EP1924539A1

EP1924539A1 - Nickel or iron catalysed carbon-carbon coupling reaction of arylenes, alkenes and alkines

Info

Publication number: EP1924539A1
Application number: EP06793446A
Authority: EP
Inventors: Paul Knochel; Andrei Gavriushin; Christiane Charlotte Kofink; Georg Manolikakes
Original assignee: Saltigo GmbH
Current assignee: Saltigo GmbH
Priority date: 2005-09-12
Filing date: 2006-09-12
Publication date: 2008-05-28
Also published as: DE102005043337A1; WO2007031511A1; CN101300209A; US20100184977A1; JP2009509937A

Abstract

According to the invention, organozink compounds of R1-Ar1-ZnY (1) type are convertible, with different functionalised aryl halides R2-Ar2-X (2) in the presence of Ni or Fe catalytic quantities in a polar solvent or a polar solvent mixture, into a polyfunctional biarylene of R1-Ar1-AR2-R2 (3) type. The type (1) organic compounds are obtainable by a transmetallisation reaction of aryl-magnesium halides or lithium-aryl compounds, for example with ZnBr2.

Description

Nickel- or iron-catalyzed carbon-carbon coupling reaction of arylenes, alkenes, and alkynes

The present invention relates to a process for the formation of carbon-carbon bonds starting from a zinc compound of an aryl, heteroaryl, alkene or alkyne and an aryl, heteroaryl, alkene or alkyne compound having a suitable leaving group.

Background of the invention

Transition-metal-catalyzed cross-coupling reactions are very powerful reactions for the formation of C-C bonds, especially between Csp ² centers, where typical S _N 2- substitutions are not possible. ^[1] Aryl-aryl cross-coupling is one of the most important ways to build carbon-carbon bonds. Many of the aromatics obtained thereby, and in particular the heteroaromatics, are of great interest for the agrochemical and pharmaceutical industries as well as for materials science. For this purpose, mostly reliable palladium (0) catalysts, ^[1 ' ^2] primarily in the presence of a corresponding ligands, such as sterically hindered phosphines used. ^[3] The palladium-phosphine complexes are usually used in an amount of 1-3 mol%. However, since both palladium and the corresponding phosphine ligands are expensive, there is a need for cheap and highly effective catalysts.

The work of Kochi following, ¹ - ^{41. An} iron-catalyzed cross-coupling researched lately intensively on their performance in cross-coupling reactions. ^C5] Although very efficient cross-coupling reactions were carried out between a number of alkyl magnesium reagents and aryl halides or aryl sulfonates, remained catalyzed cross-coupling of two aryl radicals due to the considerable homo coupling reaction of the aryl magnesium species problematic and it has so far not a synthetic solution becoming found to this problem ⁵ ^'6 But dehalogenation of the aryl halide also occurs. The object of the present invention is therefore to provide a simple process for the targeted formation of carbon-carbon bonds between arylene, alkenes and alkynes in high yields and at low cost.

This object is achieved by the claim 1. Preferred embodiments are set forth in the dependent claims.

Summary of the invention

The inventors turned their attention to other organometallic compound classes and found that organozinc compounds of the type R'-Ar'-ZnY (1), with various functionalized aryl halides R ² -Ar ² -X (2) in the presence of catalytic amounts of Ni or Fe react in a polar solvent or solvent mixture and result in polyfunctional biaryls of type (3).

Organozinc compounds of type (1) can be prepared by the transmetallation reaction of functionalized aryl magnesium halides or lithium aryl compounds with, for example, ZnBr ₂ . The term aryl is to be understood here and below as aryl, heteroaryl, alkene, or alkyne. These compounds may be monosubstituted or polysubstituted. Essential for the invention is the presence of an aryl, alkene or alkyne compound, whose characteristic aryl, alkene or Alkinmerkmalen starts the reaction.

