Process for creating carbon-carbon bonds using carbonyl compounds

Abstract

The present invention concerns a process for preparing a compound of formula (I) by reaction between a compound of formula (II) and a compound of formula (III) in the presence of a copper-containing catalyst, a ligand and base. The invention also concerns the implementing of this process for the preparation of building blocks to prepare molecules of interest in particular in the pharmaceutical, agro-chemical fields, etc. ##STR00001##

Claims

1. A process for preparing a compound of formula (I) by reaction between a compound of formula (II) and a compound of formula (III) in the presence of a copper-containing catalyst, a ligand and a base ##STR00060## where: R.sup.1 is: a hydrogen atom, a straight-chain or branched alkyl group having 1 to 15 carbon atoms, a straight-chain or branched alkenyl group having 1 to 15 carbon atoms and comprising at least one double bond, a substituted or unsubstituted aryl group having 6 to 10 carbon atoms, or a substituted or unsubstituted heteroaryl group having 5 to 10 members including at least one heteroatom selected in particular from among a nitrogen atom or oxygen atom; R.sup.2 is: a straight-chain or branched alkyl group having 1 to 15 carbon atoms, a straight-chain or branched alkenyl group having 1 to 15 carbon atoms and comprising at least one double bond, a substituted or unsubstituted aryl group having 6 to 10 carbon atoms, or a substituted or unsubstituted heteroaryl group having 5 to 10 members including at least one heteroatom selected in particular from among a nitrogen atom or oxygen atom; R.sup.3 is: a substituted or unsubstituted vinyl group, a substituted or unsubstituted aryl group having 6 to 10 carbon atoms, or a substituted or unsubstituted heteroaryl group having 5 to 10 members including at least one heteroatom selected in particular from among a nitrogen atom or oxygen atom; X is a halogen atom selected from among fluorine, chlorine, bromine and iodine, a tosylate group, or mesylate group; and the ligand is selected from among: diketones, diamines, and aromatic polycyclic compounds having at least two heteroatoms, unsubstituted or substituted by one or more C1 to C10 alkyl groups, NO.sub.2 group, aryl group having 6 to 10 carbon atoms.

2. The process according to claim 1 wherein R.sup.3 represents an aryl having 6 to 10 carbon atoms, unsubstituted or substituted by one or more substituents selected from among: a straight-chain or branched group of formula (O).sub.nalkyl having 1 to 15 carbon atoms, optionally substituted by one or more halogen atoms, and n is 0 or 1; a straight-chain or branched alkenyl group having 1 to 15 carbon atoms and comprising at least one double bond; a halogen atom selected from among chlorine, fluorine, bromine or iodine; a group of formula CN; a group of formula NH.sub.2; a substituted or unsubstituted aryl group having 6 to 10 carbon atoms; a group of formula (CH.sub.2).sub.m-aryl wherein m is an integer ranging from 1 to 10, and the aryl group, substituted or unsubstituted, comprises 6 to 10 carbon atoms.

3. The process according to claim 1 wherein R.sup.3 represents a phenyl substituted by one or more substituents selected from among: a straight-chain or branched group of formula (O).sub.nalkyl having 1 to 10 carbon atoms, and n is 0 or 1; a straight-chain or branched trifluoroalkyl group having 1 to 10 carbon atoms; a fluorine atom; and a chlorine atom.

4. The process according to claim 1 wherein the formula (II) compound is a compound of formula (IIa) ##STR00061## where: X is such as defined for the formula (II) compound; R.sup.4, R.sup.5 and R.sup.6, the same or different, represent: a hydrogen atom; a straight-chain or branched alkyl group having 1 to 15 carbon atoms, possibly comprising one or more unsaturations; a substituted or unsubstituted aryl group having 6 to 10 carbon atoms; a halogen atom selected from among chlorine, bromine, fluorine and iodine.

5. The process according to claim 1 wherein R.sup.3 represents a heteroaryl having 5 to 10 members including at least one heteroatom selected from among a nitrogen atom or oxygen atom, unsubstituted or substituted by one or more substituents selected from among: a straight-chain or branched group of formula (O).sub.nalkyl having 1 to 15 carbon atoms, optionally substituted by one or more halogen atoms and n is 0 or 1; a straight-chain or branched alkenyl group having 1 to 15 carbon atoms and comprising at least one double bond; a halogen atom selected in particular from among chlorine, fluorine, bromine and iodine.

6. The process according to claim 1 wherein for the compounds of formula (I) and (III), R.sup.1 is selected from among: a hydrogen atom; a straight-chain or branched alkyl group having 1 to 15 carbon atoms; a straight-chain or branched alkenyl group having 1 to 15 carbon atoms and comprising at least one double bond; an aryl group having 6 to 10 carbon atoms, unsubstituted or substituted by one or more substituents selected from among: a halogen atom selected from among chlorine, bromine, fluorine or iodine; a straight-chain or branched group of formula (O).sub.palkyl having 1 to 15 carbon atoms and p is 0 or 1; a hydroxy group; a straight-chain or branched alkenyl group having 1 to 15 carbon atoms and comprising at least one double bond; and a straight-chain or branched trifluoroalkyl having 1 to 10 carbon atoms.

7. The process according to claim 1 wherein for the compounds of formula (I) and (III), R.sup.2 is selected from among: a straight-chain or branched alkyl group having 1 to 15 carbon atoms; a straight-chain or branched alkenyl group having 1 to 15 carbon atoms and comprising at least one double bond; an aryl group having 6 to 10 carbon atoms unsubstituted or substituted by one or more substituents selected from among: a halogen atom selected from among chlorine, bromine, fluorine or iodine; a hydroxy group; a straight-chain or branched group of formula (O).sub.qalkyl having 1 to 15 carbon atoms, and q is 0 or 1; a straight-chain or branched alkenyl group having 1 to 15 carbon atoms and comprising at least one double bond; and a straight-chain or branched trifluoroalkyl group having 1 to 10 carbon atoms.

8. The process according to claim 1 wherein X represents iodine.

9. The process according to claim 1 wherein the catalyst is selected from among metallic copper, copper(I) or copper(II) oxides, copper(I) or copper(II) hydroxides, inorganic or organic salts of copper(I) or copper(II) and complexes of copper(I) or copper(II) with ligands, or mixtures thereof.

10. The process according to claim 1 implemented in the presence of a solvent selected from among dioxane and tert-butanol.

11. The process according to claim 1 wherein the ligand is selected from among: diketones of formula (i): ##STR00062## where: R.sup.a and R.sup.b, the same or different, represent a straight-chain or branched C.sub.1 to C.sub.10 alkyl chain, or C.sub.6 to C.sub.10 aryl radical; R.sup.c and R.sup.d are a hydrogen atom; or R.sup.a or R.sup.b, together with their carrier group C(O) and with one of R.sup.c or R.sup.d, forms a 6-membered carbocycle; and diamines of formula (ii)
NR.sup.eR.sup.f(CH.sub.2).sub.rNR.sup.gR.sup.h(ii) where: R.sup.e, R.sup.f, R.sup.g, R.sup.h, the same or different, represent a hydrogen atom or C.sub.1 to C.sub.10 alkyl group; r is an integer ranging from 1 to 10; or aromatic polycyclic compounds having at least two heteroatoms, unsubstituted or substituted by one or more C.sub.1 to C.sub.10 alkyl groups, NO.sub.2 group, aryl group having 6 to 10 carbon atoms.

