WO2016016414A1 - Method for creating uncatalyzed carbon-carbon bonds from carbonylated compounds - Google Patents

Abstract

The present invention relates to a method for preparing a compound of Formula (I) via reaction between a compound of Formula (II) and a compound of Formula (III) in the absence of a catalyst, particularly a metal catalyst, and a ligand and in the presence of a base (I), (II), or (III). The invention also relates to the use of said method for preparing compounds of interest, particularly Tamoxifen.

Description

 Process for creating uncatalyzed carbon-to-carbon bonds from

 carbonyl compounds

The present invention relates to a process for the creation of carbon-carbon bonds (CC bond) from a carbonyl compound, and in particular to a process for alpha-arylation (α-arylation) of carbonyl compounds, in the absence of a catalyst, especially metal catalyst, and ligand. The present invention also relates to the preparation of synthons (or "building blocks") for the preparation of molecules of interest, particularly in the field of pharmacy, cosmetics, agrochemistry, etc.

Usually, any molecule resulting from the arylation of carbonyl compounds is obtained by palladium catalysis using phosphine-type complex ligands (Bellina et al., Chem.Rev., 2010, 10, 1082-1146 and Johansson et al., Angew.Chem.Int., 2010, 49, 676-707). However, the palladium catalysts and the ligands used in these methods are very expensive and toxic.

 Methods have also been developed employing milder copper catalysis (WO2013182640). However, this process still requires the implementation of a metal catalyst and ligands.

It is therefore necessary to provide a process for the creation of CC bonds from a carbonyl compound, and in particular a carbonyl type nucleophilic arylation process, which makes it possible to meet the drawbacks of the methods of the state of the art, and in particular, which is economical and has less or no toxicity.

An object of the present invention is therefore to provide a carbon-carbon bonding process (C-C) from carbonyl compounds, using no catalyst, including metal catalyst or ligand.

 An object of the present invention is in particular to provide such a process which is a method of arylation of carbonyl compounds, preferably alpha-arylation of carbonyl compounds.

Yet another object of the present invention is to provide a process for the preparation of synthons for the preparation of molecules of interest, in particular in the field of pharmacy, agrochemistry, etc. Yet another object of the present invention is to provide a process for the preparation of molecules of interest, in particular in the field of pharmacy, agrochemistry, etc.

 Still other objects will appear on reading the description of the invention which follows.

The present invention relates to a process for the preparation of a compound of formula (I) by reaction between a compound of formula (II) and a compound of formula (III) in the absence of a catalyst, in particular a metal catalyst, and a ligand and in the presence of a base

in which :

R ¹ represents:

 a hydrogen atom;

 an alkyl group comprising from 1 to 15 carbon atoms, linear or branched,

an alkenyl group comprising from 1 to 15 carbon atoms, linear or branched, and comprising at least one unsaturation,

 an aryl group comprising from 6 to 14, preferably from 6 to 10, carbon atoms, substituted or unsubstituted,

 a heteroaryl group comprising from 5 to 14, preferably from 5 to 10, members of which at least one heteroatom, chosen in particular from the nitrogen atom, the sulfur atom or the oxygen atom, substituted or unsubstituted; substituted

 a cycloalkyl group comprising from 3 to 14, preferably from 3 to 10, carbon atoms, substituted or unsubstituted, and optionally comprising at least one unsaturation,

 a heterocyclic group comprising from 5 to 14, preferably from 5 to 10, members, of which at least one heteroatom selected from the nitrogen atom, the sulfur atom or the oxygen atom, substituted or unsubstituted and optionally comprising at least one unsaturation,

- R ² represents:

 an alkyl group comprising from 1 to 15 carbon atoms, linear or branched,

an alkenyl group comprising from 1 to 15 carbon atoms, linear or branched, and comprising at least one double bond, an aryl group comprising from 6 to 14, preferably from 6 to 10, carbon atoms, substituted or unsubstituted,

 a heteroaryl group comprising from 5 to 14, preferably from 5 to 10, members of which at least one heteroatom, chosen in particular from the nitrogen atom, the sulfur atom or the oxygen atom, substituted or unsubstituted; substituted

 a heterocyclic group comprising from 5 to 14 members, preferably from 5 to 10, of which at least one heteroatom chosen from the nitrogen atom, the sulfur atom or the oxygen atom, substituted or unsubstituted, and optionally comprising at least one unsaturation,

 an O-alkyl group, alkyl, linear or branched, comprising from 1 to 15 carbon atoms,

 an O-aryl group, aryl, substituted or unsubstituted, comprising from 6 to 14, preferably from 6 to 10, carbon atoms,

 an O-heteroaryl group, substituted or unsubstituted heteroaryl, comprising from 5 to 14, preferably from 5 to 10, members of which at least one heteroatom, in particular chosen from the nitrogen atom, the sulfur or the oxygen atom,

a cycloalkyl group comprising from 3 to 14, preferably from 3 to 10, carbon atoms, substituted or unsubstituted, and optionally comprising at least one unsaturation,

 an O-cycloalkyl group, cycloalkyl, which is substituted or unsubstituted, comprising

3 to 14, preferably 3 to 10 carbon atoms and optionally comprising at least one unsaturation;

R ³ represents:

 a vinyl group comprising from 2 to 10 carbon atoms, substituted or unsubstituted,

 an aryl group comprising from 6 to 14, preferably from 6 to 10, carbon atoms, substituted or unsubstituted,

 a heteroaryl group comprising from 5 to 14, preferably from 5 to 10, members of which at least one heteroatom, chosen in particular from the nitrogen atom, the sulfur atom or the oxygen atom, substituted or unsubstituted; substituted

 X represents a halogen atom chosen from chlorine, bromine or iodine or sulphonic acid esters, for example tosylate, mesylate or triflate.