A first aspect of the present invention relates to a process for producing a compound of the general formula (3)

R ^! -Ar'-Ar ² -R ² (3)

by a compound of the general formula (1)

R'-Ar'-ZnY (1) with a compound of the general formula (2)

R ² -Ar ² -X (2)

is reacted under the action of a Ni or Fe catalyst in a solvent, wherein

X is a leaving group suitable for nucleophilic substitution;

Y is Cl, Br, I, R ¹ COO, V ₂ SO ₄ , NO ₃ , R ¹ SO ₃ ;

R ¹ and R ² independently represent one or more substituents selected from H; substituted or unsubstituted aryl or heteroaryl containing one or more

Contains heteroatoms; straight, branched or cyclic, substituted or unsubstituted alkyl, alkenyl, alkynyl; or derivatives thereof;

Ar ¹ and Ar ^{2 are} independently an aryl, fused aryl, heteroaryl or fused heteroaryl containing one or more heteroatoms; an alkenyl or

alkynyl; or derivatives thereof.

The leaving group X represents a leaving group commonly used for nucleophilic substitution. The group designated Ar may also be substituted with several substituents satisfying the definition of R or R, if possible.

According to a Ausfiihrungsfoπn the invention, the reaction is conducted at a temperature between 0 ⁰ C and 150 ⁰ C, preferably between 1O ⁰ C and 12O ⁰ C, more preferably between 2O ⁰ C and 100 ⁰ C, at bevorzugtesten between 25 ° C and 8O ⁰ C performed.

In another embodiment, the catalyst comprises a Fe (III) complex, a Fe (III) salt, a Fe (II) complex, a Fe (II) salt, or a reduced form of an Fe salt or complex , preferably Fe (acac) ₃ or Fe (DBM) ₃ , wherein iron is coordinated to acetylacetonate (acac) or dibenzoylmethane (DBM).

In yet another embodiment, the catalyst comprises a Ni (II) and / or a Ni (0) catalyst, or other reduced form of a Ni (II) salt and / or complex. According to yet another embodiment, the catalyst is a complex with aza heterocycles polyaza heterocycles and / or phosphites of the general formula (R ³ O) ₂ P (O) H, wherein R ^a is a straight, branched or cyclic, substituted or unsubstituted Alkyl, preferably with a chain length of C] to C ₁₀ , is, as ligands.

In another embodiment, X may preferably be I, Br, Cl, OTf, N ₂ ⁺ , OSO ₂ R ^s or OP (O) (OR ^S ) ₂ where R ^{s is} straight chain, branched or cyclic, substituted or unsubstituted alkyl, fused aryl , substituted or unsubstituted aryl or heteroaryl, more preferably I or Br, even more preferably I.

In another embodiment, the compound (1) is in a molar ratio of 0.2 to 5, preferably in a molar ratio of 1 to 3, more preferably in a molar ratio of 1, 1 to 2.5 based on the molar amount added to compound (2).

In another embodiment, R ¹ and R may independently of each other contain a substituted or unsubstituted C ₄ -C ₂₄ aryl or C ₃ -C ₂₄ heteroaryl containing one or more heteroatoms such as B, O, N, S, Se, P; a straight-chain or branched, substituted or unsubstituted C ₁ -C ₂₀ -alkyl, C ₂ -C ₂ O-alkenyl, C ₂ -C ₂₀ -alkynyl; or a substituted or unsubstituted C ₃ -C ₂₀ cycloalkyl; or derivatives thereof.

According to another embodiment, the catalyst is present in a molecular ratio of 0.00001 to 10%, more preferably 0.001 to 1 mol%, more preferably 0.02 to 0.2 mol%, based on the compound of the formula (1) or (2) used.

According to a further embodiment, the solvent used is a polar solvent or solvent mixture, preferably an ethereal solvent, a dipolar, aprotic solvent or their solvent mixtures, and most preferably a solvent selected from the group comprising THF, DME, NMP, DMAC or mixtures thereof , used.