12. The process according to claim 1 wherein the ligand is selected from among the compounds of formula: ##STR00063##

13. The process according to claim 1 wherein the base is selected from among: alkaline or alkaline-earth alcoholates of formula (M.sup.1(OR).sub.s); and/or alkaline or alkaline-earth phosphates of formula (M.sup.1.sub.t(OH).sub.u(PO.sub.4).sub.v); and/or alkaline or alkaline-earth carbonates of formula (M.sup.1.sub.w(CO.sub.3).sub.y), or mixtures thereof wherein M.sup.1 is Li, Na, K, Rb, Cs, Fr, Be, Mg, Ca, Sr, Ba or Ra; s is 1 or 2; R is selected from the group formed by the alkyl, benzyl and aryl groups; t is an integer ranging from 1 to 10; u is an integer ranging from 0 to 2; v is an integer ranging from 1 to 10; w is an integer ranging from 1 to 10; y is an integer ranging from 1 to 10.

14. The process according to claim 1 implemented at a temperature ranging from 50 to 200 C.

15. The process according to claim 1 wherein the molar quantity of catalyst is 0.001 to 100% relative to the number of moles of the formula (II) compound.

16. The process according to claim 1 wherein the ligand/catalyst molar ratio is 0.5 to 100.

17. The process according to claim 1 wherein the molar ratio of formula (II) compound/formula (III) compound is 0.5 to 10.

18. The process according to claim 1 wherein the molar quantity of base is 0.2 to 4 equivalents relative to the molar quantity of formula (II) compound.

19. A process for preparing a compound of formula (IV) comprising the implementing of the process according to claim 1: ##STR00064## wherein R is a hydrogen atom or hydroxyl group, comprising the following steps: a) preparing a compound of formula (Ia) comprising the implementing of the process according to claim 1: ##STR00065## b) reacting the formula (Ia) compound with EtMgBr to obtain the compound of formula (V): ##STR00066## c) reacting the formula (V) compound with a compound of formula Y(CH.sub.2).sub.2N(Me).sub.2 where Y is a halogen atom, to obtain the compound of formula (IV).

20. A process for preparing a compound of formula (IV) comprising the following steps: a) preparing a compound of formula (Ib) comprising the implementing of the process to create a CC bond according to claim 1, in the presence of a compound of formula YC.sub.6H.sub.4O(CH.sub.2).sub.2N(Me).sub.2 where Y is a halogen atom; ##STR00067## where R is a hydrogen atom or hydroxy group; b) reacting the formula (Ib) compound with EtMgBr to obtain the compound of formula (IV).

Description

EXAMPLE 1

Implementation of the Process of the Invention

(1) Procedure (A)

(2) After several standard draining and purging cycles of the tubes using a flow of argon or nitrogen, the reactor is charged with 0.01 mmol (19 mg) of CuI, 1.5 mmol of formula (III) compound, 2 mmol (650 mg) of Cs.sub.2CO.sub.3, 0.1 mmol of ligand and 1 mmol of formula (II) compound if it is a solid. If the formula (II) compound is a liquid, it is added to the reaction medium using a syringe at ambient temperature followed by the addition of 1 ml of anhydrous or degassed tert-butanol or 1 ml of anhydrous or degassed dioxane. The reactor is closed under positive nitrogen or argon pressure. The reaction mixture is left under agitation and heated to 110 C. for 24 hours. After cooling down to ambient temperature, the reaction mixture is acidified with a 10% aqueous HCl solution and extracted twice with ethyl acetate. The organic phases obtained are combined and washed with brine solution, dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The product obtained is purified by silica gel chromatography.

1,2-diphenyl-2-p-tolylethanone

EXAMPLE 1.1

(3) Procedure (A) was implemented using: formula (II) compound: 4-iodotoluene (218 mg, 1.0 mmol), formula (III) compound: deoxybenzoin, ligand: bathophenantroline, solvent: t-BuOH

(4) The yield obtained was 85% (chromatography eluent: petroleum ether/diethylether 95:5)

(5) ##STR00011##

(6) .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 8.06-7.91 (m, 3H); 7.56-7.43 (m, 2H); 7.44-7.34 (m, 2H); 7.34-7.20 (m, 3H); 7.19-7.09 (m, 4H); 6.00 (s, 1H); 2.30 (s, 3H).

(7) .sup.13C NMR (100 MHz, CDCl.sub.3) ppm 198.4; 139.4; 136.9; 136.8; 136.1; 133.0; 129.5; 129.1; 129.0; 129.0; 128.7; 128.6; 127.1; 59.1; 21.1.

(8) HRMS calculated for C.sub.21H.sub.19O (M+H) 287.1436. Found: 287.1427.

1,2-diphenyl-2-m-tolylethanone

EXAMPLE 1.2

(9) Procedure (A) was implemented using: formula (II) compound: 3-iodotoluene (130 L, 1.0 mmol), formula (III) compound: deoxybenzoin, ligand: bathophenantroline, solvent t-BuOH

(10) The yield obtained was 95% (chromatography eluent: petroleum ether/diethylether 95:5).

(11) ##STR00012##

(12) .sup.1H NMR (400 MHz, CDCl3) ppm 7.96-7.87 (m, 3H), 7.63-7.53 (m, 2H), 7.47-7.38 (m, 2H), 7.36-7.28 (m, 1H), 7.27-7.09 (m, 4H), 6.99 (dd, J=13.7, 6.1 Hz, 2H), 5.93 (s, 1H), 2.22 (s, 3H).

(13) .sup.13C NMR (100 MHz, CDCl.sub.3) ppm 198.3; 139.2; 138.9; 138.5; 136.9; 135.0; 133.0; 130.0; 129.8; 129.2; 129.1; 129.0; 128.7; 128.6; 128.0; 127.2; 126.2; 59.5; 21.6.

(14) HRMS calculated for C.sub.21H.sub.19O (M+H) 287.1436. Found: 287.1441.

2-(3,5-dimethylphenyl)-1,2-diphenylethanone

EXAMPLE 1.3

(15) Procedure (A) was implemented using: formula (II) compound: 3-iodoxylene (145 L, 1.0 mmol), formula (III) compound: deoxybenzoin, ligand: bathophenantroline, solvent: t-BuOH

(16) The yield obtained was 95% (chromatography eluent: petroleum ether/diethylether 95:5).

(17) ##STR00013##

(18) .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 7.97-7.85 (m, 3H); 7.48-7.37 (m, 2H); 7.36-7.28 (m, 2H); 7.27-7.11 (m, 3H); 6.89-6.70 (m, 3H); 5.89 (d, J=2.55 Hz, 1H); 2.18 (s, 6H).

(19) .sup.13C NMR (100 MHz, CDCl.sub.3) ppm 198.3; 139.2; 138.7; 138.2; 136.9; 132.9; 129.9; 129.1; 128.9; 128.6; 128.5; 127.0; 126.8; 59.3; 21.3.

(20) HRMS calculated for C.sub.22H.sub.21O (M+H) 301.1592. Found: 301.1589.

