of which at least at least one of the two rings is aromatic and forms between them ortho- or ortho- and peri-condensed 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 ortho- or ortho- and peri-condensed systems.   33. Method according to any one of claims 28 to 32, characterized in that D represents a benzene ring.   34. Process according to any one of claims 28 to 33, characterized in that n is less than or equal to 4.   35. Process according to any one of the preceding claims, characterized in that the said unsaturated compound is represented by the formula: Rb-Y (II) in which formula: Rb represents a hydrocarbon group comprising from 2 to 20 carbon atoms and has a double bond or a triple bond located in position a of the group Y; and Y represents an electron-withdrawing group.   36. Process according to claim 35, characterized in that Y is chosen from groups of formula -COR ', -CN, -SO2R, -COOR ", perhaloalkyl, -NO2, where R represents an optionally substituted alkyl, cycloalkyl radical. with one or more fluorine atoms, R 'represents an alkyl, cycloalkyl, aryl, aralkyl or alkenyl radical and R "represents a hydrogen atom or an alkyl, aryl or aralkyl radical.   37. Process according to claim 35 or 36, characterized in that Y represents the radicals -COOR ", -COR ', -CN.   38. Process according to any one of claims 35 to 37, characterized in that the compounds of formula (II) are represented by the formula (II '): in which formula (II'): represents a double or triple binding, it being understood that when represents a triple bond, R1 or R3 form with R2 a bond; R1, R2, R3, which may be identical or different, 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 or aromatic, monocyclic or polycyclic carbocyclic or heterocyclic group; a chain of aliphatic and / or carbocyclic and / or heterocyclic groups as above, optionally substituted, or R1 or R3 together with R2 a bond, - Y is as defined in any one of claims 36 or 37.   39. Process according to claim 38, characterized in that R1, R2 and R3 represent more particularly a hydrogen atom or R1 represents a phenyl group and R2, R3 represent a hydrogen atom.   40. Composition comprising a cobalt derivative, a reducing agent, a solvent medium comprising an aromatic-type organic solvent, and, optionally, a salt, as defined in any one of Claims 1 to 10.   41. A composition according to claim 40 further comprising a cobalt complexing agent and / or the products of formula (I) and / or (II), and / or an acid or molecular iodine as defined in any one of claims 11 to 39.   41. Use of the composition according to claim 39 or 40 for carrying out the method according to any one of claims 1 to 38.