WO2012032261A1

WO2012032261A1 - Method for synthesising biaryl ether or biheteroaryl ether

Info

Publication number: WO2012032261A1
Application number: PCT/FR2011/052044
Authority: WO
Inventors: Marc Taillefer; Florian Monnier; Anis Tlili
Original assignee: Centre National De La Recherche Scientifique (C.N.R.S); Ecole Nationale Supérieure De Chimie De Montpellier
Priority date: 2010-09-07
Filing date: 2011-09-07
Publication date: 2012-03-15
Also published as: FR2964380A1

Abstract

The invention relates to a method (P) for preparing a compound of formula (I), including reacting a compound of formula Ar¹-X with a compound of formula Ar¹-Y in the presence of at least one oxygen source, a catalyst including iron and/or copper and a ligand, a base, and optionally a solvent, where: Ar¹ and Ar², which are identical or different, are: an optionally substituted mono- or polycyclic aryl including 6 to 14 carbon atoms, or an optionally substituted mono- or polycyclic heteroaryl including 5 to 12 carbon atoms; and X and Y, which are identical or different, are a halogen atom.

Description

Process for synthesizing biarylether or biheteroarylether

The invention relates to a process for preparing a biaryl ether or a biheteroaryl ether of formula (I) from an aryl halide or a heteroaryl halide.

Biaryl ethers are an important family of active compounds from natural products and are also widely used in polymer chemistry.

The known syntheses of biarylethers correspond to a coupling process between a phenol and an aryl halide in the presence of a catalytic system comprising palladium or copper. These methods have the disadvantage of requiring the use of phenol.

Two methods, which do not require the presence of a phenol, have been described (Buchwald et al., J.Am.Chem.Soc, 2006, 128, 10694-10695 and Kwong et al., Tet.Lett., 2007 , 48, 473-476). In both of these processes, two aryl halides are coupled to oxygen via an inorganic oxygen source (K ₃ PO ₄ / H ₂ O or KOH). However, only processes for the preparation of symmetrical biarylethers are described and these methods have the disadvantage of requiring the use of palladium.

It is also known from Taillefer et al (Angew Chem Int.Ed., 2009, 48, 8725-8728) and Fu et al (Chem.Eur J., 2010, 16, 2366-2370) that biarylethers can be obtained as by-products of the phenol preparation. However, the yield of biarylether is very low.

An object of the invention is to provide a process for preparing biaryl ether removing the disadvantages of the methods of the state of the art.

Another object of the invention is to provide a process for the preparation of biarylether employing neither phenol nor palladium catalyst.

Yet another object of the invention is to provide a choice of a method for preparing symmetrical or asymmetrical biarylethers.

Another object of the invention is to provide a process for the preparation of symmetrical or asymmetric biaryl ethers with good yield and good selectivity.

Other objectives will appear on reading the following description of the invention.

The invention relates to a process (P) for preparing a compound of formula (I)

(I) comprising the reaction between a compound of formula Ar-X and a compound of formula Ar ² -Y in the presence of at least one source of oxygen, a catalyst comprising iron and / or copper and a ligand, a base and optionally a solvent,

in which :

Ar ¹ and Ar ² , identical or different, represent:

aryl, mono- or polycyclic, comprising from 6 to 14 carbon atoms, preferably from 6 to 10 carbon atoms, substituted or unsubstituted; or a mono or polycyclic heteroaryl comprising from 5 to 12 carbon atoms, preferably from 5 to 8 carbon atoms, substituted or unsubstituted; X and Y, identical or different, represent a halogen atom, preferably bromine, iodine, chlorine, more preferably iodine or bromine, still more preferred iodine.

The invention relates more particularly to a process (P) for preparing a compound of formula (I)

Art ²

(L)

comprising the reaction between a compound of formula Ar-X and a compound of formula Ar ² -Y in the presence of at least one source of oxygen, a catalyst comprising iron and / or copper and a ligand, a base selected from alkali or alkaline-earth alkoxides of formula (M (OR) _n ) and / or alkali or alkaline-earth phosphates of formula (M _p (OH) _r (PO ₄ ) q) and / or carbonates alkaline or alkaline earth metals of formula (M _s (CO ₃ ) _t ); M ¹ is selected from the group consisting of Li, Na, K, Rb, Cs, Fr, Be, Mg, Ca, Sr, Ba or Ra, n is 1 or 2, R is selected from the group consisting of alkyl groups. , benzyl and aryl, p is an integer from 1 to 10, r is an integer from 0 to 2, q is an integer from 1 to 10, s is an integer from 1 to 10, and t is an integer between 1 and 10, or mixtures thereof and optionally a solvent,

in which :

Ar ¹ and Ar ² , identical or different, represent:

an aryl, mono or polycyclic, comprising from 6 to 14 carbon atoms, preferably from 6 to 10 carbon atoms, substituted or unsubstituted; or a mono or polycyclic heteroaryl comprising from 5 to 12 carbon atoms, preferably from 5 to 8 carbon atoms, substituted or unsubstituted;

• X and Y, identical or different, represent a halogen atom, preferably bromine, iodine, chlorine, more preferably iodine or bromine, still more preferred iodine. In the context of the present invention, an integer between x and y is understood to mean an integer ranging from x to y.

Advantageously, Ar and Ar ² , which are identical or different, represent

Aryl, preferably phenyl, substituted or unsubstituted by at least:

a halogen atom, preferably chlorine, bromine or iodine;

- an alkyl group, linear or branched Ci to d _0, preferably methyl, ethyl;

a trihaloalkyl group Ci-Ci ₂ , preferably Ci-C ₃ , preferably trifluoroalkyl, preferably trifluoromethyl.

a group of formula COR ¹ , in which R represents a linear or branched C ₁ -C 10 alkyl, preferably methyl or ethyl;

a group of formula OR ² , in which R ² represents a linear or branched C ₁ -C 10 alkyl, preferably methyl or ethyl;

a group of formula N0 ₂ ;

a group of CN formula; or

A heteroaryl, preferably pyridine, substituted or unsubstituted by at least:

a halogen atom, preferably chlorine, iodine or bromine;

- an alkyl group, linear or branched Ci to Ci _0, preferably methyl, ethyl;

a trihaloalkyl group Ci-Ci ₂ , preferably Ci-C ₃ , preferably trifluoroalkyl, preferably trifluoromethyl;

- a group of formula COR ^1, wherein R ¹ represents a linear or branched alkyl, Ci-Ci _0, preferably methyl, ethyl;

a group of formula N0 ₂ ; or

- a group of CN formula.

According to the invention, the following terms have the following meanings, unless otherwise indicated: "alkyl" or "alkyl-" represents a saturated, linear or branched hydrocarbon radical containing from 1 to 10 carbon atoms, preferably from 1 to 10 carbon atoms. 6 carbon atoms, and in particular the methyl, ethyl radical, the propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl and decyl radicals;

"Aryl" or "aryl-" represents a mono or polycyclic aromatic hydrocarbon radical, and for example the phenyl radical or the naphthyl radical;

"Heteroaryl" or "heteroaryl-" represents a mono or polycyclic aromatic hydrocarbon radical, further comprising one or more heteroatoms, which are identical or different, chosen from nitrogen, oxygen, sulfur and phosphorus, each of the rings comprising 5 or 6 links; examples of heteroaryl radicals are pyridyl, quinolyl, imidazolyl and tetrazolyl radicals, without this list constituting any limitation;

"Hydrocarbon radical" as indicated for the radicals R 1 R ² and R ³ represents a linear or cyclic branched hydrocarbon radical (mono- or polycyclic) containing from 1 to 20 carbon atoms, and which may comprise one or more unsaturations in the form of double (s) and / or triple (s) bond (s), for example and without limitation methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, cyclohexyl, benzyl phenyl, vinyl, allyl, and the like;

in the terms "alkoxy, aryloxy, heteroaryloxy, monoalkylamino and dialkylamino", the definitions of the terms alkyl-, aryl- and heteroaryl- correspond to the generic terms defined above;

"Halogen" refers to fluorine, chlorine, bromine and iodine.

All the radicals whose definitions appear in the invention may optionally be substituted by one or more halogen atoms, or halogen as defined above, with one or more alkyl radicals, as defined in the invention, by a or more than one hydroxy, alkoxy, aryl, heteroaryl or amino radical, the substituents being identical or different. According to the invention, the term oxygen source means any molecule comprising at least one oxygen atom that can be involved in the bond between the two rings of the compound of formula (I).