2-(4-methoxyphenyl)-1,2-diphenylethanone

EXAMPLE 1.4

(21) Procedure (A) was implemented using: formula (II) compound: 4-iodoanisole (234 mg, 1.0 mmol), formula (III) compound: deoxybenzoin, ligand: phenantroline, solvent: t-BuOH

(22) The yield obtained was 74% (chromatography eluent: petroleum ether/toluene 1:1).

(23) ##STR00014##

(24) .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 7.92 (dd, J=8.4, 1.2 Hz, 2H), 7.48-7.39 (m, 1H), 7.37-7.29 (m, 2H), 7.24 (ddd, J=7.1, 4.5, 1.2 Hz, 2H), 7.20-7.15 (m, 3H), 7.14-7.09 (m, 2H), 6.82-6.73 (m, 2H), 5.91 (s, 1H), 3.69 (s, 3H).

(25) .sup.13C NMR (100 MHz, CDCl.sub.3) ppm 198.5; 158.7; 158.3; 139.5; 136.9; 133.0; 131.1; 130.2; 129.1; 129.0; 128.7; 128.6; 127.1; 114.2; 58.7; 55.3.

(26) HRMS calculated for C.sub.21H.sub.19O.sub.2 (M+H) 303.1385. Found: 303.1388.

2-(3-methoxyphenyl)-1,2-diphenylethanone

EXAMPLE 1.5

(27) Procedure (A) was implemented using: formula (II) compound: 3-iodoanisole (120 l, 1.0 mmol), formula (III) compound: deoxybenzoin, ligand: bathophenantroline, solvent: t-BuOH

(28) The yield obtained was 83% (chromatography eluent: petroleum ether/toluene 1:1).

(29) ##STR00015##

(30) .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 7.95-7.89 (m, 2H), 7.48-7.37 (m, 1H), 7.36-7.28 (m, 2H), 7.27-7.11 (m, 6H), 6.79 (dd, J=7.4, 0.7 Hz, 1H), 6.76-6.74 (m, 1H), 6.71 (ddd, J=8.2, 2.6, 0.7 Hz, 1H), 5.93 (s, 1H), 3.67 (s, 3H).

(31) .sup.13C NMR (100 MHz, CDCl.sub.3) ppm 195.7, 157.4, 138.1, 136.5, 134.5, 130.7, 127.3, 126.8, 126.6, 126.3, 126.3, 124.8, 119.2, 112.7, 110.0, 57.0, 52.8.

(32) HRMS calculated for C.sub.21H.sub.19O.sub.2 (M+H) 303.1385. Found: 303.1375.

2-(2-methoxyphenyl)-1,2-diphenylethanone

EXAMPLE 1.6

(33) Procedure (A) was implemented using: formula (II) compound: 2-iodoanisole (130 l, 1.0 mmol), formula (III) compound: deoxybenzoin, ligand: phenantroline, solvent: t-BuOH

(34) The yield obtained was 50% (chromatography eluent: petroleum ether/toluene 1:1).

(35) ##STR00016##

(36) .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 8.14-7.77 (m, 2H), 7.44-7.35 (m, 1H), 7.34-7.26 (m, 2H), 7.27-7.21 (m, 4H), 7.21-7.11 (m, 2H), 6.84 (dd, J=7.4, 1.8 Hz, 1H), 6.78 (dd, J=11.5, 4.3 Hz, 2H), 6.26 (s, 1H), 3.67 (s, 3H).

(37) .sup.13C NMR (100 MHz, CDCl.sub.3) ppm 198.9; 156.3; 137.6; 137.1; 132.7; 129.8; 128.8; 128.8; 128.5; 128.4; 127.2; 120.7; 110.4; 55.5; 53.1.

(38) HRMS calculated for C.sub.21H.sub.19O.sub.2 (M+H) 303.1385. Found: 303.1378.

1-phenyl-2,2-dip-tolylethanone

EXAMPLE 1.7

(39) Procedure (A) was implemented using: formula (II) compound: 4-iodotoluene (218 mg, 1.0 mmol), formula (III) compound: 4-methylbenzylphenylketone, ligand: bathophenantroline, solvent: t-BuOH

(40) The yield obtained was 70% (chromatography eluent: petroleum ether/diethylether 95:5).

(41) ##STR00017##

(42) .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 8.11-7.72 (m, 2H); 7.48-7.37 (m, 1H); 7.36-7.28 (m, 2H); 7.13-6.98 (m, 8H); 5.88 (s, 1H); 2.23 (s, 6H).

(43) .sup.13C NMR (100 MHz, CDCl.sub.3) ppm 198.5; 137.0; 136.7; 136.3; 132.9; 129.4; 129.0; 128.6; 58.8; 21.1.

(44) HRMS calculated for C.sub.22H.sub.21O (M+H) 301.1592. Found: 301.1588.

1-phenyl-2-m-tolyl-2-p-tolylethanone

EXAMPLE 1.8

(45) Procedure (A) was implemented using: formula (II) compound: 3-iodotoluene (130 L, 1.0 mmol), formula (III) compound: 4-methylbenzylphenylketone, ligand: phenantroline, solvent: t-BuOH

(46) The yield obtained was 54% (chromatography eluent: petroleum ether/diethylether 95:5).

(47) ##STR00018##

(48) .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 7.98-7.85 (m, 2H); 7.46-7.37 (m, 1H); 7.37-7.27 (m, 2H); 7.18-7.02 (m, 5H); 7.02-6.94 (m, 3H); 5.88 (s, 1H); 2.23 (s, 3H); 2.22 (s, 3H).

(49) .sup.13C NMR (100 MHz, CDCl.sub.3) ppm 198.4; 139.1; 138.3; 136.9; 136.7; 136.1; 132.9; 129.7; 129.4; 129.0; 128.9; 128.5; 127.9; 126.1; 59.0; 21.5; 21.0.

(50) HRMS calculated for C.sub.22H.sub.21O (M+H) 301.1592. Found: 301.1602.

2-(3,5-dimethylphenyl)-1-phenyl-2-p-tolylethanone

EXAMPLE 1.9

(51) Procedure (A) was implemented using: formula (II) compound: 4-iodoxylene (145 L, 1.0 mmol), formula (III) compound: 4-methylbenzylphenylketone, ligand: bathophenantroline, solvent: t-BuOH

(52) The yield obtained was 90% (chromatography eluent: petroleum ether/diethylether 95:5).

(53) ##STR00019##

(54) .sup.1H NMR (250 MHz, CDCl.sub.3) ppm 8.01-7.84 (m, 2H), 7.50-7.38 (m, 1H), 7.39-7.27 (m, 2H), 7.13-7.00 (m, 4H), 6.81 (app s, 3H), 5.86 (s, 1H), 2.24 (s, 3H), 2.19 (s, 6H).

(55) .sup.13C NMR (100 MHz, CDCl.sub.3) ppm 198.8, 139.0, 138.4, 137.0, 136.6, 136.2, 132.8, 129.4, 129.1, 128.9, 128.6, 126.9, 58.9, 30.8, 21.1.

(56) HRMS calculated for C.sub.23H.sub.23O.sub.2 (M+H) 315.1749. Found: 315.1744.