This new approach opens up economic access (about three times cheaper compared to Pd-catalyzed reactions) to perform aryl-aryl cross-coupling reactions. Detailed description of the invention

The present invention will be described in more detail below.

Unless otherwise specified, the technical and scientific terms used herein are to have the same meaning as commonly understood to one of ordinary skill in the art.

The organo-zinc compounds used in the cross-coupling can be easily prepared by transmetallation reaction of the corresponding magnesium or lithium organo-metal compounds (Knöchel, P., Dohle, W. Gommermann, N., Kneisel, FF, Kopp, F. Korn, T., Sapountzis, L., Vu, VA Angew. Chem. Int Ed 2003, 42, 4302.) The direct insertion of zinc is also possible (Rieke RD Science 1989, 246, 1260. Burns, TP Rieke, RDJ Org. Chem. 1987, 52, 3674; Lee, J .; Velarde-Ortiz, R .; Guijarro, A .; Wurst, JR; Rieke, RDJ Org. Chem. 2000, 65, 5428); as well as by I / Zn exchange reaction (Kneisel, FF; Dochnahl, M .; Knöchel, P. Angew Chem .. Int Ed 2004, 43, 1017. Gong, L.-Z .; Knöchel, P. Synlett 2005, 267). These different routes allow easy access to the zinc organic starting compounds.

Iron-catalyzed reaction

As mentioned above, corresponding aryl-zinc compounds are readily available by transmetalation of the corresponding aryl Grignard compound. A schematic representation of the reaction procedure is shown in Scheme 1 below.

ZnBr ₂ Fe (DBM) ₃ (3-5 mol%)

Ar ¹ MgBr - Ar ¹ ZnBr - T * - Ar ¹ -Ar ²

THF Ar ² Br, THF-NMP, 110 ⁰ C, 3-36h

Scheme 1: Representation of the reaction with iron catalyst.

In this case, a cross-coupling between the aryl-zinc compound Ar ¹ ZnBr with an aryl bromide Ar ² Br in the presence of iron (III) tris-dibenzoylmethanat, Fe (DBM) ₃ , performed in a solvent mixture such as THF-NMP. The iron catalyst is here for example, in 3 to 5 mol% added and the reaction is carried out at, for example, 110 ⁰ C for 3 to 36 hours.

As iron compounds, it is possible to use any iron (II) and / or iron (III) salts and / or complexes such as FeCl ₂ , FeCl ₃ , FeBr ₂ , FeBr ₃ , Fe (OAc) ₂ , Fe (OAc) ₃ , etc and / or other iron complexes with iron in other oxidation states, also reduced iron complexes in which the iron has a negative oxidation state, or mixtures thereof.

The iron catalyst may preferably be contained in an amount of from 0.01 to 10 mol%, more preferably in an amount of from 0.1 to 8 mol%, and most preferably from 0.5 to 6 mol%, based on one of the reactants (1) or ( 2) can be used.

As can be seen from Table 2, the cross-coupling products are obtained in good yields. The aryl bromides used here by way of example may in turn be substituted. Substitution by fluorine, chlorine, trifluoromethyl or carboethoxy is not hindering the reaction. Also, heterocyclic aryl compounds, e.g. 3-bromopyridine, are accessible for the reaction. Also, zinc compounds containing electron-withdrawing groups, e.g. an ester group, can be used for the reaction (see entry c in Table 2).

Nickel-catalyzed reaction

Particularly preferably, the present invention can be carried out under the action of nickel catalysts. As already mentioned above, the corresponding organozinc compounds are easily accessible in various ways.

By way of example, a corresponding cross-coupling reaction procedure could be represented as follows:

3: 68-94% Scheme 2: Nickel-catalyzed cross-coupling reaction of aryl-zinc derivatives with aryl halides.