According to the invention, the oxygen source may be chosen from compounds of formula MOH, in which M represents a hydrogen atom; an alkali or alkaline earth metal, preferably cesium or potassium; a transition metal, preferably copper. According to the invention, the source of oxygen may be chosen from water, CsOH or KOH, or mixtures thereof; preferably water and CsOH.

Advantageously, when the water is used as an oxygen source, it may be the water contained in the solvent.

Advantageously, the source of oxygen is the water contained in the solvent, advantageously the solvent comprises water and another solvent.

According to the invention, the catalyst may be a copper-based catalyst chosen from copper metal, copper (I) or copper (II) oxides, copper (I) or copper (II) hydroxides, inorganic salts or organic copper (I) or copper (II) and copper (I) or copper (II) complexes, or combinations thereof. The copper-based catalyst included, in particular, copper (0), copper halides (examples: copper iodide (I), copper (I) bromide, copper (II) bromide, copper (I) chloride copper (II) chloride), copper oxides or hydroxides (examples: copper (I) oxide, copper (II) oxide, copper (II) hydroxide), copper nitrates (examples: copper nitrate (I), copper (II) nitrate), sulphates or sulphites of copper (example: copper sulphate (I), sulphate of copper (II) sulphite of copper (I)) the organic salts of copper in which the cons ion has at least one carbon atom (examples: copper (II) carbonate copper (I) acetate copper (II) acetate, copper (II) trifluoromethylsulfonate, copper (I) methoxide, copper (II) methoxide , acetylacetonate copper (II)), or combinations thereof.

Advantageously, the copper-based catalyst is chosen from copper (0), copper iodide (I) (Cu), copper (II) oxide (CuO), copper (II) acetylacetonate [ Cu (acac) ₂ ], Cul + Cu (acac) ₂ . Preferably, the copper-based catalyst is copper iodide Cul.

According to the invention, the catalyst may be an iron-based catalyst chosen from iron metal, iron (II) or iron (III) oxides, iron (II) or iron (III) hydroxides, inorganic salts or organic iron (II) or iron (III) and iron (II) or iron (III) complexes, or their combinations.

The iron-based catalyst includes, in particular, iron (O), iron halides (examples: iron iodide (II), iron (II) bromide, iron (II) chloride), oxides or hydroxides of copper (examples: iron (II) oxide, iron (III) oxide, iron (II, III) oxide, iron (II) hydroxide), iron nitrates (example: iron (III) nitrate), sulphates or sulphites of iron (examples: iron (II) sulfate, iron (II) sulphite) organic iron salts in which the counterion has at least one carbon atom (example: iron (III) carbonate, iron (III) acetate, iron (II) trifluoromethylsulfonate, iron (II) methoxide, iron (III) acetylacetonate (Fe (acac) ₃ ) or iron (II) (Fe (acac) ₂ )).

Advantageously, the iron-based catalyst is chosen from iron (O), FeCl ₃ , FeCl ₂ , Fe (OH) ₂ , Fe (OH) ₃ , Fe (acac) ₂ , Fe (acac) ₃ .

Preferably, the iron-based catalyst is Fe (acac) ₂ or Fe (acac) ₃ .

According to the invention, many types of ligand may be suitable, in particular ligands

bidentates, in particular chosen from diketones,

which R ^A and R ^B , which are identical or different, represent a linear or branched C ₁ -C ₁₀ , preferably C ₁ -C ₄ , alkyl chain, for example t-butyl, methyl, or a radical aryl, C ₅ to Ci _0, in particular phenyl; the diamines in particular of formula NHA- (CH ₂ ) _n -NHA, in which A, identical or different, represents a hydrogen or a C ₁ -C ₁₀ alkyl, n represents an integer between 1 and 10, preferably between 1 and 5; polycyclic aromatic compounds comprising at least two heteroatoms, especially nitrogen, including tricycles.

Advantageously, the ligand is chosen from diketones, in particular of formula

in which in which R ^A and R ^B , which are identical or different, represent a linear or branched C ₁ to C ₁₀ , preferably C 1 to C ₄ , alkyl chain, for example t-butyl, methyl, or a C ₅ aryl radical; Ci ₀ , especially phenyl; polycyclic aromatic compounds comprising at least two heteroatoms, especially nitrogen, including tricycles.

Advantageously, the ligand can be chosen from:

Advantageously, the ligand is chosen from L1, L2, L3 and L5.

Advantageously, the ligand is L1.

According to the invention, the base may be chosen from alkali or alkaline-earth alkoxides of formula (M ¹ (OR) _n ) and / or alkaline or alkaline-earth metal phosphates of formula (M p (OH) _r (PO ₄ _q ) and / or alkali or alkaline earth carbonates of formula (M _s (CO ₃ ) _t ), or mixtures thereof.

According to the invention the base may be an alkali or alkaline-earth alkoxide of formula (M ¹ (OR) _n ) in which M ¹ represents Li, Na, K, Rb, Cs, Fr, Be, Mg, Ca, Sr, Ba or Ra, preferably Na; n is 1 or 2 and R is selected from the group consisting of alkyl, benzyl and aryl; in particular the base may be potassium terbutylate.

According to the invention, the base may be an alkaline or alkaline earth phosphate of formula (M _p (OH) _r (PO ₄ ) _q ) in which M ¹ represents Li, Na, K, Rb, Cs, Fr, Be, Mg Ca, Sr, Ba or Ra, preferably K; p is an integer from 1 to 10, preferably from 1 to 5; r is an integer between 0 and 2 and q is an integer between 1 and 10, in particular the base may be potassium phosphate (K ₃ PO ₄ ).

According to the invention, the base may be an alkaline or alkaline earth carbonate of formula (M _s (CO ₃ ) _t ) in which M ¹ is chosen from the group consisting of Li, Na, K, Rb, Cs, Fr, Be , Mg, Ca, Sr, Ba or Ra, preferably Cs or K; s is an integer from 1 to 10, preferably s is 2, and t is an integer from 1 to 10, preferably t is 1; in particular the base may be a cesium carbonate (Cs ₂ CO ₃ ) or a potassium carbonate (K ₂ CO ₃ ).

Advantageously, the base may be chosen from Cs ₂ CO ₃ , K ₂ CO ₃ and K ₃ PO ₄ .

According to the invention, the solvent may be chosen from water and / or organic solvents chosen from:

- alcohols, in particular Ci-d _0, preferably methanol, ethanol;

linear or cyclic carboxamides, preferably N-dimethylacetamide

(DMAC), Ν, Ν-diethylacetamide, dimethylformamide (DMF), diethylformamide or 1-methyl-2-pyrrolidinone (NMP);

dimethylsulfoxide (DMSO);

hexamethylphosphotriamide (HMPT);

tetramethylurea;

- benzene;

nitro compounds, preferably nitromethane, nitroethane, 1-nitropropane, 2-nitropropane or nitrobenzene;

aliphatic or aromatic nitriles, preferably acetonitrile, propionitrile, butanenitrile, isobutanenitrile, pentanenitrile, 2-methylglutaronitrile or adiponitrile;

tetramethylene sulfone;

organic carbonates, preferably dimethylcarbonate, diisopropylcarbonate or di-n-butylcarbonate;

alkyl esters, preferably ethyl acetate or isopropyl acetate;

aliphatic or aromatic ethers, preferably 1,4-dioxane;

halogenated or non-halogenated hydrocarbon compounds, preferably toluene or chlorobenzene;

ketones preferably acetone, methyl ethyl ketone, methyl isobutyl ketone (MIBK), cyclopentanone, cyclohexanone;

heterocycles comprising a nitrogen group, preferably pyridine, picoline or quinolines;

alone or in mixture. According to the invention, the solvent may be chosen from DMSO, water, ethanol and MIBK, alone or as a mixture. In particular, the solvent may be chosen from DMSO; a DMSO / water mixture, especially a DMSO / water (1/1) mixture, ethanol, an ethanol / water mixture, in particular an ethanol / water (1/1) mixture, water, MIBK. Advantageously, in the method of the invention, the molar ratio Ar -X / oxygen source, Ar ² -Y / oxygen source or (Ar -X + Ar ² -Y) / oxygen source can be between 1/1 and 1/4, preferably between 1/1 and 1/3, preferably 1/3. This ratio does not take into account any water present as a source of oxygen and is not applicable when water is the only source of oxygen.