Preferably X represents a halogen atom selected from chlorine, bromine or iodine. Preferably, R ¹ is chosen from:

 a linear or branched alkyl group comprising from 1 to 15 carbon atoms,

 an alkenyl group comprising from 1 to 15 carbon atoms, linear or branched, and comprising at least one unsaturation,

 an aryl group comprising from 6 to 14, preferably from 6 to 10, carbon atoms, which is unsubstituted or substituted, in particular with one or more substituents chosen from:

^■ a halogen atom, preferably chlorine, bromine, fluorine, preferably chlorine;

^■ an OH group;

^■ a group of formyl - (0) _p alkyl, alkyl, linear or branched, comprising 1 to 15 carbon atoms, preferably 1 to 10 carbon atoms, for example from 1 to 6 carbon atoms and p represents 0 or 1;

^■ an alkenyl group, linear or branched, comprising 1 to 15 carbon atoms and comprising at least one unsaturation;

^■ perfluoroalkyl, alkyl, linear or branched, comprising 1 to 15 carbon atoms, preferably trifluoroalkyl, eg, trifluoromethyl;

^■ an aryl comprising from 6 to 14, preferably 6 to 10 carbon atoms substituted or unsubstituted.

Preferably, R ¹ represents an aryl group comprising from 6 to 14, preferably from 6 to 10, carbon atoms, preferably phenyl, which is unsubstituted or substituted in particular with one or more substituents chosen from:

^■ a halogen atom, preferably chlorine, bromine, fluorine, preferably chlorine;

^■ an OH group;

^■ a group of formyl - (0) _p alkyl, H'alkyle linear or branched comprising from 1 to 15 carbon atoms, preferably 1 to 10 carbon atoms, for example from 1 to 6 carbon atoms and p represents 0 or 1;

^■ perfluoroalkyl, alkyl, linear or branched, comprising 1 to 15 carbon atoms, preferably trifluoroalkyl, eg, trifluoromethyl;

^■ an aryl comprising from 6 to 14, preferably 6 to 10 carbon atoms substituted or unsubstituted, preferably phenyl. Preferably, R ² is chosen from:

 a linear or branched alkyl group comprising from 1 to 15 carbon atoms,

 a cycloalkyl group comprising from 3 to 14, preferably from 3 to 10, optionally substituted carbon atoms,

 a linear or branched alkyl group, Oalkyl, comprising from 1 to 15 carbon atoms,

 an aryl group comprising from 6 to 14, preferably from 6 to 10, carbon atoms, preferably phenyl, which is unsubstituted or substituted in particular with one or more substituents chosen from:

^■ a halogen atom, preferably chlorine, bromine, fluorine, preferably chlorine;

^■ an OH group;

^■ a group of formyl - (0) _p alkyl, alkyl, linear or branched, comprising 1 to 15 carbon atoms, preferably 1 to 10 carbon atoms, for example from 1 to 6 carbon atoms and p represents 0 or 1;

^■ a linear or branched alkenyl group comprising 1 to 15 carbon atoms and comprising at least one unsaturation;

^■ perfluoroalkyl, alkyl, linear or branched, comprising 1 to 15 carbon atoms, preferably trifluoroalkyl, eg, trifluoromethyl;

^■ an aryl comprising from 6 to 14, preferably 6 to 10 carbon atoms substituted or unsubstituted.

Preferably, R ³ is chosen from:

 a heteroaryl group comprising from 5 to 14, preferably from 5 to 10, members of which at least one heteroatom, preferably pyridine, which is unsubstituted or substituted in particular with one or more substituents chosen from:

^■ a halogen atom, preferably chlorine, bromine, fluorine, preferably chlorine;

^■ an OH group;

^■ a group of formyl - (0) _p alkyl, alkyl, linear or branched, comprising 1 to 15 carbon atoms, preferably 1 to 10 carbon atoms, for example from 1 to 6 carbon atoms and p represents 0 or 1; ^■ a linear or branched alkenyl group comprising 1 to 15 carbon atoms and comprising at least one unsaturation;

^■ perfluoroalkyl, alkyl, linear or branched, comprising 1 to 15 carbon atoms, preferably trifluoroalkyl, eg, trifluoromethyl;

^■ an aryl comprising from 6 to 14, preferably 6 to 10 carbon atoms substituted or unsubstituted.

 an aryl group comprising from 6 to 14, preferably from 6 to 10, members, preferably phenyl or naphthyl, unsubstituted or substituted in particular with one or more substituents chosen from:

^■ a halogen atom, preferably chlorine, bromine, fluorine, preferably chlorine;

^■ an OH group;

^■ a group of formyl - (0) _p alkyl, alkyl, linear or branched, comprising 1 to 15 carbon atoms, preferably 1 to 10 carbon atoms, for example from 1 to 6 carbon atoms and p represents 0 or 1;

^■ a linear or branched alkenyl group comprising 1 to 15 carbon atoms and comprising at least one unsaturation;

^■ perfluoroalkyl, alkyl, linear or branched, comprising 1 to 15 carbon atoms, preferably trifluoroalkyl, eg, trifluoromethyl;

^■ an aryl comprising from 6 to 14, preferably 6 to 10 carbon atoms substituted or unsubstituted. erence, R ³ is selected from:

 a heteroaryl group comprising from 5 to 14, preferably from 5 to 10, members of which at least one heteroatom, preferably pyridine, which is unsubstituted or substituted in particular with one or more substituents chosen from:

^■ an OH group;

A group of formyl - (O) _p alkyl, alkyl, linear or branched, comprising

1 to 15 carbon atoms, preferably 1 to 10 carbon atoms, for example 1 to 6 carbon atoms and p is 0 or 1;

^■ a linear or branched alkenyl group comprising 1 to 15 carbon atoms and comprising at least one unsaturation; ^■ perfluoroalkyl, alkyl, linear or branched, having 1 to 15 carbon atoms, preferably trifluoroalkyl, eg trifluoromethyl;

^■ an aryl comprising from 6 to 14, preferably 6 to 10 carbon atoms substituted or unsubstituted.

 an aryl group comprising from 6 to 14, preferably from 6 to 10, members, preferably phenyl or naphthyl, unsubstituted or substituted in particular by one or more substituents chosen from:

^■ an OH group;

^■ a group of formyl - (0) _p alkyl, alkyl, linear or branched, comprising 1 to 15 carbon atoms, preferably 1 to 10 carbon atoms, for example from 1 to 6 carbon atoms and p represents 0 or 1;

^■ a linear or branched alkenyl group comprising 1 to 15 carbon atoms and comprising at least one unsaturation;

^■ perfluoroalkyl, alkyl, linear or branched, comprising 1 to 15 carbon atoms, preferably trifluoroalkyl, eg, trifluoromethyl;

^■ an aryl comprising from 6 to 14, preferably 6 to 10 carbon atoms substituted or unsubstituted.