The reaction with nickel as a catalyst offers various advantages over the Reaktionsfuhrung used previously. The reaction can be carried out at significantly lower temperatures in the range of 0 to 100 ^° C. As a result, the reaction is also accessible to heat-sensitive starting materials and products. In addition, no or little additional energy, such as heating or irradiation, must be used on an industrial scale.

The amount of nickel catalyst used can also advantageously be extremely low. Molecular ratios of from 0.00001 to about 10 mol%, more preferably from 0.001 to 1 mol%, more preferably from 0.02 to 0.2 mol%, based on one of the educts (1) or (2), are preferably used here. Such small amounts of catalyst not only represent a cost advantage, but are also beneficial from an environmental point of view.

As nickel compounds nickel salts or complexes with the oxidation state II or nickel complexes with the oxidation state (0) can be used. Examples of complexes which may be mentioned here are Ni (COD) ₂ , Ni (R 1 P) ₄ , Ni (CR ¹ O) ₃ P) ₄ , where COD is 1,5-cyclooctadiene and R is as defined above. Nickel salts may be selected, for example, from the group comprising NiCl ₂ , NiBr ₂ , Ni (OAc) ₂ , Ni (acac) ₂ , Ni (NO ₃ ) ₂ , NiSO ₄ . Particular preference is given to using NiCl ₂ .

Complex ligands which can be used are phosphites (R ³ O) ₂ P (O) H and nitrogen-containing heterocycles of the following general formulas:

wherein Z = R ¹ , OR ¹ , NR * ₂ , halogen, cyano, fused substituted and unsubstituted rings; R ¹ and R ^{2 are} as defined above, and wherein R ^{a is} a straight, branched or cyclic, substituted or unsubstituted alkyl.

As the phosphites preferably (MeO) ₂ P (O) H, (EtO) ₂ P (O) H, (n-PrO) ₂ P (O) H, (n-BuO) ₂ P (O) H, (1 -BuO) ₂ P (O) H used. Particularly preferred here is diethyl phosphite, (EtO) ₂ P (O) H. As the nitrogen-containing heterocycle, A-dimethylaminopyridine (DMAP) has been found to be advantageous. The different complex ligands can be used alone or in common. Particularly advantageous here, the combination of (EtO) ₂ P (O) H and DMAP has been found.

The complex ligands are preferably used in an amount of 0.001 to 5 mol%, more preferably 0.01 to 1 mol%, even more preferably 0.1 to 0.5 mol%, and most preferably 0.2 mol % based on one of the starting materials (1) or (2) used. Also, according to the small amount of catalyst metal small amounts of complex ligands used represent a cost advantage and a lower environmental impact.

Essentially ethereal solvents or dipolar, aprotic solvents or mixtures thereof can be used as the solvent. Examples of such solvents include tetrahydrofuran (THF), Dimethylimidazolidnon (DMI), N ₅ N'-dimethylpropylene urea (DMPU) or 1,2-dimethoxyethane (DME), and N-substituted pyrrolidones, such as N-ethyl pyrrolidone (NEP), N-methylpyrrolidone (NMP), N-2-methoxyethylpyrrolidinone and N, N'-dimethylimidazolidin-2-one, but are not limited thereto. Furthermore, N, N-dimethylacetamide (DMAC) can be used. Particularly suitable are mixtures of ethereal solvents and nitrogen-containing solvents. Preferred mixing ratios here are between 20: 1 and 1:20 of ethereal solvent to nitrogen-containing solvent.

The advantageous properties of the invention will now be explained by way of example with reference to some examples. However, these examples should not be interpreted as limiting the invention.

Examples Unless otherwise stated, all reactions were carried out under magnetic stirring and in the case of air or moisture sensitive compounds in baked glassware under argon as the blanketing gas. Syringes were used to transfer the reagents and the solvents were purged with argon prior to use. The reactions were checked by gas chromatography (GC and GC-MS) or thin layer chromatography. Solutions of organomagnesium compounds were prepared by the reaction of magnesium with aryl bromides in THF, unless noted otherwise, and titrated with a standard solution of I ₂ in 0.5 M LiCl in THF and diluted with THF to the indicated concentration. ZnBr ₂ and ZnCl ₂ were at 140 ⁰ C in a high vacuum for 30 min. dried and then dissolved in dry THF.