Advantageously, in the process of the invention, the molar ratio Ar -X / base, Ar ² -Y / base or (Ar -X + Ar ² -Y) / base can be between 1/1 and 1 / 5, preferably between 1/1 and 1/4. Advantageously, in the process of the invention, the amount of catalyst may be between 1 and 20 mol% relative to Ar -X, Ar ² -Y or (Ar -X + Ar ² -Y), preferably between 5 and 15 mol%.

Advantageously, in the process of the invention, the amount of ligand can be between 5 and 50 mol% relative to Ar -X, Ar ² -Y or (Ar -X + Ar ² -Y), preferably between 10 and 40 mol%.

Advantageously, the process of the invention may be carried out at a temperature of between 25 ° C and 250 ° C, preferably between 50 and 200 ° C, preferably between 100 and 150 ° C, for example between 100 and 150 ° C. and 130 ° C.

The invention also relates to a process (P1) for preparing a compound of formula (I)

Ar ¹ - r ²

(I)

comprising the reaction between a compound of formula Ar-X and a compound of formula Ar ² -Y in the presence of at least one source of oxygen, a catalyst comprising copper and / or iron and a ligand, a base and optionally a solvent,

in which :

Ar ¹ and Ar ² , identical, represent:

• X and Y, identical or different, represent a halogen atom, preferably bromine, iodine, chlorine, more preferably iodine or bromine, still more preferred iodine.

The invention also relates more particularly to a process (P1) for preparing a compound of formula (I)

Ar ¹ - r ²

(I)

comprising the reaction between a compound of formula Ar-X and a compound of formula Ar ² -Y in the presence of at least one source of oxygen, a catalyst comprising copper and / or iron and a ligand, a base selected from alkali or alkaline-earth alkoxides of formula (M (OR) _n ) and / or alkali or alkaline-earth phosphates of formula (M _p (OH) _r (PO ₄ ) _q ) and / or carbonates alkali or alkaline earth metal of the formula (M _s (C0 ₃₎ _t); M ¹ is selected from the group consisting of Li, Na, K, Rb, Cs, Fr, Be, Mg, Ca, Sr, Ba or Ra, n is 1 or 2, R is selected from the group consisting of alkyl groups. , benzyl and aryl, p is an integer from 1 to 10, r is an integer from 0 to 2, q is an integer from 1 to 10, s is an integer from 1 to 10, and t is an integer between 1 and 10, or mixtures thereof and optionally a solvent,

in which :

Ar ¹ and Ar ² , identical, represent:

aryl, mono- or polycyclic, comprising from 6 to 14 carbon atoms, preferably from 6 to 10 carbon atoms, substituted or unsubstituted; or - a mono or polycyclic heteroaryl comprising from 5 to 12 carbon atoms, preferably from 5 to 8 carbon atoms, substituted or unsubstituted;

• X and Y, identical or different, represent a halogen atom, preferably bromine, iodine, chlorine, more preferably iodine or bromine, still more preferred iodine. Advantageously, Ar ¹ and Ar ² , which are identical, represent

An aryl, preferably phenyl, substituted or unsubstituted by at least:

a halogen atom, preferably chlorine, bromine or iodine;

- an alkyl group, linear or branched Ci to d _0, preferably methyl, ethyl;

a trihaloalkyl group Ci-Ci ₂ , preferably Ci-C ₃ , preferably trifluoroalkyl, preferably trifluoromethyl. a group of formula COR ¹ , in which R represents a linear or branched C ₁ -C 10 alkyl, preferably methyl or ethyl;

a group of formula N0 ₂ ;

a group of CN formula; or

heteroaryl, preferably pyridine, substituted or unsubstituted by at least:

a halogen atom, preferably chlorine, iodine or bromine;

- an alkyl group, linear or branched Ci to d _0, preferably methyl, ethyl;

a group of formula N0 ₂ ; or

- a group of CN formula.

Advantageously, X and Y, which are identical or different, are chosen from bromine and iodine.

For the process (P1) according to the invention the source of oxygen, the catalyst comprising iron and / or copper and a ligand and the base are as defined for process P according to the invention.

For the process (P1) according to the invention the amount of ligand relative to Ar -X, Ar ² -Y or (Ar -X + Ar ² -Y), the amount of catalyst relative to Ar -X, Ar ² -Y or (Ar -X + Ar ² -Y), the molar ratio Ar -X / base, Ar ² -Y / base or (Ar -X + Ar ² -Y) / base and the molar ratio Ar -X / oxygen source, Ar ² -Y / oxygen source or (Ar -X + Ar ² -Y) / oxygen source are as defined for process P.

Advantageously, for the process (P1) the solvent is a water / ethanol mixture and the only source of oxygen is the water contained in the solvent.

Advantageously, for the process (P1) the base is K ₃ PO ₄ .

The invention also relates to a process (P2) for preparing a compound of formula (I)

Ar ¹ - r ²

in which :

· Ar ¹ and Ar ² , different, represent:

Advantageously Ar ¹ and Ar ² , different, represent

An aryl, preferably phenyl, substituted or unsubstituted by at least:

a halogen atom, preferably chlorine, iodine or bromine;

- an alkyl group, linear or branched Ci to Ci _0, preferably methyl, ethyl;

a group of formula N0 ₂ ;

a group of CN formula; or

A heteroaryl, preferably pyridine, substituted or unsubstituted by at least:

a halogen atom, preferably chlorine, iodine or bromine;

- an alkyl group, linear or branched Ci to Ci _0, preferably methyl, ethyl;

a group of formula N0 ₂ ; or

- a group of CN formula. Advantageously, in the process (P2), at least one of X or Y represents iodine and the other is selected from iodine, bromine or chlorine.

For the process (P2) according to the invention the source of oxygen, the catalyst comprising iron and / or copper and a ligand and the base are as defined in method P.

For the process (P2) according to the invention the amount of ligand relative to Ar -X, Ar ² -Y or (Ar -X + Ar ² -Y), the amount of catalyst relative to Ar -X, Ar ² -Y or (Ar -X + Ar ² -Y), the molar ratio Ar -X / base, Ar ² -Y / base or Ar -X + Ar ² -Y) / base and the molar ratio Ar -X / source of oxygen, Ar ² -Y / oxygen source or (Ar -X + Ar ² -Y) / oxygen source are as defined for process P.

Advantageously, for the process P2, the oxygen source is CsOH

Advantageously, for the process P2, the base is Cs ₂ CO ₃ .

Advantageously, for process P2, the solvent is DMSO.

Advantageously, for process P2, the oxygen source is CsOH, the base is Cs ₂ 0 ₃ and the solvent is DMSO.

The invention will now be described using non-limiting examples. Examples:

All reactions are carried out in a 35 ml Schlenk or ThermoFisher Scientific Carousel Omnisation under a nitrogen atmosphere. Ethanol and DMSO are distilled and stored on 4A molecular sieve and under nitrogen. The other solvents are distilled and stored under nitrogen. Example 1 Study of the Influence of the Oxygen Source, the Base and the Solvent

Cul (0.1 eq) / L1 (0.5 eq), solvent [a] Q

2Ph1 + oxygen source * - Ph '"Ph base, 30h, 130/1 10 ° C

L1 = 2,2,6,6-tetramethyl-3,5-heptanedione

0.1 equivalent of Cul, 3 equivalent of base and 1 equivalent of aryl or heteroaryl halide are introduced into a dry tube. A stream of nitrogen is passed through the tube. 0.3 equivalent of ligand L1, 1 ml of anhydrous and degassed ethanol and 1 ml of degassed water are added under a stream of nitrogen at room temperature. The tube is closed under a positive pressure of nitrogen and heated at 130 ° C. for 30 hours. The reaction mixture is cooled to ambient temperature, 10 ml of dichloromethane are added and then 130 μl of 1,3-dimethoxybenzene (internal standard). The reaction mixture is filtered and the filtrate is washed twice with water. The aqueous phases are combined and extracted 5 times with dichloromethane. The organic phases thus obtained are combined and dried over Na ₂ SO ₄ , filtered and concentrated under vacuum in order to obtain a crude product. A sample of the crude product is analyzed by gas chromatography (GC). The crude product is purified by chromatography on silica gel with heptane. The products have been characterized, some by comparison with their known NMR data. GC yields were determined by obtaining the correction factor by using authentic samples of the expected products. The results obtained are recorded in Table 1.