2-(4-methoxyphenyl)-1-phenyl-2-p-tolylethanone

EXAMPLE 1.10

(57) Procedure (A) was implemented using: formula (II) compound: 4-iodoanisole (234 mg, 1.0 mmol), formula (III) compound: 4-methylbenzylphenylketone, ligand: bathophenantroline, solvent: t-BuOH

(58) The yield obtained was 66% (chromatography eluent: petroleum ether/toluene 1:1).

(59) ##STR00020##

(60) .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 8.08-7.74 (m, 2H), 7.47-7.36 (m, 1H), 7.36-7.25 (m, 2H), 7.18-6.97 (m, 6H), 6.81-6.70 (m, 2H), 5.87 (s, 1H), 3.67 (s, 3H), 2.22 (s, 3H).

(61) .sup.13C NMR (100 MHz, CDCl.sub.3) ppm 198.7; 158.6; 136.9; 136.7; 136.5; 133.0; 131.4; 130.2; 129.5; 129.0; 129.0; 128.6; 114.1; 58.3; 55.2; 31.0; 21.1.

(62) HRMS calculated for C.sub.22H.sub.21O.sub.2 (M+H) 317.1542. Found: 317.1531.

1-(4-chlorophenyl)-2-phenyl-2-p-tolylethanone

EXAMPLE 1.11

(63) Procedure (A) was implemented using: formula (II) compound: 4-iodotoluene (218 mg, 1.0 mmol), formula (III) compound: 4-chlorophenylbenzylketone, ligand: phenantroline, solvent: dioxane

(64) The yield obtained was 95% (chromatography eluent: petroleum ether/diethylether 95:5).

(65) ##STR00021##

(66) .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 7.94-7.73 (m, 2H), 7.31-7.24 (m, 2H), 7.25-7.19 (m, 2H), 7.19-7.12 (m, 3H), 7.09-7.01 (m, 4H), 5.84 (s, 1H), 2.22 (s, 3H).

(67) .sup.13C NMR (100 MHz, CDCl.sub.3) ppm 197.2; 139.4; 139.0; 137.0; 135.7; 135.2; 130.4; 129.6; 129.1; 129.0; 128.9; 128.8; 127.2; 59.3; 21.1.

(68) HRMS calculated for C.sub.21H.sub.18OCl (M+H) 321.1046. Found: 321.1023.

1-(4-chlorophenyl)-2-phenyl-2-m-tolylethanone

EXAMPLE 1.12

(69) Procedure (A) was implemented using: formula (II) compound: 3-iodotoluene (130 L, 1.0 mmol), formula (III) compound: 4-chlorophenylbenzylketone, ligand: phenantroline, solvent: t-BuOH

(70) The yield was 96% (chromatography eluent: petroleum ether/diethylether 95:5).

(71) ##STR00022##

(72) .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 7.98-7.69 (m, 2H), 7.33-7.27 (m, 2H), 7.27-7.21 (m, 2H), 7.21-7.10 (m, 4H), 7.03-6.93 (m, 3H), 5.85 (s, 1H), 2.23 (s, 3H)

(73) .sup.13C NMR (100 MHz, CDCl.sub.3) ppm, 197.0, 139.5, 138.9, 138.6, 138.5, 135.2, 130.4, 129.7, 129.1, 128.9, 128.7, 128.7, 128.1, 127.2, 126.1, 59.6, 21.5.

(74) HRMS calculated for C.sub.21H.sub.18OCl (M+H) 321.1046. Found: 321.1046.

1-(4-chlorophenyl)-2-(3,5-dimethylphenyl)-2-phenylethanone

EXAMPLE 1.13

(75) Procedure (A) was implemented using: formula (II) compound: 3-iodoxylene (145 L, 1.0 mmol), formula (III) compound: 4-chlorophenylbenzylketone, ligand: phenantroline, solvent: dioxane

(76) The yield obtained was 95% (chromatography eluent: petroleum ether/diethylether 95:5).

(77) ##STR00023##

(78) .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 8.04-7.67 (m, 3H), 7.47-7.37 (m, 1H), 7.32-7.25 (m, 2H), 7.25-7.20 (m, 1H), 7.20-7.12 (m, 2H), 6.85-6.75 (m, 3H), 5.81 (s, 1H), 2.18 (s, 6H).

(79) .sup.13C NMR (100 MHz, CDCl.sub.3) ppm 197.2, 139.5, 139.0, 138.4, 135.2, 135.1, 131.3, 130.4, 129.2, 129.1, 128.9, 128.7, 126.8, 59.4, 21.5.

(80) HRMS calculated for C.sub.22H.sub.20OCl (M+H) 335.1203. Found: 335.1189.

1-(4-chlorophenyl)-2-(4-methoxyphenyl)-2-phenylethanone

EXAMPLE 1.14

(81) Procedure (A) was implemented using: formula (II) compound: 4-iodoanisole (234 mg, 1.0 mmol), formula (III) compound: 4-chlorophenylbenzylketone, ligand: phenantroline, solvent: dioxane

(82) The yield obtained was 70% (chromatography eluent: petroleum ether/toluene 1:1).

(83) ##STR00024##

(84) .sup.x1H RMN (400 MHz, CDCl.sub.3) ppm 8.00-7.68 (m, 2H); 7.32-7.27 (m, 2H); 7.26-7.21 (m, 2H); 7.20-7.12 (m, 3H); 7.12-7.06 (m, 2H); 6.85-6.70 (m, 2H); 5.83 (s, 1H); 3.69 (s, 3H).

(85) .sup.13C NMR (100 MHz, CDCl.sub.3) ppm 197.2; 158.8; 139.4; 139.1; 135.1; 130.7; 130.3; 130.1; 129.0; 128.9; 128.7; 127.2; 114.2; 58.7; 55.2.

(86) HRMS calculated for C.sub.21H.sub.18O.sub.2Cl (M+H) 337.0995. Found: 337.0988.

1-(4-chlorophenyl)-2-(3-methoxyphenyl)-2-phenylethanone

EXAMPLE 1.15

(87) Procedure (A) was implemented using: formula (II) compound: 3-iodoanisole (120 L, 1.0 mmol), formula (III) compound: 4-chlorophenylbenzylketone, ligand: phenantroline, solvent: dioxane

(88) The yield obtained was 75% (chromatography eluent: petroleum ether/toluene 95:5).

(89) ##STR00025##

(90) .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 7.88-7.80 (m, 2H), 7.34-7.26 (m, 2H), 7.26-7.21 (m, 2H), 7.20-7.14 (m, 4H), 6.82-6.74 (m, 1H), 6.74-6.69 (m, 2H), 5.84 (s, 1H), 3.67 (s, 3H).

(91) .sup.13C NMR (100 MHz, CDCl.sub.3) ppm 196.8, 160.0, 140.2, 139.5, 138.6, 135.1, 130.4, 129.8, 129.1, 129.0, 128.8, 127.3, 121.6, 115.2, 112.4, 59.5, 55.2.

(92) HRMS calculated for C.sub.21H.sub.18O.sub.2Cl (M+H) 337.0995. Found: 337.0999.