Preferably, R ³ is chosen from:

 a heteroaryl group comprising from 5 to 14, preferably from 5 to 10, members of which at least one heteroatom, preferably pyridine, which is unsubstituted or substituted in particular with one or more substituents chosen from:

^■ an alkyl, linear or branched, comprising 1 to 15 carbon atoms, preferably 1 to 10 carbon atoms, for example from 1 to 6 carbon atoms and p represents 0 or 1;

^■ a halogen atom, preferably chlorine, bromine, fluorine, preferably chlorine;

 an aryl group comprising from 6 to 14, preferably from 6 to 10, members, preferably phenyl or naphthyl, unsubstituted or substituted in particular by one or more substituents chosen from:

^■ a halogen atom, preferably chlorine, bromine, fluorine, preferably chlorine;

^■ an OH group; ^■ a group of formyl - (0) _p alkyl, alkyl, linear or branched, comprising 1 to 15 carbon atoms, preferably 1 to 10 carbon atoms, for example from 1 to 6 carbon atoms and p represents 0 or 1;

^■ a linear or branched alkenyl group comprising 1 to 15 carbon atoms and comprising at least one unsaturation.

Preferably, R ³ is chosen from:

 a heteroaryl group comprising from 5 to 14, preferably from 5 to 10, members of which at least one heteroatom, preferably pyridine, which is unsubstituted or substituted in particular with one or more substituents chosen from:

^■ an alkyl, linear or branched, comprising 1 to 15 carbon atoms, preferably 1 to 10 carbon atoms, for example from 1 to 6 carbon atoms and p represents 0 or 1;

 an aryl group comprising from 6 to 14, preferably from 6 to 10, members, preferably phenyl or naphthyl, unsubstituted or substituted in particular by one or more substituents chosen from:

^■ an OH group;

^■ a group of formyl - (0) _p alkyl, alkyl, linear or branched, comprising 1 to 15 carbon atoms, preferably 1 to 10 carbon atoms, for example from 1 to 6 carbon atoms and p represents 0 or 1;

^■ a linear or branched alkenyl group comprising 1 to 15 carbon atoms and comprising at least one unsaturation.

Preferably, R ³ is chosen from:

 an aryl group comprising from 6 to 14, preferably from 6 to 10, members, preferably phenyl or naphthyl, unsubstituted or substituted in particular by one or more substituents chosen from:

^■ OH;

^■ a group of formyl - (0) _p alkyl, alkyl, linear or branched, comprising 1 to 15 carbon atoms, preferably 1 to 10 carbon atoms, for example from 1 to 6 carbon atoms and p represents 0 or 1;

^■ a linear or branched alkenyl group comprising 1 to 15 carbon atoms and comprising at least one unsaturation. preferably X is iodine or bromine, preferably iodine. In the context of the invention, the following terms mean:

 a halogen atom, a fluorine, chlorine, bromine or iodine atom;

 an alkyl group, a saturated, linear or branched aliphatic group comprising from 1 to 15 carbon atoms. For example, mention may be made of methyl, ethyl, propyl, butyl or tert-butyl.

 an alkenyl group, a mono or polyunsaturated, linear or branched aliphatic group comprising from 1 to 15 carbon atoms, for example comprising 1 or 2 ethylenic unsaturations;

 an aryl group, a mono or polycyclic aromatic ring group comprising from 6 to 14, preferably from 6 to 10, carbon atoms; said cycle being optionally substituted;

 a cycloalkyl group, a mono or polycyclic aliphatic cyclic group, comprising from 3 to 14, preferably from 3 to 10, carbon atoms, and optionally one or more unsaturation; said cycle being optionally substituted; said cycle being optionally substituted;

 a heteroaryl group, an aromatic cyclic group, mono or polycyclic, comprising from 5 to 14, preferably from 5 to 10, members of which at least one heteroatom, chosen in particular from nitrogen, oxygen and sulfur, preferably nitrogen or oxygen; said cycle being optionally substituted;

a heterocycle group, a cyclic group, mono or polycyclic, comprising from 5 to 14, preferably from 5 to 10, members of which at least one heteroatom, chosen in particular from nitrogen, oxygen and sulfur, preferably nitrogen or oxygen; and optionally one or more unsaturation; said cycle being optionally substituted;

a hydroxyl group, a group of formula OH.

In one embodiment, the process of the invention is carried out in the presence of a solvent.

Preferably, the solvent is chosen from acetamide and its derivatives, alkylsulfoxides, the alkyl being linear or branched and comprising from 1 to 15, preferably from 1 to 10, carbon atoms. By acetamide derivatives is meant in particular dialkylformamides, the alkyl, identical or different, is linear or branched and comprises from 1 to 15, preferably from 1 to 10, carbon atoms. Preferably, the solvent is chosen from acetamide and its derivatives. Preferably, the solvent is dimethylformamide (DMF) or dimethylsulfoxide (DMSO), preferably dimethylformamide. According to the invention, the base may be chosen from alkali or alkaline earth alkoxides of formula (M ¹ (OR) _s ) or mixtures thereof.

Preferably, M ¹ represents Li, Na, K, Rb, Cs, Fr, Be, Mg, Ca, Sr, Ba or Ra, preferably K, s represents 1 or 2 and R is chosen from the group consisting of groups alkyl, benzyl and aryl; in particular the base may be potassium terbutylate.