General Procedure 1 (AVI): Nickel-catalyzed reaction procedure

The solution of the nickel catalyst was prepared as follows. In a 25 ml Schlenk tube, anhydrous nickel chloride (8.2 mg, 0.063 mmol), (EtO) ₂ P (O) H (34.5 mg, 0.25 mmol) and DMAP (30.5 mg, 0.25 mmol under argon in dry, degassed N-ethylpyrrolidinone (10.0 ml). In a heated and argon-purged 25 ml flask equipped with a magnetic stirrer flask and septum, the appropriate arylmagnesium reagent in THF (1.20 mmol) was added slowly to the solution of ZnBr ₂ (0.67 ml of a 1, 5 molar solution in THF, 1.00 mmol) and NEP (0.17 ml). To this solution was added the electrophile (aryl halide or sulfonate, 1.0 mmol), followed by the solution of the catalyst (0.08 ml). The final THF-NEP volume ratio should be approximately 8: 1. The reaction mixture was stirred at the indicated temperature until gas chromatographic verification of an aliquot showed complete reaction of the reaction products. Subsequently, the reaction was quenched with saturated NH ₄ Cl solution, extracted with ether and the product purified by column chromatography.

3-fluoro-4'-methoxy-1,1'-biphenyl (3a):

Production according to AVl. To the ZnBr ₂ solution (0.67 mL, 1.5 M in THF) and NEP (0.17 mL) was added dropwise 4-methoxyphenylmagnesium bromide (1.57 mL, 0.83 M in THF), and then the Catalyst solution (0.08 ml) and 3-bromofluorobenzene (175 mg, 1.00 mmol) were added. This solution was stirred for 2 hours at room temperature. The usual

Work-up and purification by column chromatography (pentane / ether 19: 1) gave 3a as a white solid (174 mg, 86%).

Mp .: 67-67.5 ⁰ C. (Lourak, M .; Vander Gown, R .; Fort, Y .; Caubere, PJ Org. Chem. 1989, 54,

4844: 68 ° C)

¹ H-NMR _(CDCl3, 300 MHz, 25 ⁰ C): δ = 7.39 (d, J = 8.9 Hz, 2H), 7.28-7.1 1 (m, 3H), 6.90-

6.84 (m, 3H), 3.72 (s, 3H).

¹³ C-NMR (CDCl _3, 75 MHz, 25 ⁰ C): δ = 163.2 (q, ¹ J (C, F) = 245 Hz), 159.5, 143.1 (q, ³ J (C, F)

= 7.6 Hz), 132.4 (q, ⁴ J (C, F) = 2.1 Hz), 130.1 (q, ³ J (C, F) = 8.2 Hz), 128.1, 122.2 (q, ⁴ J (C, F)

= 2.6 Hz), 1 14.5, 1 13.5 (q, ² J (C, F) = 21.7 Hz), 1 13.3 (q, ² J (C, F) = 21. I Hz), 55.3.

IR (KBr): 2963 (w), 2840 (w), 1610 (vs), 1589 (s), 1573 (m), 1522 (s), 1487 (s), 1447 (m),

1292 (s), 1264 (s), 1252 (s), 1 189 (vs), 1162 (m), 1026 (m), 879 (m), 830 (vs), 782 (s).

MS (70 eV, EI), m / z (%): 209 (100, M ⁺ ), 187 (50), 159 (54), 133 (24), 107 (10), 77 (13).

HRMS m / z: Calculated for CI ₃ HHFO: 202.0794; found: 202.0790.