1-(4-chlorophenyl)-2-(2-methoxyphenyl)-2-phenylethanone

EXAMPLE 1.16

(93) Procedure (A) was implemented using: formula (II) compound: 2-iodoanisole (130 L, 1.0 mmol), formula (III) compound: 4-chlorophenylbenzylketone, ligand: phenantroline, solvent: dioxane

(94) The yield obtained was 56% (chromatography eluent: petroleum ether/toluene 1:1).

(95) ##STR00026##

(96) .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 7.89-7.83 (m, 2H), 7.33-7.24 (m, 4H), 7.24-7.19 (m, 3H), 7.18-7.14 (m, 1H), 6.85-6.75 (m, 3H), 6.18 (s, 1H), 3.69 (s, 3H).

(97) .sup.13C NMR (100 MHz, CDCl.sub.3) ppm 197.6, 156.2, 139.0, 137.3, 135.4, 131.0, 130.2, 129.7, 128.8, 128.8, 128.5, 128.4, 127.4, 120.7, 110.5, 55.5, 53.2.

(98) HRMS calculated for C.sub.21H.sub.18O.sub.2Cl (M+H) 337.0995. Found: 321.0991.

2-(3,5-dimethylphenyl)-2-(2-fluorophenyl)-1-phenylethanone

EXAMPLE 1.17

(99) Procedure (A) was implemented using: formula (II) compound: 3-iodoxylene (145 L, 1.0 mmol), formula (III) compound: 2-fluorobenzylphenylketone, ligand: bathophenantroline, solvent: t-BuOH

(100) The yield obtained was 96% (chromatography eluent: petroleum ether/diethylether 95:5).

(101) ##STR00027##

(102) .sup.1H NMR (250 MHz, CDCl.sub.3) ppm 8.04-7.82 (m, 2H), 7.46-7.35 (m, 1H), 7.34-7.27 (m, 2H), 7.18-7.09 (m, 1H), 7.04-6.90 (m, 3H), 6.87-6.80 (m, 3H), 6.16 (s, 1H), 2.19 (s, 6H).

(103) .sup.13C NMR (100 MHz, CDCl.sub.3) ppm 197.6, 161.5, 159.0, 138.6, 136.8, 136.5, 133.1, 130.9, 130.8, 129.3, 129.0, 129.0, 129.0, 128.6, 127.2, 127.1, 124.2, 124.1, 115.3, 115.0, 52.0, 21.4.

2-(3,5-dimethylphenyl)-2-(4-chlorophenyl)-1-Phenylethanone

EXAMPLE 1.18

(104) Procedure (A) was implemented using: formula (II) compound: 3-iodoxylene (145 L, 1.0 mmol), formula (III) compound: 4-chlorobenzylphenylketone, ligand: bathophenantroline, solvent: t-BuOH

(105) The yield obtained was 99% (chromatography eluent: petroleum ether/diethylether 95:5).

(106) ##STR00028##

(107) .sup.1H NMR (250 MHz, CDCl.sub.3) ppm 8.04-7.78 (m, 2H), 7.52-7.39 (m, 1H), 7.39-7.31 (m, 1H), 7.25-7.18 (m, 2H), 7.15-7.09 (m, 2H), 6.82 (br s, 1H), 6.80 (br s, 2H), 5.85 (s, 1H), 2.20 (s, 6H).

(108) .sup.13C NMR (100 MHz, CDCl.sub.3) ppm 198.0, 138.5, 138.3, 137.9, 136.7, 133.2, 133.0, 130.6, 129.2, 129.0, 128.7, 128.7, 126.7, 58.7, 21.3.

(109) Procedure B

(110) After several standard draining and purging cycles of the tubes with a flow or argon or nitrogen, the reactor is charged with 0.01 mmol (19 mg) of CuI, 1.5 mmol of formula (III) compound, 2 mmol (650 mg) of Cs.sub.2CO.sub.3, 0.1 mmol of 2-acetylcyclohexanone and 1 mmol of formula (II) compound if it is solid. If the formula (II) compound is liquid it is added to the reaction medium using a syringe at ambient temperature with 2-acetylcyclohexanone (0.1 mmol, 13 L) followed by the addition of 1 ml of anhydrous, degassed tert-butanol. The reactor is closed under positive pressure of nitrogen or argon. The reaction mixture is left under agitation and heated to 70 or 90 C. for 24 hours. After cooling down to ambient temperature, 13 L of 1,3-dimethoxybenzene (internal standard) then 1 ml of ethyl acetate are added. A sample of the reaction medium is taken and acidified with a 10% aqueous HCl solution, the organic phase is then filtered over celite and the residue washed with ethyl acetate. The filtrate is analysed by proton NMR. The reaction mixture is acidified with a 10% aqueous HCl solution and extracted twice with ethyl acetate. The organic phases obtained are combined and washed in brine solution, dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The product obtained is purified by silica gel chromatography.

1,2-diphenyl-2-(4-fluorophenyl)ethanone

EXAMPLE 1.19

(111) Procedure (B) was implemented at 70 C. using:

(112) Formula (II) compound: 4-iodofluorobenzene (115 L, 1.0 mmol)

(113) Formula (III) compound: deoxybenzoin

(114) Product (I) was obtained with a yield of 75% (eluent: petroleum ether/diethylether=95:5).

(115) ##STR00029##

(116) .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 7.90 (td, J=8.6, 1.6 Hz, 2H), 7.46-7.35 (m, 1H), 7.36-7.27 (m, 2H), 7.27-7.19 (m, 2H), 7.19-7.10 (m, 5H), 6.98-6.83 (m, 2H), 5.93 (s, 1H)

(117) .sup.13C NMR (100 MHz, CDCl.sub.3) ppm 198.0; 163.0; 160.6; 138.8; 136.5; 134.9; 134.8; 133.1; 130.7; 130.6; 128.9; 128.9; 128.8; 128.6; 127.2; 115.6; 115.4; 58.5.

(118) HRMS calculated for C.sub.20H.sub.16OF (M+H) 291.1185. Found: 291.1173.

1,2-diphenyl-2-(4-bromophenyl)ethanone

EXAMPLE 1.20

(119) Procedure (B) was implemented at 70 C. using:

(120) Formula (II) compound: 4-iodobromobenzene (283 mg, 1.0 mmol)

(121) Formula (III) compound: deoxybenzoin

(122) Product (I) was obtained with a yield of 60% (eluent: petroleum ether/diethylether 95:5).

(123) ##STR00030##

(124) .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 7.90 (td, J=8.6, 1.7 Hz, 2H), 7.49-7.40 (m, 1H), 7.39-7.30 (m, 4H), 7.29-7.21 (m, 2H), 7.21-7.15 (m, 3H), 7.09-7.03 (m, 2H), 5.91 (s, 1H).

(125) .sup.13C NMR (100 MHz, CDCl.sub.3) ppm 197.8, 138.5, 138.2, 136.5, 133.3, 131.8, 130.9, 129.0, 129.0, 129.0, 127.4, 121.3, 58.8.

1,2-diphenyl-2-(4-(trifluoromethyl)phenyl)ethanone

EXAMPLE 1.21

(126) Procedure (B) was implemented at 70 C. using:

(127) Formula (II) compound: 4-iodobenzotrifluoride (150 L, 1.0 mmol)

(128) Formula (III) compound: deoxybenzoin

(129) Product (I) was obtained with a yield of 55% (eluent: petroleum ether/diethylether 95:5).