Preferably, the process of the invention is carried out in the presence of a solvent chosen from acetamide and its derivatives, alkylsulfoxides, the alkyl being linear or branched and comprising from 1 to 15, preferably from 1 to 10, carbon atoms, as defined above and in the presence of a base selected from alkali or alkaline earth alkoxides of formula (M ¹ (OR) _s ) or mixtures thereof as defined above.

Preferably, the process of the invention is carried out in the presence of a solvent chosen from acetamide and its derivatives, and in the presence of a base chosen from alkali or alkaline-earth alkoxides of formula (M ¹ ( OR) _s ) or mixtures thereof as defined above.

Preferably, the base is potassium terbutylate and the solvent is DMF or DMSO, preferably DMF.

Particularly advantageously, the process of the invention can be carried out at lower temperatures than palladium-catalyzed processes of the state of the art, this may allow energy savings.

 Thus, the process of the invention can be carried out at a temperature ranging from

20 to 200 ° C, preferably 40 to 150 ° C.

 Preferably, the process is carried out at atmospheric pressure, autogenous pressure of the medium or with a slight overpressure. Preferably, in the process of the invention, the molar ratio of compound of formula

(III) / compound of formula (II) is from 0.5 to 10, preferably from 0.5 to 5, especially from 1.5 to 5.

Preferably, in the process of the invention, the molar amount of base is from 0.2 to 6 equivalents, preferably from 0.5 to 5 equivalents, for example from 0.5 to 2 equivalents, relative to the amount molar compound of formula (II). Usually, the reaction time is between 1 and 36 hours, preferably 12 to 48 hours. Advantageously, the method of the invention may allow the preparation of synthons (or "building blocks") for the preparation of molecules of interest, in particular in the field of pharmacy, agrochemistry, etc. The method of the invention thus implemented has the advantage of being compatible with numerous chemical functions thus making it possible to reduce or even avoid the implementation of protection / deprotection reactions.

Thus, the invention also relates to a method for preparing synthons for the preparation of molecules of interest comprising the following steps:

 1) implementation of the process for preparing a compound of formula (I) according to the invention;

 2) functionalization of the compound of formula (I) by methods known to those skilled in the art.

 Preferably, the functionalization may consist for example of:

 an addition reaction of an organometallic reagent to the carbonyl of the compound of formula (I);

 the addition of an alkyl, aryl or heteroaryl group;

 an olefination reaction; or

 - a reaction of Shapiro. In particular, the invention also relates to the preparation of a compound of formula (IV) with R represents a hydroxyl group comprising the implementation of the carbon-carbon bond creation process according to the invention

Preferably, the compounds of formula (IV) are the following compounds preferably

 The invention relates to a process for the preparation of a compound of formula (IV) comprising the preparation of a compound of formula (Ia) by carrying out the C-C bonding creation process according to the invention

 In one embodiment, the process for preparing the compound of formula (IV) comprises the following steps:

 a) preparing a compound of formula (Ia) by carrying out the C-C bonding creation process according to the invention;

b) reacting the compound of formula (la) with a compound of formula Li-Ph-O (CH ₂ ) ₂ -NMe ₂ in THF at low temperature, especially below 0 ° C., preferably of the order of 78 ° C;

 c) reaction of the compound obtained in b) with HCl in an alcohol, for example methanol, at reflux.

The process of the present invention can also be used in processes for the preparation of polycyclic compounds, especially compounds comprising fused heterocycles.

The present invention will now be described using non-limiting examples of implementation of the method according to the invention. All reactions were carried out in Schlenk tubes under an argon atmosphere.

A - General procedure

In a Schlenk tube are introduced, under argon, the base (3, 4 or 5 molar equivalents), the compound of formula (II) (1 molar equivalent) and the compound of formula (III) (1, 2, 2 or 4 molar equivalents) if these compounds are solid. 3 ml of an anhydrous solvent are added using a syringe, in the case where the compounds of formulas (II) and (III) are liquid, they are then added at this stage in the Schlenk tube to the using a syringe. The mixture is stirred for 10 minutes at room temperature. The mixture is then heated with stirring at 60 ° C for 13 hours. The reaction mixture is then allowed to cool and then 2 ml of 1N HCl are added and the mixture is stirred for 10 minutes at room temperature. 56.1 mg 1, 3,5-trimethoxybenzene (0.33 mmol) are added as an internal standard. The mixture obtained is diluted with diethyl ether (10 ml) and washed three times with 2 ml of water and 2 ml of brine. The organic phases are collected, dried over MgSO ₄ and the diethyl ether is evaporated under reduced pressure. The residue is purified on a chromatographic column to give the corresponding compound of formula (I). Example 1 - Influence of the base and the solvent

 The general procedure (A) is applied for different reagents, bases and solvents.

Yield = yield; [a]: yield obtained with 5 equivalents of DMF; [b]: yield after 48h of reaction, the yield was 99% after 72h of reaction Example 2 - Variation of the Compounds of Formulas (I) and (II)

The general procedure (A) is carried out, the results are grouped in the table below (DMF solvent and base KOtBU 5 molar equivalents).