MOH Yield

Example Solvent (2mL) Base (n equiv.) T (° C)

(3 equiv.) (%) ^[A]

DMSO / H ₂ O

1.1 CsOH Cs ₂ CO ₃ (1) 98 130

(1/1)

1.2 DMSO CsOH Cs ₂ CO ₃ (1) 95 130

1.3 EtOH CsOH Cs ₂ CO ₃ (1) 70 130

1.4 EtOH / H ₂ O (1/1) CsOH Cs ₂ CO ₃ (1) 100 130

1.5 EtOH / H ₂ O (1/1) - Cs ₂ CO ₃ (4) 90 130

1.6 EtOH / H ₂ O (1/1) - K ₂ CO ₃ (4) 60 130

1.7 EtOH / H ₂ O (1/1) - K ₃ P0 ₄ (3) 97, 96 ^[b] 130

DMSO / H ₂ O

1.8 - Cs ₂ C0 ₃ 20 130

(1/1)

1.9 DMSO CsOH K ₃ P0 ₄ 70 130

1.10 DMSO CsOH NaOtBu 60 130

1.11 DMSO CsOH K ₂ CO ₃ 95 130

1.12 DMSO KO H Cs ₂ C0 ₃ 70 130

1.13 MIBK KO H Cs ₂ C0 ₃ 50 130 1 .14 EtOH KO H Cs ₂ CO ₃ 60 130

1 .15 EtOH / H ₂ O (1/1) KO H Cs ₂ CO ₃ 100 130

1 .16 EtOH / H ₂ O (1/1) KO HK ₂ CO ₃ 80 130

EtOH / H ₂ O ( ^1/1 ) - Cs ₂ CO ₃ ^{40,100 laJ} GC yields determined with 1,3-dimethoxybenzene as the internal standard. ^{1 1} reaction carried out with 0.3 eq. THMD (L1) and 3 eq. of K ₃ P0 ₄ .

Table 1 These results show that the process according to the invention makes it possible, whatever the solvent, the base and the source of oxygen, to obtain compounds of formula (I), from aryl halide or from heteroaryl halide, with good yields and in the absence of palladium catalyst. Example 2: Test with different liqands

30h, 130 ° C

H ₂ O / EtOH (1/1)

0.1 equivalent of Cul, 3 equivalents of K ₃ PO ₄ and 1 equivalent of phenyl iodide are introduced into a dry tube. A stream of nitrogen is passed through the tube. 0.3 equivalent of ligand, 1 ml of anhydrous and degassed ethanol and 1 ml of degassed water are added under a stream of nitrogen at room temperature. The tube is closed under a positive pressure of nitrogen and heated at 130 ° C for 30h. The reaction mixture is cooled to ambient temperature, 10 ml of dichloromethane are added and then 130 μl of 1,3-dimethoxybenzene (internal standard). The reaction mixture is filtered and the filtrate is washed twice with water. The aqueous phases are combined and extracted 5 times with dichloromethane. The organic phases thus obtained are combined and dried over Na ₂ SO ₄ , filtered and concentrated in vacuo in order to obtain a crude product. A sample of the crude product is analyzed by gas chromatography (GC). The crude product is purified by chromatography on silica gel with heptane. The products have been characterized, some by comparison with their known NMR data. GC yields were determined by obtaining the correction factor by using authentic samples of the expected products. The results obtained are shown in Table 2.

^aJ the GC yield determined with 1, 3-dimethoxybenzene as an internal standard; ^the GC The same performance is obtained with 50% L 1; ^[cl the same GC yield is obtained with 30% L 1

Table 2

These results show that the process of the invention makes it possible, with a varied range of ligands, to obtain compounds of formula (I).

Example 3 Synthesis of Compounds of Formula (I) Symmetric

30h, 130 ^< C

H ₂ O / EtOH (1/1)

L1 = 2,2,6,6-tetramethyl-3,5-heptanedione

0.1 mmol of Cul (0.1 equivalent), 3 mmol of K ₃ PO ₄ (3 equivalents) and 1 mmol of aryl or heteroaryl halide (1 equivalent) are introduced into a dry tube. A stream of nitrogen is passed through the tube. 0.3 mmol of L1 ligand (0.3 equivalents), 1 ml of anhydrous and degassed ethanol and 1 ml of degassed water are added under a stream of nitrogen at room temperature. The tube is closed under a positive pressure of nitrogen and heated at 130 ° C. for 30 hours. The reaction mixture is cooled to ambient temperature, 10 ml of dichloromethane are added and then 130 μl of 1,3-dimethoxybenzene (internal standard). The reaction mixture is filtered and the filtrate is washed twice with water. The aqueous phases are combined and extracted 5 times with dichloromethane. The organic phases thus obtained are combined and dried over Na ₂ SO ₄ , filtered and concentrated under vacuum in order to obtain a crude product. A sample of the crude product is analyzed by gas chromatography (GC). The crude product is purified by chromatography on silica gel with heptane. The products have been characterized, some by comparison with their known NMR data. GC yields were determined by obtaining the correction factor by using authentic samples of the expected products. The results obtained are shown in Table 3.

Table 3 The compounds were analyzed. The compounds (except compounds 3.8 and 3.10) are known, their characteristics have therefore been compared with those of the known compounds. The characteristics of the known compounds are described in particular in the publications mentioned for each example 3.1 to 3.7 and 3.9).

Diphenylether (compound 3.1, analytical data compared with those of the compound of H.-J. Cristal P. Cellier, J.-F. Spindler, M. Taillefer, Ora Lett, 2004. 6, 913)

The procedure of Example 3 was followed with 12% iodobenzene (1.0 mmol). The product is obtained in the form of a colorless oil. The yield is 94% (eluent heptane).

5 HH NMR (400 MHz, CDCl ₃ ): δ 7.08-7.10 (m, 4H, H _{2.6.8 12} ), 7.15-7.19 (m, 2H, H _4.10 ) , 7.38-7.43

3C NMR (100 MHz, CDCl ₃ ): δ 1 19.0 (C ₂ , ₆ , 8, i ₂ ), 123.4 (C ₄ , ₁₀ ), 129.8 (C ₂ , ₆ , 9, n) , 157.4 (C ₁₇ ) ,. GC / MS: rt = 15.20 min, M / Z = 170.

HRMS calc for C ₁₂ H ₁₀ O (M + H) 171, 0810. Experimental value: 171, 0812 · 1,1 '- (4,4'-oxybis (4,1-phenylene)) diethanone (Compound 3.2) compared with that of J. Simon S. Salzbrunn's compound GKS Prakash NA Petasis, GA Olah J. Ora, Chem 2001, 66, 633).

The procedure of Example 3 was followed with 246 mg of 4'-iodoacetophenone (1.0 mmol). The product is obtained in the form of a white solid. The yield is 85% (eluent: ethyl acetate / heptane = 10/90).

MP (melting point): 99-100 ^< C

1 H NMR (400 MHz, CDCl ₃ ): δ 2.53 (s, 6H, H _{14 16} ), 7.01 -7.03 (d, 4H, H _{2 6.8 12} ), 7.91 -7, 94 (d, 4H, H ₃ 5 9 n).

3C NMR (100 MHz, CDCl ₃ ): δ 26.5 (C ₁₃ , ₁₄ ), 1 18.8 (C ₂ , ₆ , 8, i ₂ ), 130.9 (C ₃ , ₅ , 9, ii) , 133.2 (C4,10), 160.3 (C _7), 196.8 (Ci3, i _5).

GC / MS: t = 25.21 min, M / Z = 254.

HRMS calc for C ₁₆ H ₁₄ O ₃ (M + H) 255.1021. Experimental value: 255,1018 Anal, calculated for Ci Hi ₆ ₄ 0 _3: C, 75.57; H, 5.55. Experimental value: C, 75.31; H, 5.49.

4,4'-oxybis (chlorobenzene) (Compound 3.3, Analytical Data Compared to those of the Compound of H.-J. Cristal, Cellier, J.-F. Spindler, M. Taillefer, Ora.Lact 2004., 6,913). The procedure of Example 3 was followed with 250 mg of 4-chloro-benzene (1.0 mmol). The product is obtained in the form of a white solid. The yield is 90% (eluent: heptane).