(130) ##STR00031##

(131) .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 7.94-7.86 (m, 2H), 7.47 (d, J=8.1 Hz, 2H), 7.45-7.39 (m, 1H), 7.35-7.25 (m, 1H), 7.24 (ddd, J=7.1, 4.4, 1.7 Hz, 2H), 7.21-7.16 (m, 3H), 6.00 (s, 1H)

(132) .sup.13C NMR (100 MHz, CDCl.sub.3) ppm 197.5, 143.4, 138.2, 136.6, 133.4, 129.6, 129.1, 129.1, 129.0, 128.8, 127.6, 125.6, 59.2.

1,2-diphenyl-2-(3-fluorophenyl)ethanone

EXAMPLE 1.22

(133) Procedure (B) was implemented at 70 C. using:

(134) Formula (II) compound: 3-iodofluorobenzene (120 L, 1.0 mmol)

(135) Formula (III) compound: deoxybenzoin

(136) Product (I) was obtained with a yield of 48% (eluent: petroleum ether/diethylether 95:5).

(137) ##STR00032##

(138) .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 8.03-7.77 (m, 2H), 7.50-7.30 (m, 3H), 7.29-7.11 (m, 6H), 7.03-6.77 (m, 3H), 5.94 (s, 1H)

(139) .sup.13C NMR (100 MHz, CDCl.sub.3) ppm 197.6, 164.9, 160.9, 141.7, 141.6, 138.4, 136.6, 133.3, 130.1, 130.0, 129.1, 129.0, 128.7, 127.5, 124.9, 124.8, 116.5, 116.1, 114.3, 114.0, 59.0.

1,2-diphenyl-2-(3-(trifluoromethyl)phenyl)ethanone

EXAMPLE 1.23

(140) Procedure (B) was implemented at 70 C. using: Formula (II) compound: 3-iodobenzotrifluoride (150 L, 1.0 mmol)

(141) Formula (III) compound: deoxybenzoin

(142) Product (I) was obtained with a yield of 60% (eluent: petroleum ether/diethylether 95:5).

(143) ##STR00033##

(144) .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 7.92 (td, J=8.6, 1.7 Hz, 2H), 7.49-7.41 (m, 3H), 7.40-7.30 (m, 4H), 7.27 (ddd, J=7.1, 4.4, 1.7 Hz, 2H), 7.23-7.18 (m, 3H), 6.01 (s, 1H)

(145) .sup.13C NMR (100 MHz, CDCl.sub.3) ppm 197.5, 140.2, 138.2, 136.4, 133.4, 132.7, 129.1, 129.0, 129.0, 128.8, 127.6, 125.9, 124.1, 59.1.

2-(4-fluorophenyl)-1-phenyl-2-p-tolylethanone

EXAMPLE 1.24

(146) Procedure (B) was implemented at 90 C. using::

(147) Formula (II) compound: 4-fluoroiodobenzene (115 L, 1.0 mmol)

(148) Formula (III) compound: 4-methylbenzylphenylketone

(149) Product (I) was obtained with a yield of 57% (eluent: petroleum ether/diethylether 95:5).

(150) ##STR00034##

(151) .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 7.91 (td, J=8.55, 1.69, 1.69 Hz, 2H), 7.48-7.41 (m, 1H), 7.37-7.30 (m, 2H), 7.20-7.10 (m, 3H), 7.10-7.04 (m, 3H), 6.96-6.88 (m, 2H), 5.90 (s, 1H), 2.24 (s, 3H).

(152) .sup.13C NMR (100 MHz, CDCl.sub.3) ppm 198.2, 163.1, 160.7, 137.1, 136.7, 135.9, 135.2, 133.2, 130.7, 130.7, 129.7, 129.0, 128.8, 128.7, 115.6, 115.4, 58.3, 21.1.

(153) HRMS calculated for C.sub.21H.sub.18OF (M+H) 305.1342. Found: 305.1335.

2-(3-fluorophenyl)-1-phenyl-2-p-tolylethanone

EXAMPLE 1.25

(154) Procedure (B) was implemented at 90 C. using::

(155) Formula (II) compound: 3-fluoroiodobenzene (115 L, 1.0 mmol)

(156) Formula (III) compound: 4-methylbenzylphenylketone

(157) Product (I) was obtained with a yield of 54% (eluent: petroleum ether/diethylether 95:5).

(158) ##STR00035##

(159) .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 7.90 (td, J=8.6, 1.7 Hz, 2H), 7.48-7.37 (m, 1H), 7.36-7.27 (m, 2H), 7.22-7.13 (m, 1H), 7.12-7.02 (m, 4H), 6.98-6.92 (m, 1H), 6.91-6.80 (m, 2H), 5.90 (s, 1H), 2.22 (s, 3H)

(160) .sup.13C NMR (100 MHz, CDCl.sub.3) ppm 197.8, 164.1, 161.7, 141.9, 137.2, 136.7, 135.4, 133.2, 130.0, 129.9, 129.7, 129.0, 128.9, 128.7, 124.8, 124.8, 116.4, 116.2, 114.2, 113.9, 58.6, 21.2.

1-phenyl-2-p-tolyl-2-(3-(trifluoromethyl)phenyl)ethanone

EXAMPLE 1.26

(161) Procedure (B) was implemented at 90 C. using:

(162) Formula (II) compound: 3-iodobenzotrifluoride (150 L, 1.0 mmol)

(163) Formula (III) compound: 4-methylbenzylphenylketone

(164) Product (I) was obtained with a yield of 40% (eluent: petroleum ether/diethylether 95:5).

(165) ##STR00036##

(166) .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 7.92 (td, J=8.6, 1.6 Hz, 2H), 7.52-7.40 (m, 3H), 7.40-7.30 (m, 4H), 7.14-7.04 (m, 4H), 5.97 (s, 1H), 2.24 (s, 3H).

(167) .sup.13C NMR (100 MHz, CDCl.sub.3) ppm 197.6, 140.4, 137.4, 136.5, 135.1, 133.3, 132.7, 129.9, 129.0, 129.0, 128.8, 128.7, 125.9, 124.0, 58.7, 21.1.

(168) HRMS calculated for C.sub.22H.sub.18OF.sub.3 (M+H) 355.1310. Found: 355.1308.

1-(4-chlorophenyl)-2-(4-fluorophenyl)-2-phenylethanone

EXAMPLE 1.27

(169) Procedure (B) was implemented at 70 C. with:

(170) Formula (II) compound: 4-fluoroiodobenzene (115 L, 1.0 mmol)

(171) Formula (III) compound: 4-chlorophenylbenzylketone

(172) Product (I) was obtained with a yield of 90% (eluent: petroleum ether/diethylether 95:5).

(173) ##STR00037##

(174) .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 7.91-7.74 (m, 2H), 7.31-7.24 (m, 2H), 7.24-7.20 (m, 2H), 7.19-7.07 (m, 5H), 6.96-6.85 (m, 2H), 5.85 (s, 1H)

(175) .sup.13C NMR (100 MHz, CDCl.sub.3) ppm 196.9, 163.3, 160.9, 139.7, 138.6, 134.9, 134.6, 130.8, 130.7, 130.4, 129.0, 129.0, 127.5, 115.8, 115.5, 58.7.