Example 3 - Process for the preparation of 2-cyclopropyl-1-phenylethan-1 -one

In a 100 ml reactor is added, under argon, the turn of magnesium (0.658 g, 27.1 mmol, 1.1 molar equivalents). 50 ml of anhydrous tetrahydrofuran (THF) are added and then 4.26 g of bromobenzene (27.1 mmol, 1.1 molar equivalents). The reactor is equipped with a condenser and the reaction mixture is refluxed for 1 hour (temperature rise slow from room temperature to 80 ° C). The reaction mixture is then allowed to cool to ambient temperature and then 2 g of cycloprolylacetonitrile (24.7 mmol, 1 molar equivalent) in 20 ml of THF are added. The reaction mixture is left stirring overnight at room temperature. 25 ml of a solution of H ₂ SO ₄ (0.2M) are added and the reaction mixture is refluxed for 2 hours. The reaction household is then allowed to cool to room temperature. The resulting mixture is extracted with 3 times 50 ml of diethyl ether. The organic phases are combined, washed with 5 ml of water and 5 ml of brine. The organic phases are dried over MgSO ₄ and the solvent is evaporated off under reduced pressure. The residue was purified on a chromatographic column (eluent hexane / ethyl acetate 90:10) to give 2-cyclopropyl-1-phenylethan-1-one in 85% yield (3.36 g). Example 4 - Preparation of Bicyclic Compounds

Synthesis of 3-methyl-2-phenylbenzofuran

In a 50 ml reactor are added, under argon, 2 g of iodophenol (9.1 mmol, 1 molar equivalent) and 0.173 g of para-toluenesulfonic acid monohydrate (0.91 mmol, 0.1 molar equivalents). 20 ml of anhydrous THF and 4.15 ml of 3,4-dihydropropane (45.5 mmol, 5 equivalents) are added and the reaction mixture is stirred at room temperature for 1.5 hours. The reaction is quenched by the addition of saturated NaHCO _{3 solution} (10 ml). The reaction mixture is extracted with 3 times 20 ml of ethyl acetate. The organic phases are combined, washed with 5 ml of water and 5 ml of brine. The organic phases are then dried over MgSO ₄ and the solvent is evaporated under reduced pressure. The residue is purified by column chromatography (eluent hexane / ethyl acetate 96: 4) to give 2-iodophenol, in which the alcohol is protected by THP (tetrahydropyran). In a Schlenk tube 561.05 mg of t-BuOK (5 mmol, 5 molar equivalents) are added under argon. 3 ml of anhydrous DMF are added using a syringe. The mixture is stirred for 10 minutes at room temperature. Then 305 mg of the above compound (2-iodophenol, in which the alcohol is protected by THP, 1 mmol, 1 molar equivalent) and 530 μl of propiophenone (4 mmol, 4 molar equivalents) are added successively. The reaction mixture is heated at 60 ° C with stirring for 13 hours. The reaction mixture is then allowed to cool to room temperature. The resulting mixture is diluted with 10 ml of diethyl ether and then washed with 3 times 2 ml of water and 2 ml of brine. The organic phases are dried over MgSO ₄ and the solvent is evaporated off under reduced pressure. The residue is purified on a chromatographic column (eluent hexane / ethyl acetate 99: 1) to give 3-methyl-2-phenylbenzofuran with a yield of 52% (108 mg).

Synthesis of 2- (2- (1,3-dioxolan-2-yl) phenyl) -1-phenylpropan-1-one:

 In a 50 ml reactor are added, under argon, 2 g of 2-iodobenzyl alcohol (8.54 mmol, 1 molar equivalent) and 0.163 g of para-toluenesulfonic acid monohydrate (0.86 mmol, 0.1 equivalent). molar).

20 ml of anhydrous THF and 3.9 ml of 3,4-dihydropyran (42.7 mmol, 5 equivalents) are added and the reaction mixture is stirred at room temperature for 1.5 hours. The reaction is quenched by the addition of saturated NaHCO _{3 solution} (10 ml).

The reaction mixture is extracted with 3 times 20 ml of ethyl acetate. The organic phases are combined, washed with 5 ml of water and 5 ml of brine. The organic phases are then dried over MgSO ₄ and the solvent is evaporated under reduced pressure. The residue is purified by column chromatography (eluent hexane / ethyl acetate 96: 4) to give 2-iodobenzyl alcohol, in which the alcohol is protected by

THP (tetrahydropyran).

In a Schlenk tube 561.05 mg of t-BuOK (5 mmol, 5 molar equivalents) are added under argon. 3 ml of anhydrous DMF are added using a syringe. The mixture is stirred for 10 minutes at room temperature. Then 318 mg of the above compound (2-iodobenzyl alcohol, in which the alcohol is protected by THP, 1 mmol, 1 molar equivalent) and 536 μl of propiophenone (4 mmol, 4 molar equivalents) are added successively. The reaction mixture is heated to 60.degree. stirring for 13 hours. The reaction mixture is then allowed to cool to room temperature. 15 ml of a 4/2/1 acetic acid / THF / water solution are added and the mixture is stirred for 3.5 hours at 35 ° C. The resulting mixture is diluted with 10 ml of diethyl ether and then washed with 3 times 2 ml of water and 2 ml of brine. The organic phases are dried over MgSO ₄ and the solvent is evaporated off under reduced pressure. The residue is purified on a chromatographic column (eluent hexane / ethyl acetate 95: 5) to give lactol with a yield of 77% (185 mg). 144.5 mg of this lactol are dissolved in 10 ml of methanol. 2 ml of 6N HCl are added and the mixture is refluxed for 13 hours. The mixture obtained is extracted with 3 times 10 ml of ethyl acetate. The organic phases are combined, washed with 3 ml of water and 3 ml of brine. The organic phases are dried over MgSO ₄ and the solvent is evaporated off under reduced pressure. The residue is purified by column chromatography (eluent hexane / ethyl acetate 96: 4) to give 4-methyl-3-phenyl-1H-isochromene in 60% yield (82 mg).

Synthesis of 3-methyl-2-phenylbenzofuran

 In a 50 ml reactor are added, under argon, 462 mg of 2-iodobenzaldehyde (2 mmol, 1 molar equivalent) and 38 mg of para-toluenesulfonic acid monohydrate (0.2 mmol, 0.1 molar equivalent). 20 ml of anhydrous toluene and 555 μl of ethylene glycol (10 mmol, 5 equivalents) are added. The reactor is equipped with a Dean-Stark apparatus and the reaction mixture is heated at reflux for 13h, then the solvent is evaporated under vacuum. The residue was purified by column chromatography (hexane / ethyl acetate 98: 2 to 95: 5 gradient eluent) to give dioxolane in 58% yield (320 mg).