H NMR (400 MHz, CDCl _3): δ 6.85 to 6.87 (d, 4H, H _2,6,8,12), 7.21 -7.24 (d, 4H, H _3, _5, 9 _, n) - 3C NMR (100 MHz, CDCl ₃ ): δ 120.1 (C ₂ , ₆ , ₈ , ₁₂ ), 128.7 (C ₄ , ₁₀ ), 129.8 (C ₃ , ₅ , 9, ii ), 155.5 (C ₁ ).

GC / MS: rt = 19.81 min, M / Z = 237.

4,4'-oxybis (bromobenzene) (Compound 3.4 Analytical Data Compared to Compounds of J. Simon, S. Salzbrunn, G. K. S. Prakash, N. A. Petasis, G. A. Olah J. Org Chem 2001, 66, 633)

The procedure of Example 3 was followed with 282 mg of 4-iodobromobenzene (1.0 mmol). The product is obtained in the form of a yellow solid. The yield is 95% (eluent: heptane).

Mp (melting point): 60-62 ° C

1 H NMR (400 MHz, CDCl ₃ ): δ 6.80-6.82 (d, 4H, H ₂ , 6, 8, 12), 7.36-7.38 (d, 4H, H ₃ , ₅ , 9 _, n) -3C NMR (100 MHz, CDCl ₃ ): δ 1 15.1 (C ₄ , ₁₀ ), 1 19.5 (C ₂ , ₆ , ₈ , ₁₂ ), 131, 8 (C ₃ , ₅ , e, ii), 154.9 (C ₁ ). GC / MS: t = 20.78 min, M / Z = 328.

Anal. Calculated for C ₁₂ H ₈ Br ₂ O: C, 43.94; H, 2.46. Experimental value: C, 43.92; H, 2.64. 3,3'-oxybis (bromobenzene) (Compound 3.5, analytical data compared with those of U. Oern, L. Erikson, E. Jakobsson, A. Bergman, Acta Chem, Scand., 1996, 50, 802).

The procedure of Example 3 was followed with 127 μl of 3-iodobromobenzene (1.0 mmol). The product is obtained in the form of a colorless oil. The yield is 76% (eluent: heptane).

1 H NMR (400 MHz, CDCl ₃ ): δ 6.86-6.89 (m, 2H, H _6.12 ), 7.08-7.09 (m, 2H, H ₅ , n), 7.14 -7.16 (m, 2H, H _4.10 ), 7.20 (s, 1H, H _2.8 ).

3C NMR (100 MHz, CDCl ₃ ): δ 1 17.7 (C _{6 12} ), 122.3 (C _2.6 ), 123.0 (C _3.9 ), 127.1 (C _4.10 ) , 131, 0

GC / MS: rt = 21.70 min, M / Z = 328.

4,4'-oxybis (methoxybenzene) (Compound 3.6, analytical data compared with those of J. Simon, S. Salzbrunn, G. K. S. Prakash, N.A. Petasis, G.A. Olah, J.Org.Chem 2001, 66, 633)

The procedure of Example 3 was followed with 246 mg of 4-methoxyiodobenzene (1.0 mmol). The product is obtained in the form of a white solid. The yield is 82% (eluent ethyl acetate / heptane = 10/90).

1 H NMR (400 MHz, CDCl ₃ ): δ 3.72 (s, 6H, H _{13 14} ), 6.77-6.79 (m, 4H, H ₃ , ₅ , 9, n), 6.84- 6.86 (m, 0 MHz, CDCl ₃ ): δ 55.7 (C _13.14 ), 1 14.7 (C _3.5.9, ii), 1 19.6 (C _{2.6.8 , 12} ), 151, 6 (C ₁ ),

GC / MS: rt = 21.0 min, M / Z = 230.

Anal. Calculated for C ₁₄ H ₁₄ O ₃ : C, 73.03; H, 6.13. Experimental value: C, 72.81; H, 5.81. 4,4'-oxybis (methylbenzene) (compound 3.7, analytical data compared with those of J. Simon, S. Salzbrunn, GKS Prakash, NA Petasis, GA Olah J. Org Chem 2001, 66, 633)

The procedure of Example 3 was followed with 218 mg of A, 4-iodotoluene (1.0 mmol). The product is obtained in the form of a colorless oil. The yield is 90% (eluent heptane).

1 H NMR (400 MHz, CDCl ₃ ): δ 2.25 (s, 6H, H _13.14 ), 6.80-6.82 (d, 4H, H ₂ , 6, 8, ₁₂ ), 7.03 -7.05 (d, 4H, H _{3 5 9 11} ).

3 C NMR (100 MHz, CDCl ₃ ): δ 20.9 (C ₁₃ , ₁₄ ), 18.6 (C ₂ , ₆ , ₈ , ₁₂ ), 130.3 (C ₃ , ₅ , 9, ii), 132.5 (C ₄ , ₁₀ ), 155.2 (C ₁ ).

GC / MS: t = 19.32 min, M / Z = 198.

• 5,5'-oxybis (1,3-dimethylbenzene) (Compound 3.8)

The general procedure of Example 3 was followed with 142 μl of 5-iodo-m-xylene (1.0 mmol). The product is obtained in the form of a colorless oil. The yield is 95% (eluent heptane).

1 H NMR (400 MHz, CDCl ₃ ): δ 2.21 (s, 12H, H _13, i ₄ , i 5, i 6), 6.54 (s, 4H, H 2, 6, 8, ₁₂ ), 6.63 (s, 21H, MHz, CDCl ₃ ): δ 20.4 (C _{1 3} , i 4, i 5, i ₆ ), 1 15.7 (C ₂ , ₅ , 8, i ₂ ), 128.9 (C ₄ , ₁₀ ), 138.5 (C ₃ , ₅ , 9, ii),

GC / MS: t = 18.59 min, M / Z = 226.

HRMS calc for C ₁₆ H ₁₈ O (M + H) 227.1436. Experimental value: 227.1436

3,3'-oxybis (methylbenzene) (compound 3.9, analytical data compared with that of the compound of Y. M. Al-Hiani, B.A. Sweileh, Asian J. Chem., 2006, 18, 2285-2298)

The general procedure of Example 3 was followed with 128 μl of 3-methyliodobenzene (1.0 mmol). The product is obtained in the form of a colorless oil. The yield is 95% (eluent heptane).

1H NMR (400 MHz, CDCl ₃ ): δ 2.2 (s, 6H, H _13.14 ), 6.72-6.73 (m, 4H, Η _4.6, ιο, ΐ 2), 6, 82-6.84 (2H, H ₂ , ₈ ), 7.1-1 -7.15 (m, 2H, H ₅ , n).

3C NMR (100 MHz, CDCl _3): δ 21, 3 ₍₁₃ C, _14), 1 16.1 (C _6, _12), 1 19.6 (C _2, _8), 123.9 (C _4, io), 129.35 (C ₅ , n), 139.9 (C ₃ , ₉ ), 157.4 (C ₁ ).

GC / MS: t = 18.21 min, M / Z = 198.

2,2'-Oxidipyridine (Compound 3.10)

The general procedure of Example 3 was followed with 95 μl of 2-bromopyridine (1.0 mmol). The product was obtained as a yellow oil. The yield is 82% (eluent ethyl acetate / heptane = 10/90).

1 H NMR (400 MHz, CDCl ₃ ): δ 7.01 -7.06 (m, 4H, H 2 A _7.9 ), 7.86-7.72 (m, 2H, H _3.8 ), 8.39 (br, 2 Hz, CDCl _3): δ 1 14.1 ₍₂ C _7), 1 19.9 (C _49), 139.8 (C _{3 8),} 148.1 (C _5.10) 161, 9

GC / MS: t = 18.54 min, M / Z = 172.

HRMS calc for C ₁₀ H ₈ N ₂ O (M + H) 173.0715. Experimental value: 173.0712

These results show that the process of the invention makes it possible to obtain compounds of formula (I) and various heteroaryl ethers in good yields, without a palladium catalyst.