(176) HRMS calculated for C.sub.20H.sub.15OFCl (M+H) 325.0795. Found: 325.0791.

1,2-bis(4-chlorophenyl)-2-phenylethanone

EXAMPLE 1.28

(177) Procedure (B) was implemented at 70 C. using:

(178) Formula (II) compound: 4-chloroiodobenzene (239 mg, 1.0 mmol)

(179) Formula (III) compound: 4-chlorophenylbenzylketone

(180) Product (I) was obtained with a yield of 75% (eluent: petroleum ether/diethylether 95:5).

(181) ##STR00038##

(182) .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 7.97-7.86 (m, 2H), 7.50-7.41 (m, 1H), 7.38-7.30 (m, 2H), 7.29-7.21 (m, 3H), 7.21-7.16 (m, 3H), 7.15-7.09 (m, 2H), 5.93 (s, 1H).

(183) .sup.13C NMR (100 MHz, CDCl.sub.3) ppm 197.8, 138.6, 137.7, 136.5, 133.3, 133.2, 130.6, 129.0, 129.0, 129.0, 128.8, 128.7, 127.4, 58.7.

(184) HRMS calculated for C.sub.23H.sub.14OCl.sub.2 (M+H) 341.0005. Found: 341.0011.

1-(4-chlorophenyl)-2-phenyl-2-(4-(trifluoromethyl)phenyl)ethanone

EXAMPLE 1.29

(185) Procedure (B) was implemented at 70 C. using:

(186) Formula (II) compound: 4-iodobenzotrifluoride (150 L, 1.0 mmol)

(187) Formula (III) compound: 4-chlorophenylbenzylketone

(188) Product (I) was obtained with a yield of 35% (eluent: petroleum ether/diethylether 95:5).

(189) ##STR00039##

(190) .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 7.86-7.78 (m, 2H), 7.47 (d, J=8.1 Hz, 2H), 7.31-7.21 (m, 6H), 7.21-7.14 (m, 3H), 5.92 (s, 1H).

(191) .sup.13C NMR (100 MHz, CDCl.sub.3) ppm 196.3, 142.9, 139.9, 137.8, 134.7, 130.5, 129.6, 129.3, 129.1, 129.0, 127.8, 125.6, 59.3.

(192) HRMS calculated for C.sub.21H.sub.15OF.sub.3Cl (M+H) 375.0764. Found: 375.0770.

1-(4-chlorophenyl)-2-(3-fluorophenyl)-2-phenylethanone

EXAMPLE 1.30

(193) Procedure (B) was implemented at 70 C. using:

(194) Formula (II) compound: 3-fluoroiodobenzene (120 L, 1.0 mmol)

(195) Formula (III) compound: 4-chlorophenylbenzylketone

(196) Product (I) was obtained with a yield of 55% (eluent: petroleum ether/diethylether 95:5).

(197) ##STR00040##

(198) .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 7.91-7.79 (m, 2H), 7.35-7.24 (m, 4H), 7.23-7.15 (m, 4H), 6.95 (td, J=7.6, 1.4 Hz, 1H), 6.92-6.84 (m, 2H), 5.88 (s, 1H).

(199) .sup.13C NMR (100 MHz, CDCl.sub.3) ppm 196.4, 164.2, 161.7, 141.2, 139.8, 138.0, 134.8, 130.4, 130.2, 130.1, 129.2, 129.1, 129.0, 127.6, 124.8, 116.3, 114.3, 59.1.

(200) HRMS calculated for C.sub.20H.sub.15OClF (M+H) 325.0795. Found: 325.0803.

1-(4-chlorophenyl)-2-phenyl-2-(3-(trifluoromethyl)phenyl)ethanone

EXAMPLE 1.31

(201) Procedure (B) was implemented at 70 C. using:

(202) Formula (II) compound: 3-iodobenzotrifluoride (150 L, 1.0 mmol)

(203) Formula (III) compound: 4-chlorophenylbenzylketone

(204) Product (I) was obtained with a yield of 20% (eluent: petroleum ether/diethylether 95:5).

(205) ##STR00041##

(206) .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 7.86-7.79 (m, 2H), 7.47-7.39 (m, 2H), 7.36-7.31 (m, 2H), 7.30-7.26 (m, 2H), 7.26-7.22 (m, 2H), 7.21-7.15 (m, 3H), 5.93 (s, 1H)

(207) .sup.13C NMR (100 MHz, CDCl.sub.3) ppm 196.3, 139.9, 139.9, 137.9, 134.7, 132.7, 130.4, 129.3, 129.1, 128.9, 127.8, 125.9, 124.2, 59.2.

(208) HRMS calculated for C.sub.21H.sub.15OF.sub.3Cl (M+H) 375.0764. Found: 375.0766.

2-(4-fluorophenyl)-2-(4-chlorophenyl)-1-phenylethanone

EXAMPLE 1.32

(209) Procedure (B) was implemented at 70 C. using:

(210) Formula (II) compound: 4-fluoroiodobenzene (115 L, 1.0 mmol)

(211) Formula (III) compound: 4-chlorophenylbenzylketone

(212) Product (I) was obtained with a yield of 95% (eluent: petroleum ether/diethylether 95:5).

(213) ##STR00042##

(214) .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 7.97-7.83 (m, 2H), 7.54-7.41 (m, 1H), 7.40-7.29 (m, 2H), 7.28-7.05 (m, 6H), 7.01-6.87 (m, 2H), 5.91 (s, 1H).

(215) .sup.13C NMR (100 MHz, CDCl.sub.3) ppm 197.7, 163.3, 160.8, 137.4, 136.3, 134.4, 133.4, 133.4, 130.7, 130.6, 130.4, 129.0, 129.0, 128.8, 115.9, 115.7, 57.7.

(216) Procedure C

(217) After several standard draining and purging cycles of the tubes with a flow of argon or nitrogen, the reactor is charged with 0.01 mmol (19 mg) of CuI, 1.5 mmol of formula (III) compound, 2 mmol (650 mg) of Cs.sub.2CO.sub.3, 0.1 mmol of bathophenanthroline and 1 mmol of formula (II) compound (II) if it is a solid. If the formula (II) compound is a liquid, it is added to the reaction medium using a syringe under a flow of nitrogen at ambient temperature followed by the addition of 1 ml of anhydrous, degassed de tert-butanol. The reactor is closed under positive pressure of nitrogen or argon. The reaction mixture is left under agitation and heated to 110 C. for 24 hours. After cooling down to ambient temperature, 13 L of 1,3-dimethoxybenzene (internal standard) then 1 ml of ethyl acetate are added. A sample of the reaction medium is taken and acidified with 10% aqueous HCl solution, the organic phase is then filtered through celite and the residue washed in ethyl acetate. The organic phases obtained are combined and washed with brine solution, dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The product obtained is purified by silica gel chromatography and analysed by NMR.

(218) The results obtained are summarised in the Table below:

(219) TABLE-US-00001 Formula (I) Formula (II) Formula (III) Examples compound compound compound Yield (%) Example 1.33 10 Example 1.34 17 Example 1.35 0 15 Example 1.36 11 Example 1.37 11

EXAMPLE 2

Influence of the Catalyst, of the Solvent and of the Base

(220) The process of the invention was carried out in accordance with procedure A using different solvents, different bases (2 mmol) and different catalysts (10 mole % relative to the formula (III) compound), using 4-methyliodobenzene (1 mmol) as formula (II) compound and deoxybenzoin (1.5 mmol) as formula (III) compound, and compound L1 (0.1 mmol) as ligand. The yield was determined by NMR using 1,3 dimethoxybenzene as internal standard.