In a Schlenk tube 561.05 mg of t-BuOK (5 mmol, 5 molar equivalents) are added under argon. 3 ml of anhydrous DMF are added using a syringe. The mixture is stirred for 10 minutes at room temperature. Then 276 mg of the above compound (dioxolane, 1 mmol, 1 molar equivalent) and 532 μl of propiophenone (4 mmol, 4 molar equivalents) are added successively. The reaction mixture is heated at 60 ° C with stirring for 13 hours. The reaction mixture is then allowed to cool to room temperature. The resulting mixture is diluted with 10 ml of diethyl ether and then washed with 3 times 2 ml of water and 2 ml of brine. The organic phases are dried over MgSO ₄ and the solvent is evaporated off under reduced pressure. The residue was purified on a chromatographic column (gradient eluent hexane / ethyl acetate 97: 3 to 90:10) to give 3-methyl-2-phenylbenzofuran in a yield of 49% (109 mg).

Example 4 - Preparation of Tamoxifen

In a Schlenk tube 561.05 mg of KOtBu (5 mmol, 5 molar equivalent) are added under argon. 3 ml of anhydrous DMF are added using a syringe. The reaction mixture is stirred for 10 minutes at room temperature. Then 1 12 μΙ of iodobenzene (1 mmol, 1 molar equivalent) and 291 ml of butyrophenone (2 mmol, 2 molar equivalents) are added successively. The reaction mixture is stirred and heated at 60 ° C for 13 hours. The mixture is then allowed to cool to room temperature. Then 2 ml of 1N HCl are added and the reaction mixture is stirred for 10 min at room temperature. The mixture obtained is diluted with 10 ml of diethyl ether and then washed with 3 times 2 ml of water and 2 ml of brine. The organic phases are combined, dried over MgSO ₄ and the diethyl ether is evaporated under reduced pressure. The residue was purified on a chromatography column (eluent hexane / toluene 70:30) to give 1,2-diphenylbutan-1-one in 97% yield (218 mg).

1,2-Diphenylbutan-1-one was also prepared from bromobenzene.

In a Schlenk tube 561.05 mg of KOtBu (5 mmol, 5 molar equivalent) are added under argon. 3 ml of anhydrous DMF are added using a syringe. The reaction mixture is stirred for 10 minutes at room temperature. Then 105 μl of bromobenzene (1 mmol, 1 molar equivalent) and 291 ml of butyrophenone (2 mmol, 2 molar equivalents) are added successively. The reaction mixture is stirred and heated at 120 ° C for 13 hours. The mixture is then allowed to cool to room temperature. Then 2 ml of 1N HCl are added and the reaction mixture is stirred for 10 min at room temperature. The mixture obtained is diluted with 10 ml of diethyl ether and then washed with 3 times 2 ml of water and 2 ml of brine. The organic phases are combined, dried over MgSO ₄ and the diethyl ether is evaporated under reduced pressure. The residue was purified on a chromatography column (eluent hexane / toluene 70:30) to give 1,2-diphenylbutan-1-one in 74% yield (166 mg). A test for the preparation of 1, 2-diphenylbutan-1-one was also carried out on a larger scale, each of the quantities having been multiplied by 20. The 1,2-diphenylbutanone is obtained in a yield of 62%. (2.79 g). In a reactor are added 0.90 g of sodium hydride (22.5 mmol, 3 molar equivalents) and 6 ml of anhydrous DMF. The mixture is cooled to 0 ° C. and then a 2.6 g solution of 4-bromophenol (15 mmol, 2 molar equivalents) in 6 ml of anhydrous DMF is added. The mixture is stirred for 30 minutes at 0 ° C. 1 molar equivalent of 2-chloro-N, N-dimethylethan-1-ammonium chloride are added in 3 times and the resulting reaction mixture is heated at 50 ° C for 3 hours. After cooling the solution to 0 ° C, 5 ml of saturated NH ₄ Cl solution are added. The mixture obtained is extracted with 3 times 20 ml of ethyl acetate. The organic phases are washed with 5 ml of water and 5 ml of brine then dried over MgSO ₄ and the solvent is evaporated under reduced pressure. The residue is purified on a chromatographic column (gradient eluent dichloromethane / methanol 98: 2 to 80:20) to give 2- (4-bromophenoxy) -N, N-dimethylethan-1-amine in a yield of 70% (1, 27 g).

408 mg of 2- (4-bromophenoxy) -N, N-dimethylethan-1-amine (1.67 mmol, 1.1 molar equivalents) and then 5 ml of anhydrous THF are added under argon to a Schlenk tube. The solution is cooled to -78 ° C. 0.8 ml of n-butyllithium (2.3 M in hexane) is added dropwise and the reaction mixture is stirred for 30 minutes at -78 ° C. 337 mg of a solution of 1,2-diphenylbutan-1-one (1.5 mmol, 1 equivalent) in 5 ml of anhydrous THF are added dropwise. The mixture is allowed to warm slowly to room temperature for 3 hours. The resulting mixture is extracted with 3 times 20 ml of ethyl acetate. The organic phases are washed with 5 ml of water and 5 ml of brine then dried over MgSO ₄ and the solvent is evaporated under reduced pressure. The residue is dissolved in 10 ml of methanol and 1 ml of 37% HCl. The reaction medium is refluxed for 15 hours and then the solvent is evaporated under reduced pressure. The residue is extracted with 3 times 10 ml of ethyl acetate. The organic phases are washed with 5 ml of water and 5 ml of brine then dried over MgSO ₄ and the solvent is evaporated under reduced pressure. The residue obtained is purified on a chromatographic column (eluent dichloromethane / methanol 95: 5) to give Tamoxifen in a ratio Z / E of 2.8 / 1 and in an overall yield of 442 mg.