Example 4 Synthesis of Compounds of Formula (I) Asymmetric

L1 = 2,2,6,6-tetramethyl-3,5-heptanedione 0.05 mmol of Cul (0.1 equivalent), 1.5 mmol of CsOH (3 equivalents), 0.5 mmol of Cs ₂ O ₃ (1 equivalent) and 0.05 mmol of each aryl or aryl halide. heteroaryl (1 equivalent) are introduced into a dry tube. A stream of nitrogen is passed through the tube. 0.25 mmol of L1 ligand (0.5 equivalent), 2 ml of anhydrous and degassed DMSO are added under a stream of nitrogen at room temperature. The tube is closed under a positive pressure of nitrogen and heated at 130 ° C for 30h. The reaction mixture is cooled to ambient temperature, 10 ml of dichloromethane are added and then 130 μl of 1,3-dimethoxybenzene (internal standard). The reaction mixture is filtered and the filtrate is washed twice with water. The aqueous phases are combined and extracted 5 times with dichloromethane. The organic phases thus obtained are combined and dried over Na ₂ SO ₄ , filtered and concentrated in vacuo in order to obtain a crude product. A sample of the crude product is analyzed by gas chromatography (GC). The crude product is purified by chromatography on silica gel with heptane. The products are known products and have been characterized by comparison with their NMR data. GC yields were determined by obtaining the correction factor by using authentic sample of the expected products.

The results obtained are shown in Table 4

7> 7 Isolated yield, [c] for DC H X by-products are non-reactive aryl halides (eg 20% p-CF C H Cl at the end of the reaction

6 4 3 6 4

for test 17). for AC H I the by-products are symmetrical diaryiithers (between 2 and 15% when A = H and only traces when A ≠ H), [d]

6 4

1.8 equiv. of AC H I and 1 equiv. DC H X: Yield based on DC H X.

6 4 6 4 6 4

Table 4

The compounds were analyzed. The compounds are known, their characteristics have therefore been compared with those of the known compounds. The characteristics of the known compounds are described in particular in the publications mentioned for each example 4.1 to 4.18.

1-methyl-4-phenoxybenzene (compounds 4.1, 4.7 and 4.13, analytical data compared with those of the compound of D. Ma, Q. Cai Org Lett 2003, 5, 3799)

The general procedure of Example 4 was followed with 56 μl of iodobenzene (0.5 mmol) and 109 mg of 4-iodotoluene (0.5 mmol) (compound 1), 61 μl of 4-bromotoluene (0, 5 mmol) (compound 7) or 56 μl of 4-chlorotoluene (0.5 mmol) (compound 13). The products are obtained in the form of a yellow oil. The yield is respectively 72%, 59% and 40% for compounds 1, 7 and 13 (eluent: heptane).

1 H NMR (400 MHz, CDCl ₃ ): δ 2.24 (s, 3H, H ₁₃ ), 6.82-6.84 (d, 2H, H _8.12 ), 6.88-6.90 (m , 2H, H _{2 6} ), 6.95-6.99 (t, 1H, H ₄ ), 7.03-7.05 (d, 2H, H _{9 11} ), 7.19-7.23 ( m, 2H, H _{3 5} ). ³ C NMR (100 MHz, CDCl ₃ ): δ 20.9 (C ₁₃ ), 1 18.6 (C ₈ , ₁₂ ), 1 19.4 (C ₂ , ₆ ), 122.7 (C ₄ ), 129.9 (C ₃ , ₅ ), 130.4 (C ₉ , n), 133.1 (C ₁₀ ), 154.7 (C ₇ ), 157.9 (d).

GC / MS: t = 16.72 min, M / Z = 184.

1-nitro-4-phenoxybenzene (compounds 4.2 and 4.1 1, analytical data compared with those of the compound of A. Ouali, J.-F. Spindler, H.-J. Cristau, M. Taillefer Adv.Chem. 2006. 348. 499)

The general procedure of Example 4 was followed with 56 μl of iodobenzene (0.5 mmol) and 124.5 mg of 4-iodonitrobenzene (0.5 mmol) (compound 2) or 100.5 mg of 4- bromonitrobenzene (0.5 mmol). The products are obtained in the form of a yellow solid. The yields are respectively 71% and 83% for the compounds 2 and 1 1. (eluent: heptane).

MP (melting point): 60-61 ° C

1 H NMR (400 MHz, CDCl ₃ ): δ 6.92-6.94 (d, 2H, H _{2 6} ), 7.00-7.03 (d, 2H, H _{8 12} ), 7.16-7 , (T, 1H, H ₄ ), 7.34-7.38 (d, 2H, H ₃ , ₅ ), 8.1 1 -8.13 (d, 2H, H ₉ , n).

3 C NMR (100 MHz, CDCl ₃ ): δ 1 17.1 (C _8.12 ), 120.7 (C _2.6 ), 125.6 (C ₄ ), 126.1 (C _9, n), 130.5 (C ₃ , ₅ ), 124.6 (Cio), 154.7 (d), 163.5 (C ₇ ).

GC / MS: rt = 16.72 min, M / Z = 215.

HRMS calcd for C ₁₂ H ₉ N0 ₃ (M + H) 216.0661 Experimental value: 216.0648.

Anal. Calc'd for C ₁₂ H ₉ N0 ₃ : C, 66.97; H, 4.22; N, 6.51. Experimental value: C, C, 67.22;

H, 3.87; N, 6.47.

1- (4-phenoxyphenyl) ethanone (compound 4.3, analytical data compared with those of the compound of H. Rao, Y. Jin, H. Fu, Y. Jianq, Y. Zhao Chem Eur, J. 2006. 12. 3636)

The general procedure of Example 4 was followed with 56 μl of iodobenzene (0.5 mmol) and 124 mg of 4-iodoacetophenone (0.5 mmol). The product is obtained in the form of a colorless oil. The yield is 65% (eluent heptane / ether = 9/1).

1 H NMR (400 MHz, CDCl ₃ ): δ 2.50 (s, 3H, H ₁₄ ), 6.91 -6.94 (d, 2H, H _{2 6} ), 6.99-7.01 (d, 2H, H _8, i ₂ ), 7.1 1 -7.15 (t, 1H, H ₄ ), 7.31 -7.35 (m, 2H, H _3.5 ), 7.86-7 , 88 (d, 2H, H _9, n). ³ C NMR (100 MHz, CDCl ₃ ): δ 26.5 (C ₁₄ ), 1 17.3 (C _8.12 ), 120.2 (C _2.6 ), 124.6 (C ₄ ), 130 , 1 (C _4), 130.5 (C-3,5), 130.7 (C9.1 1), 131, 9 (C _10), 156.3 (d), 162.0 (C ₇₎ , 196.98 (C ₁₃ ).

GC / MS: rt = 20.67min, M / Z = 212.

HRMS Calc'd for C ₁₄ H ₁₂ O ₂ (M + H) 213.0916. Experimental value: 213.0910.

1-chloro-4-phenoxybenzene (Compound 4.4, Analytical Data Compared to those of the Compound of H. Rao, Y. Jin, H. Fu, Y. Jiana, Y. Zhao Chem Eur, J. 2006. 12. 3636 )

The general procedure of Example 4 was followed with 19 mg of 4-chloroiodobenzene (0.5 mmol) and 56 μl of iodobenzene (0.5 mmol). The product is obtained in the form of a colorless oil. The yield is 85%. (eluent: heptanes / ethyl acetate = 9/1).

1 H NMR (400 MHz, CDCl ₃ ): δ 6.85-6.87 (m, 2H, H _{2 6} ), 6.91 -6.93 (m, 2H, H _3.5 ), 7.03- 7.07 (m, 1H, H ₄ ), 7.20-7.22 (m, 2H, H _9, n), 7.25-7.29 (m, 2H, H _8.12 ).

3C NMR (100 MHz, CDCl ₃ ): δ 1 18.9 (C ₂ , ₆ ), 120.0 (C ₈ , ₁₂ ), 123.6 (C ₄ ), 128.4 (C ₁₀ ), 129, 7 (C ₃ , ₅ ), 129.9 (C9.1 1), 156.0 (C ₇ ), 156.8 (d).

GC / MS: rt = 14.58 min, M / Z = 204.

4-phenoxybenzonitrile (compounds 4.5 and 4.12, analytical data compared with those of the compound of H. Rao, Y. Jin, H. Fu, Y. Jianq, Y. Zhao Chem Eur Eur J. 2006. 12. 3636)

The general procedure of Example 4 was followed with 56 μl of iodobenzene (0.5 mmol) and 14.5 mg of 4-ioobenzonitril (0.5 mmol) (compound 5) or 90.5 mg of 4 bromobenzonitrile (0.5 mmol) (compound 12). The product is obtained in the form of a white solid. The yield is respectively 78% and 72% for compounds 5 and 12 (eluent: heptanes / ethyl acetate = 9/1).