(221) The results are given in Table (1):

(222) TABLE-US-00002 TABLE 1 Solvent Catalyst Base Yield [%] DMF or CH.sub.3CN CuI Cs.sub.2CO.sub.3 10 DMA CuI Cs.sub.2CO.sub.3 17 t-BuOH CuI Cs.sub.2CO.sub.3 52 dioxane CuI Cs.sub.2CO.sub.3 70 dioxane CuI Rb.sub.2CO.sub.3 ou K.sub.2CO.sub.3 18-21 dioxane Cu(acac).sub.2 Cs.sub.2CO.sub.3 30 dioxane Cu(OTf).sub.2 ou Cu.sub.2O Cs.sub.2CO.sub.3 43-45 dioxane CuCl, Cu(Oac).sub.2, CuBr.sub.2, Cs.sub.2CO.sub.3 48-51 or CuCN

(223) These results show that the process of the invention can advantageously be implemented using various catalysts, bases and solvents.

EXAMPLE 3

Influence of the Ligand and Solvent

(224) The process of the invention was carried out following procedure A at 110 C. using different solvents and different ligands (10 mole % relative to the formula (III) compound), using 4-methyliodobenzene (1 mmol) as formula (II) compound, deoxybenzoin (1.5 mmol) as formula (III) compound, Cs.sub.2CO.sub.3 (2 mmol) as base and CuI as catalyst (10 mole % relative to the formula (III) compound). The yield was determined by NMR using 1,3 dimethoxybenzene as internal standard.

(225) The results are given in Table (2):

(226) TABLE-US-00003 TABLE 2 Yield [%] Solvent Solvent Ligand dioxane t-BuOH 8 6 L1 70 52 L2 27 46 L3 3 47 L4 68 84 L5 29 5 L6 23 8 L7 20 17 L8 24 58 L9 11 8

(227) These results show that the process of the invention can advantageously be implemented using various ligands and solvents and evidences some preferred combinations.

EXAMPLE 4

Synthesis of Tamoxifen (Compound of Formula (IV)

(228) After several purging cycles with argon a Schlenk tube fitted with a magnetic stir bar is charged with CuI (0.1 mmol, 19 mg), deoxybenzoin (294 mg, 1.5 mmol), Cs.sub.2CO.sub.3 (4 mmol, 1.3 g) and 4-iodophenol (220 mg, 1 mmol). The tube is purged with argon after which 2-acetylcyclohexanone (0.1 mmol, 13 L) is added using a syringe in a nitrogen atmosphere at ambient temperature, followed by the addition of 1 mL of anhydrous t-BuOH (1.0 mL). The tube is sealed under positive argon pressure and the reaction mixture is left under agitation and heated to 70 C. for 24 hours. After cooling down to ambient temperature the reaction mixture is acidified with aqueous HCl (37%) for 6 hours. The reaction mixture is then extracted twice with ethyl acetate. The organic phases are collected and washed with brine solution, dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The product obtained is purified by silica gel chromatography (eluent: petroleum ether/ethyl acetate 5:5) to give product A with a yield of 82%.

(229) ##STR00058##

(230) .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 8.01-7.84 (m, 2H), 7.51-7.40 (m, 1H), 7.38-7.30 (m, 2H), 7.29-7.21 (m, 2H), 7.20-7.13 (m, 3H), 7.12-7.02 (m, 2H), 6.76-6.66 (m, 2H), 5.90 (s, 1H).

(231) .sup.13C NMR (100 MHz, CDCl.sub.3) ppm 198.7, 154.8, 139.4, 136.8, 133.1, 131.3, 130.4, 129.1, 129.0, 128.7, 128.6, 127.1, 115.7, Product A: 58.6.

(232) To a solution of product A (100 mg, 0.347 mmol) in THF (3 mL), EtMgBr (350 L, 1.04 mmol) was added at 78 C. and the mixture left under agitation for 5 hours at ambient temperature. The resulting reaction mixture was hydrolysed with water, extracted three times with ethyl acetate. The organic phases obtained were combined, washed with brine solution, dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The product thus obtained was diluted with methanol and aqueous HCl (37%) was added. The resulting reaction mixture was left under agitation and refluxed for 15 hours. The solvent and HCl were removed by evaporation in vacuo. The crude was re-dissolved in ethyl acetate and water was added. The mixture was then extracted three times with ethyl acetate, the organic phases were collected, washed in brine solution, dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The product obtained was diluted in DMSO (1 mL) and t-BuOK (155.7 mg, 1.39 mmol) was added. The resulting reaction mixture was heated to 50 C. for 2 hours. The reaction mixture was then hydrolysed with saturated aqueous NH.sub.4CI solution at 0 C., extracted with ethyl acetate and the organic phases were collected, washed in brine solution, dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo. Finally, the crude obtained was diluted in DMF (0.5 mL) and added to NaH solution (41.6 mg, 1.04 mmol) in DMF (0.5 mL) at 0 C. After 30 minutes a 0 C., the hydrochloride of 2-Chloro-N,N-dimethylethylamine (100 mg, 0.69 mmol) was added portion-wise. After 3 hours at 50 C., the mixture was hydrolysed at 0 C. with saturated aqueous NH.sub.4Cl solution. The mixture was then extracted with ethyl acetate, the organic phases collected, washed in brine solution, dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo.

(233) The compound of formula (IV) obtained was purified by chromatography (eluent CHCl.sub.3/MeOH/Et.sub.3N, 95:5:0.1) to give a 1:1 mixture of conformation compounds Z and E with a yield of 70%.

(234) ##STR00059##

(235) .sup.1H NMR (250 MHz, CDCl.sub.3) ppm 7.36-6.73 (m, 24H), 6.69 (d, J=8.7 Hz, 2H), 6.48 (d, J=8.7 Hz, 2H), 4.01 (t, J=5.8 Hz, 2H), 3.85 (t, J=5.8 Hz, 2H), 2.67 (t, J=5.8 Hz, 2H), 2.57 (t, J=5.8 Hz, 2H), 2.43 (q, J=7.3 Hz, 2H), 2.38 (q, J=7.3 Hz, 2H), 2.28 (s, 6H), 2.21 (s, 6H), 0.87 (t, J=7.3 Hz, 3H), 0.85 (t, J=7.3 Hz, 3H).

(236) .sup.13C NMR (100 MHz, CDCl.sub.3) ppm 157.6, 156.7, 144.3, 143.8, 143.3, 143.0, 142.4, 141.9, 141.6, 141.3, 138.4, 138.2, 136.1, 135.5, 134.7, 131.8, 130.8, 130.5, 130.4, 129.7, 129.5, 129.5, 128.8, 128.1, 127.8, 127.8, 127.3, 126.5, 126.0, 125.6, 114.1, 114.1, 113.4, 65.9, 65.6, 58.4, 58.3, 45.9, 45.9, 29.0, 13.6.