Claims

1 .- A process for the preparation of a compound of formula (I) by reaction between a compound of formula (II) and a compound of formula (III) in the absence of a catalyst, in particular a metal catalyst, and a ligand, and presence of a base:

in which :

R ¹ represents:

 a hydrogen atom;

 an alkyl group comprising from 1 to 15 carbon atoms, linear or branched,

an alkenyl group comprising from 1 to 15 carbon atoms, linear or branched, and comprising at least one unsaturation,

 an aryl group comprising from 6 to 14, preferably from 6 to 10, carbon atoms, substituted or unsubstituted,

 a heteroaryl group comprising from 5 to 14, preferably from 5 to 10, members of which at least one heteroatom, chosen in particular from the nitrogen atom, the sulfur atom or the oxygen atom, substituted or unsubstituted; substituted

 a cycloalkyl group comprising from 3 to 14, preferably from 3 to 10, carbon atoms, substituted or unsubstituted, and optionally comprising at least one unsaturation,

 a heterocyclic group comprising from 5 to 14, preferably from 5 to 10, members, of which at least one heteroatom selected from the nitrogen atom, the sulfur atom or the oxygen atom, substituted or unsubstituted and optionally comprising at least one unsaturation,

- R ² represents:

 an alkyl group comprising from 1 to 15 carbon atoms, linear or branched,

an alkenyl group comprising from 1 to 15 carbon atoms, linear or branched, and comprising at least one double bond,

 an aryl group comprising from 6 to 14, preferably from 6 to 10, carbon atoms, substituted or unsubstituted,

a heteroaryl group comprising from 5 to 14, preferably from 5 to 10, members of which at least one heteroatom, chosen in particular from the nitrogen atom, the sulfur atom or the oxygen atom, substituted or unsubstituted; substituted a heterocyclic group comprising from 5 to 14 members, preferably from 5 to 10, of which at least one heteroatom chosen from the nitrogen atom, the sulfur atom or the oxygen atom, substituted or unsubstituted, and optionally comprising at least one unsaturation,

 an O-alkyl group, alkyl, linear or branched, comprising from 1 to 15 carbon atoms,

 an O-aryl group, aryl, substituted or unsubstituted, comprising from 6 to 14, preferably from 6 to 10, carbon atoms,

 an O-heteroaryl group, substituted or unsubstituted heteroaryl, comprising from 5 to 14, preferably from 5 to 10, members of which at least one heteroatom, in particular chosen from the nitrogen atom, the sulfur or the oxygen atom,

a cycloalkyl group comprising from 3 to 14, preferably from 3 to 10, carbon atoms, substituted or unsubstituted, and optionally comprising at least one unsaturation,

 an O-cycloalkyl group, cycloalkyl, which is substituted or unsubstituted, comprising

3 to 14, preferably 3 to 10 carbon atoms and optionally comprising at least one unsaturation;

R ³ represents:

 a vinyl group comprising from 2 to 10 carbon atoms, substituted or unsubstituted,

 an aryl group comprising from 6 to 14, preferably from 6 to 10, carbon atoms, substituted or unsubstituted,

 a heteroaryl group comprising from 5 to 14, preferably from 5 to 10, members of which at least one heteroatom, chosen in particular from the nitrogen atom, the sulfur atom or the oxygen atom, substituted or unsubstituted; substituted

 X represents a halogen atom chosen from chlorine, bromine or iodine or sulphonic acid esters, for example tosylate, mesylate or triflate.

2. - The method of claim 1, wherein X represents a halogen selected from chlorine, bromine or iodine, preferably bromine or iodine.

3. - Method according to one of claims 1 or 2, wherein R ¹ is chosen from:

 a linear or branched alkyl group comprising from 1 to 15 carbon atoms,

an alkenyl group comprising from 1 to 15 carbon atoms, linear or branched, and comprising at least one unsaturation, an aryl group comprising from 6 to 14, preferably 6 to 10, carbon atoms, which is unsubstituted or substituted, in particular with one or more substituents chosen from:

^■ a halogen atom, preferably chlorine, bromine, fluorine, preferably chlorine;

^■ an OH group;

^■ a group of formyl - (0) _p alkyl, alkyl, linear or branched, comprising 1 to 15 carbon atoms, preferably 1 to 10 carbon atoms, for example from 1 to 6 carbon atoms and p represents 0 or 1;

^■ an alkenyl group, linear or branched, comprising 1 to 15 carbon atoms and comprising at least one unsaturation;

^■ a perfuoroalkyle group, alkyl, linear or branched, comprising 1 to 10 carbon atoms, preferably trifluoroalkyl, eg, trifluoromethyl;

^■ an aryl comprising from 6 to 14, preferably 6 to 10 carbon atoms substituted or unsubstituted.

4. A process according to one of claims 1 or 2, wherein R ¹ represents an aryl group comprising from 6 to 14, preferably 6 to 10, carbon atoms, preferably phenyl, unsubstituted or substituted in particular with one or several substituents chosen from:

^■ a halogen atom, preferably chlorine, bromine, fluorine, preferably chlorine;

^■ an OH group;

^■ a group of formyl - (0) _p alkyl, alkyl, linear or branched, comprising 1 to 15 carbon atoms, preferably 1 to 10 carbon atoms, for example from 1 to 6 carbon atoms and p represents 0 or 1;

^■ a groupeperfuloroalkyle, alkyl, linear or branched, comprising 1 to 10 carbon atoms, preferably trifluoroalkyl, eg, trifluoromethyl;

^■ an aryl comprising from 6 to 14, preferably 6 to 10 carbon atoms substituted or unsubstituted.

5. Method according to one of claims 1 to 4, wherein R ² is chosen from:

a linear or branched alkyl group comprising from 1 to 15 carbon atoms, a cycloalkyl group comprising from 3 to 14, preferably 3 to 10, optionally substituted carbon atoms,

 a linear or branched alkyl group, Oalkyl, comprising from 1 to 15 carbon atoms,

 an aryl group comprising from 6 to 14, preferably from 6 to 10, carbon atoms, preferably phenyl, which is unsubstituted or substituted in particular with one or more substituents chosen from:

 A halogen atom, preferably chlorine, bromine, fluorine, preferably chlorine;

^■ an OH group;

a group of formyl - (O) _p alkyl, linear or branched alkyl, comprising

1 to 15 carbon atoms, preferably 1 to 10 carbon atoms, for example 1 to 6 carbon atoms and p is 0 or 1;

^■ a linear or branched alkenyl group comprising 1 to 15 carbon atoms and comprising at least one unsaturation;

 a perfuloroalkyl group, linear or branched alkyl, comprising 1 to 10 carbon atoms, preferably trifluoroalkyl, for example trifluoromethyl;

^■ an aryl comprising from 6 to 14, preferably 6 to 10 carbon atoms substituted or unsubstituted.