MP (melting point): 43 ° C

1 H NMR (400 MHz, CDCl ₃ ): δ 6.92-6.94 (d, 2H, H _{8 12} ), 6.99-7.01 (d, 2H, H _{2 6} ), 7.14-7 , 18 (t, 1H, H ₁₀ ), 7.33-7.37 (t, 2H, H _9, n), 7.52-7.54 (d, 2H, H _3.5 ).

3 C NMR (100 MHz, CDCl ₃ ): δ 104.9 (C ₄ ), 1 17.0 (C ₂ , ₆ ), 1 17.9 (C ₁₃ ), 1 19.6 (C ₈ , ₁₂ ), 124.3 (C ₁₀ ), 129.2 (C ₉ , n), 133.3 (C ₃ , ₅ ), 153.9 (C ₇ ), 160.7 (d).

GC / MS: t = 19.58 min, M / Z = 195. 1,3-dimethyl-5- (4-nitrophenoxy) benzene (compound 4.6, analytical data compared with those of the compound of N. Xia, M. Taillefer Chem Eur J. 2008, 14, 6037.)

The general procedure of Example 4 was followed with 71 μl of 5-iodo-m-xylene (0.5 mmol) and 124.5 mg of 4-iodonitrobenzene (0.5 mmol). The product is obtained in the form of a yellow solid. The yield is 93% (eluent heptane).

MP (melting point): 59 ° C

1 H NMR (400 MHz, CDCl ₃ ): δ 2.26 (s, 6H, H _13.14 ), 6.63 (brs, 2H, H _2.6 ), 6.82 (brs, 1H, H ₄ ), 6.91 -6.93 (d, 2H, H _8.12 ), 8.1 1 -8.17 (d, 2H, H ₉₁₁ ).

3 C NMR (100 MHz, CDCl ₃ ): δ _21.3 (C _13.14 ), 17.1 (C _2.6 ), 18.3 (C _8.12 ), 125.9 (C 9 ₁₁ ) , 127.3 (C ₄ ), 140.4 (C ₃ , ₅ ), 142.5 (C ₁₀ ), 154.7 (d), 163.7 (C ₇ ).

GC / MS: t = 16.72 min, M / Z = 243.

HRMS calc for C ₁₄ H ₁₃ NO ₃ (M + H) 244.0974. Experimental value: 244.0966.

Anal. Calculated for C ₁₄ H ₁₃ NO ₃ : C, 69.12; H, 5.39; N, 5.76. Experimental value: C, 69.36;

H, 5.47; N, 5.3.

2- (p-tolyloxy) pyridine (compound 4.8, analytical data compared with those of the compound of S. Inoue Phosphorus Sulfur 1985, 22. 141)

The general procedure of Example 4 was followed with 109 mg of 4-iodotoluene (0.5 mmol) and 47.5 μl of 2-bromopyridine (0.5 mmol). The product is obtained in the form of a yellow oil. The yield is 92% (eluent: heptanes / ethyl acetate = 9/1).

¹H NMR (400 MHz, CDClI ₃ ): δ 2.27 (s, 3H, H ₁₃ ), 6.72-6.81 (m, 1H, H ₄ ), 6.86-6.89 (m). , 1H, H ₂ ), 6.93-6.96 (m, 2H, H _{9 11} ), 7.10-7.12 (m, 2H, H _{8 12} ), 7.55-7.60 ( m, 1H, H ₅ ), 8.10-8.1 1 (m, 1H, H ₃ ).

3 C NMR (100 MHz, CDCl ₃ ): δ 20.9 (C ₁₃ ), 1 1 1, 4 (C ₂ ), 1 18.4 (C ₄ ), 121, 1 (C _8.12 ), 130, 2 (C _9, n), 134.4 (Cio), 139.4 (C ₃ ), 147.8 (C ₅ ), 151.9 (C ₇ ), 163.9 (d).

GC / MS: t = 17.39 min, M / Z = 185.

HRMS calcd for C ₁₂ H n NO (M + H) 186.0913 Experimental value: 186.0919. 1,3-dimethyl-5- (p-tolyloxy) benzene (compound 4.9, analytical data compared with those of the compound of N. Xia, M. Taillefer Chem Eur J. 2008, 14, 6037)

The general procedure of Example 4 was followed with 71 μl of 5-iodo-m-xylene (0.5 mmol) and 61 μl of 4-bromotoluene (0.5 mmol). The product is obtained in the form of a colorless oil. The yield is 50% (eluent heptane).

H NMR (400 MHz, CDCl _3): δ 2.19 (s, 6H, H _13,14), 2.26 (s, 3H, H _15), 6.52 (br s, 2H, H _2.6 ), 6.63 (brs, 1H, H ₄ ), 6.81 -6.84 (d, 2H, H _8.12 ), 7.04-7.06 (d, 2H, H ₉₁₁ ).

3C NMR (100 MHz, CDCl ₃ ): δ 20.8 (C ₁₅ ), _21.3 (C _13.14 ), 1 16.0 (C _2.6 ), 1 19.2 (C _8.12 ) , 124.8 (C ₄ ), 130.2 (C 9 ₁₁ ), 132.8 (C ₁₀ ), 139.6 (C _3.5 ), 154.9 (C ₇ ), 157.9 (C ₇ ) .

GC / MS: rt = 18.72 min, M / Z = 212.

HRMS calc for C ₁₅ H ₁₆ O (M + H) 213.1326 Experimental value: 213.1279.

4- (p-tolyloxy) benzonitrile (compounds 4.10 and 4.14, analytical data compared with those of R. Glosh, A.G. Samelson New J. Chem., 2004, 28, 1390)

The general procedure of Example 4 was followed with 109 mg of 4-iodotoluene (0.5 mmol) and 90.5 mg of 4-bromobenzonitrile (0.5 mmol) (compound 10) or 68.5 mg of 4 chlorobenzonitrile (0.5 mmol) (compound 14). The products are obtained in the form of a white solid. The yields are respectively 82% and 75% for the compounds 4-14 (eluent: heptane / ethyl acetate = 9/1).

1 H NMR (400 MHz, CDCl ₃ ): δ 2.30 (s, 3H, H ₁₄ ), 6.87-6.91 (m, 4H, H ₂ , 6, 8, 12), 7.12-7 , 14 (d, 2H, H ₄ ), 7.49-7.51 (d, 2H, H _3.5 ).

3C NMR (100 MHz, CDCl ₃ ): δ 21, 1 (C ₁₄ ), 105.5 (C ₄ ), 1 17.6 (C _8.12 ), 1 19.1 (C ₁₃ ), 120.4 (C _2.6 ), 130.7 (C ₉ , n), 134.0 (C ₃ , ₅ ), 152.4 (d), 162.3 (C ₇ ).

GC / MS: rt = 20.58 min, M / Z = 209.

HRMS calcd for C ₁₄ H n NO (M + H) 210.0974 experimental value: 210.0964.

Anal. Calc'd for C ₁₂ H ₉ N0 ₃ : C, 80.36; H, 5.30; N, 6.69. Experimental value C, 80.36; H

5.50; N, 6.10. 4- (4- (trifluoromethyl) phenoxy) benzonitrile (compound 4.15, analytical data compared with those of J.-K. Lee, J. Fuchter, J. Williamson, GA Leeke, E. Bush, IF McConvey, S. Saubern, JH Ryan, AB Holmes Common Chem., 2008, 39, 4780-4782)

The general procedure of Example 4 was followed with 14.5 mg of 4-ioobenzonitril (0.5 mmol) and 67.7 μl of 4-chlorobenzotrifluoride (0.5 mmol). The products are obtained in the form of a white solid. The yield is 61%. (eluent: heptane / ethyl acetate = 9/1).

1 H NMR (400 MHz, CDCl ₃ ): δ 6.99-7.01 (m, 2H, H _2.6 ), 7.06-7.08 (m, 2H, H _8.12 ), 7.58 -7.60 (m, 4H, H _{3 5 9 11} ).

3 C NMR (100 MHz, CDCl ₃ ): δ 107.4 (C ₄ ), 1 18.4 (C ₁₃ ), 1 18.8 (C _{2 6} ), 1 19.9 (C _{8 12} ), 126, 8 (C ₁₀ ), 127.1 (CM), 127.7 (C ₉ , n), 134.5 (C ₃ , ₅ ), 157.9 (C ₇ ), 160.1 (d).