6. A process according to any one of claims 1 to 5, wherein R ³ is chosen from:

 a heteroaryl group comprising from 5 to 14, preferably 5 to 10, members of which at least one heteroatom, preferably pyridine, which is unsubstituted or substituted in particular with one or more substituents chosen from:

^■ a halogen atom, preferably chlorine, bromine, fluorine, preferably chlorine;

^■ an OH group;

^■ a group of formyl - (0) _p alkyl, alkyl, linear or branched, comprising 1 to 15 carbon atoms, preferably 1 to 10 carbon atoms, for example from 1 to 6 carbon atoms and p represents 0 or 1;

^■ a linear or branched alkenyl group comprising 1 to 15 carbon atoms and comprising at least one unsaturation;

^■ trifluoroalkyl, alkyl, linear or branched, comprising 1 to 10 carbon atoms, preferably trifluoromethyl; ^■ an aryl comprising from 6 to 14, preferably 6 to 10 carbon atoms substituted or unsubstituted.

 an aryl group comprising from 6 to 14, preferably 6 to 10 members, preferably phenyl or naphthyl, unsubstituted or substituted in particular with one or more substituents chosen from:

^■ a halogen atom, preferably chlorine, bromine, fluorine, preferably chlorine;

^■ an OH group;

^■ a group of formyl - (0) _p alkyl, alkyl, linear or branched, comprising 1 to 15 carbon atoms, preferably 1 to 10 carbon atoms, for example from 1 to 6 carbon atoms and p represents 0 or 1;

^■ a linear or branched alkenyl group comprising 1 to 15 carbon atoms and comprising at least one unsaturation;

^■ perfluoroalkyl, alkyl, linear or branched, comprising 1 to 10 carbon atoms, preferably trifluoroalkyl, eg, trifluoromethyl;

^■ an aryl comprising from 6 to 14, preferably 6 to 10 carbon atoms substituted or unsubstituted.

7. A process according to any one of claims 1 to 5, wherein R ³ is chosen from:

 a heteroaryl group comprising from 5 to 14, preferably from 5 to 10, members of which at least one heteroatom, preferably pyridine, which is unsubstituted or substituted in particular with one or more substituents chosen from:

^■ an alkyl, linear or branched, comprising 1 to 15 carbon atoms, preferably 1 to 10 carbon atoms, for example from 1 to 6 carbon atoms and p represents 0 or 1;

 an aryl group comprising from 6 to 14, preferably from 6 to 10, members, preferably phenyl or naphthyl, unsubstituted or substituted in particular by one or more substituents chosen from:

^■ an OH group;

^■ a group of formyl - (0) _p alkyl, alkyl, linear or branched, comprising 1 to 15 carbon atoms, preferably 1 to 10 carbon atoms, for example from 1 to 6 carbon atoms and p represents 0 or 1;

^■ a linear or branched alkenyl group comprising 1 to 15 carbon atoms and comprising at least one unsaturation.

8. - Process according to any one of claims 1 to 7, wherein the base is selected from alkali or alkaline-earth alkoxides of formula (M ¹ (OR) s), M ¹ representing Li, Na, K, Rb Cs, Fr, Be, Mg, Ca, Sr, Ba or Ra; s is 1 or 2 and R is selected from the group consisting of alkyl, benzyl and aryl groups.

9. - Process according to any one of claims 1 to 8, implemented in the presence of a solvent selected from acetamide and its derivatives, the alkylsulfoxides, the alkyl being linear or branched and comprising from 1 to 15, preferably from 1 to 10 carbon atoms.

10. - Process according to any one of claims 1 to 7, wherein the base is selected from alkali or alkaline earth alkoxides of formula (M ¹ (OR) s), M ¹ representing Li, Na, K, Rb Cs, Fr, Be, Mg, Ca, Sr, Ba or Ra; s representing 1 or 2 and R being selected from the group consisting of alkyl, benzyl and aryl, and in the presence of a solvent selected from acetamide and its derivatives, the alkylsulfoxides, the alkyl being linear or branched and comprising from 1 to 15, preferably from 1 to 10, carbon atoms.

1 1. - Process according to any one of claims 1 to 10, wherein the base is potassium tert-butylate and the solvent is dimethylformamide.

12. - Process according to any one of claims 1 to 1 1, wherein the temperature is between 20 and 200 ° C, preferably between 40 and 150 ° C.

13. A process according to any one of claims 1 to 12, wherein the molar ratio compound of formula (III) / compound of formula (II) is from 0.5 to 10, preferably from 0.5 to 5, in particular from 1, 5 to 5.

14. - Process according to any one of claims 1 to 13, wherein the molar amount of base is from 0.2 to 4 equivalents, preferably from 0.5 to 2 equivalents, relative to the molar amount of compound of formula (II).

15. - Process for preparing a compound of formula (IV) comprising the implementation of the method according to one of claims 1 to 14

wherein R represents a hydrogen atom or a hydroxy group.

The method of claim 15, comprising the steps of:

a) preparation of a compound of formula

(la) by carrying out the method according to any one of claims 1 to 1 1;

b) reacting the compound of formula (la) with a compound of formula Li-Ph-O (CH ₂ ) ₂ -NMe ₂ in THF at low temperature, especially below 0 ° C., preferably of the order of 78 ° C;

 c) reaction of the compound obtained in b) with HCl in an alcohol, for example methanol, at reflux.

17.- Compound of formula (la):

 wherein R represents a hydrogen atom or a hydroxy group.