GC / MS: t = 19.98 min, M / Z = 263.

Anal. Calculated for C ₁₄ H ₈ F ₃ NO: C, 63.88; H, 3.06; N, 4.32. Experimental value: C, 64.02; H, 3.41; N, 4.75. 1,3-dimethyl-5- (4-nitrophenoxy) benzene (compound 4.16, analytical data compared with that of P. Ma compound, Q. Cai Org. Lett. 2003, 5, 3799)

The general procedure of Example 4 was followed with 71 μl of 5-iodo-m-xylene (0.5 mmol) and 68.5 mg of 4-chloronitrobenzene (0.5 mmol). The product is obtained in the form of a yellow solid. The yield is 73% (eluent: heptanes / ethyl acetate = 9/1).

MP (melting point): 58 ° C.

1 H NMR (400 MHz, CDCl ₃ ): δ 2.25 (s, 6H, H _{13 14} ), 6.60 (br s, 2H, H _{2 6} ), 6.79 (brs, 1H, H ₄₎ ), 6.91 -6.92 (d, 2H, H _8.12 ), 7.50-7.52 (d, 2H, H _9, n).

3 C NMR (100 MHz, CDCl ₃ ): _δ 21.2 (C _13.14 ), 105.6 (C ₁₅ ), 17.9 (C _2.6 ), 18.5 (C _8.12 ) , 1 19.1 (C ₄ ), 126.9 (C ₄ ), 134.1 (C ₉ , n), 140.2 (C ₃ , ₅ ), 154.8 (d), 162.0 (C ₇ ).

GC / MS: rt = 16.72 min, M / Z = 223.

HRMS calc for C ₁₄ H ₁₃ NO ₃ (M + H) 224.1075 Experimental value: 224.1094. 1-methyl-4- (4- (trifluoromethyl) phenoxy) benzene (compound 4.17, analytical data compared with those of the compound of S. Benvhava, F. Monnier, M. Taillefer, M. Wonq Chi Man, C. Bied, F. Ouazzani, Adv Synth Synth 2008, 350, 2205)

The general procedure of Example 4 was followed with 109 mg of 4-iodotoluene (109 mg, 0.5 mmol) reacted and 67.7 μl of chlorobenzotrifluoride (0.5 mmol). The product is obtained in the form of a white solid. The yield is 80% (eluent: heptanes / ethyl acetate =

1 H NMR (400 MHz, CDCl ₃ ): δ 2.36 (s, 3H, H ₁₃ ), 6.94-6.95 (m, 2H, H _2.6 ), 6.99-7.01 (d. , 2H, H _3,5), 7.18-7.20 (d, 2H, H _8,12), 7.53 to 7.55 (d, 2H, H _9i11).

3C NMR (100 MHz, CDCl ₃ ): δ 20.8 (C ₁₃ ), 17.5 (C _2.6 ), 120.0 (C _8.12 ), 122.9 (C ₁₀ ), 124, 9 (C ₁₄ ), 126.9 (C ₉ , n), 130.5 (C ₃ , ₅ ), 134.6 (C ₄ ), 153.2 (d), 160.9 (C ₇ ).

GC / MS: t = 16.69 min, M / Z = 252.

Anal. Calculated for C ₁₄ H ₁₈ F ₃₀ : C, 66.66; H, 4.40. Experimental value C, 66.47; H, 4.37.

1-phenoxy-4- (trifluoromethyl) benzene (compound 4.18, analytical data compared with those of the compound of S. Benvhava, F. Monnier, M. Taillefer, M. Wonq Chi Man, C. Bied, F. Ouazzani. Synth.Chem., 2008, 350, 2205)

The general procedure of Example 4 was followed with 56 μl of iodobenzene (0.5 mmol) and 67.7 μl of 4-chlorobenzotrifluoride (0.5 mmol). The product is obtained in the form of a colorless oil. The yield is 77%. (eluent: heptane).

1H NMR (400 MHz, CDCl ₃ ): δ 7.03-7.07 (m, 4H, H _2.6.8 , 12), 7.18-7.22 (m, 1H, H ₄ ), 7.38-7.42 (m, 2H, H ₃ O), 7.56-7.58 (m, 2H, H _{9 11} ).

3C NMR (100 MHz, CDCl ₃ ): δ 1 17.8 (C ₂ , ₆ ), 1 19.9 (C ₈ , ₁₂ ), 122.9 (C ₄ ), 124.5 (C ₁₀ ), 124 , 7 (C ₁₄ ), 127.1 (C ₉ , n), 130.1 (C ₃ , ₅ ), 155.8 (d), 160.6 (C ₇ ).

GC / MS: t = 15.35 min, M / Z = 238.

These results show that the process of the invention makes it possible to obtain asymmetric biaryl ethers and heteroaryl ethers of formula (I) with good yields.

Claims

claims

(I)

in which :

Ar ¹ and Ar ² , identical or different, represent:

a mono- or polycyclic aryl, comprising from 6 to 14 carbon atoms, substituted or unsubstituted; or

a mono or polycyclic heteroaryl comprising from 5 to 12 carbon atoms, substituted or unsubstituted;

• X and Y, identical or different, represent a halogen atom.

2. Method according to claim 1 wherein Ar ¹ and Ar ² , identical or different, represent:

An aryl, substituted or unsubstituted by at least:

a halogen atom;

a linear or branched C ₁ -C 10 alkyl group;

- a trihaloalkyl group Ci-Ci _2;

a group of formula COR ¹ , in which R ¹ represents a linear or branched alkyl, in Ci to d ₀ ;

a group of formula OR ² , in which R ² represents a branched linear alkyl, C 1 to C 12;

a group of formula N0 ₂ ;

a group of CN formula; or heteroaryl, substituted or unsubstituted by at least one

a halogen atom;

- an alkyl group, linear or branched Ci to d _0;

- a trihaloalkyl group Ci-Ci _2;

a group of formula COR ¹ , in which R represents a linear or branched C ₁ -C 10 alkyl;

a group of formula N0 ₂ ; or

- a group of CN formula.

3. Method according to one of claims 1 or 2 wherein the oxygen source is represented by the formula MOH wherein M represents a hydrogen atom or an alkali or alkaline earth metal, or a transition metal.

4. Method according to one of claims 1 to 3 for which the catalyst is selected from copper metal, copper oxides (I) or copper (II), hydroxides copper (I) or copper (II), the inorganic or organic salts of copper (I) or copper (II) and copper (I) or copper (II) complexes, or combinations thereof; metallic iron, iron (II) or iron (III) oxides, iron (II) or iron (III) hydroxides, inorganic or organic iron (II) or iron (III) salts and iron complexes (II) or iron (III), or their associations.

5. Method according to one of claims 1 to 4 for which the ligand is selected from diketones; the NHA- (CH ₂ ) _n -NHA diamines, in which A, which may be identical or different, represents a hydrogen or a C ₁ -C 10 alkyl, n represents an integer between 1 and 10; polycyclic aromatic compounds comprising at least two hetero atoms.

6. The method of claim 5 wherein the ligand is selected from:

Method according to one of Claims 1 to 6, for which Ar and Ar ² are identical.

8. The method of claim 7 wherein X and Y, identical or different are selected from bromine and iodine.

9. Process according to one of claims 7 or 8 for which the solvent is a water / ethanol mixture and the sole source of oxygen is the water contained in the solvent.

10. Method according to one of claims 1 to 6 for which Ar and Ar ² are different.

1 1. The process of claim 10 wherein at least one of X or Y is iodine and the other is selected from iodine, bromine or chlorine.

12. Method according to one of claims 10 or 1 1 for which the oxygen source is CsOH, the base is Cs ₂ 0 ₃ and the solvent is DMSO.

13. Method according to one of claims 1 to 12 for which the molar ratio of starting materials (Ar -X and / or Ar ² -Y) / base is between 1/1 and 1/5.

14. Method according to one of claims 1 to 13 wherein the amount of catalyst is between 1 and 20 mol% relative to the starting materials (Ar-X and / or Ar ² -Y).

15. Method according to one of claims 1 to 14 wherein the amount of ligand is between 5 and 50 mol% relative to the starting materials (Ar -X and / or Ar ² -Y).