Ethyl 4'-methoxy-biphenyl-3-carboxylate (3b)

Preparation according to AV 1. To the ZnBr ₂ solution (0.67 ml, 1.5 M in THF) and NEP (0.17 ml) was added dropwise 4-methoxyphenylmagnesium bromide (1, 57 ml, 0.83 M in THF) and then the catalyst solution (0.08 ml) and ethyl 3-bromobenzoate (229 mg, 1.00 mmol) were added. This solution was stirred for 1 hour at room temperature. The usual workup and purification by column chromatography (pentane / ether 9: 1)

3b as a colorless oil (234 mg, 91%).

¹ H-NMR _(CDCl3, 300 MHz, 25 ° C): δ = 8.26 (s, IH), 8.00-7.97 (m, IH), 7.73-7.70 (m, IH),

7.56 (d, J = 8.8 Hz, 2H), 7.46 (t, J = 7.7 Hz, I H), 6.99 (d, J = 8.7 Hz, 2H), 4.41 (q, J = 7.1 Hz,

2H), 3.83 (s, 3H), 1.41 (t, J = 7.1 Hz, 3H).

¹³ C-NMR (CDCl ₃ , 75 MHz, 25 ° C): δ = 166.5, 159.4, 140.9, 132.5, 130.9, 130.8, 128.6,

128.1, 127.6, 127.1, 114.2, 60.9, 55.2, 14.2.

IR (KBr): 2981 (w), 1717 (vs), 1610 (m), 1518 (s), 1439 (m), 1367 (w), 1300 (s), 1249 (vs),

1182 (m), 1109 (s), 1049 (m), 1030 (m), 834 (m), 758 (s), 574 (w).

MS (70 eV, EI), m / z (%): 256 (100, M ⁺ ), 241 (9), 228 (11), 211 (20), 183 (10), 168 (6), 139

(12), 105 (3).

HRMS m / z: calculated for Ci ₆ H ₁₆ O ₃ : 256.1099; found: 256.1097.

Ethyl 4'-methoxy-biphenyl-4-carboxylate (3c)

Preparation according to AV 1. To the ZnBr ₂ solution (0.67 ml, 1.5 M in THF) and NEP (0.17 ml) was added dropwise 4-methoxyphenylmagnesium bromide (1. 57 ml, 0.83 M in THF) and then the catalyst solution (0.08 ml) and ethyl 4-bromobenzoate (229 mg, 1.00 mmol) or ethyl 4-chlorobenzoate (185 mg, 1.00 mmol) were added. This solution was stirred for 1 hour at room temperature (48 hours for ethyl 4-chlorobenzoate). The usual work-up and purification by column chromatography (pentane / ether 9: 1) gave 3c as a white solid (224 mg or 87% for the reaction with ethyl 4-bromobenzoate and 214 mg or 83% for ethyl 4-chlorobenzoate). The analytical data are consistent with the literature (Nakao, Y., Oda, T., Sahoo, AK, Hiyama, TJ Organomet Chem 2003, 687 (2), 570). Mp .: 100-101 ⁰ C.

¹ H-NMR _(CDCl3, 300 MHz, 25 ° C): δ = 8:09 (d, J = 8.7 Hz, 2H), 7.62-7.55 (m, 4H), 6.99 (d, J = 8.7 Hz, 2H) , 4.39 (q, J = 7.1 Hz, 2H), 3.84 (s, 3H), 1.41 (t, J = 7.1 Hz, 3H). ¹³ C-NMR (CDCl ₃ , 75 MHz, 25 ° C): δ = 166.5, 159.8, 145.0, 132.4, 130.0, 128.6, 128.3, 126.4, 1 14.3, 60.8, 55.3, 14.3. (4'-Methoxy- [1,1'-biphenyl] -4-yl) - (phenyl) -methanone (3d)

Production according to AVl. To the ZnBr ₂ solution (0.67 mL, 1.5 M in THF) and NEP (0.17 mL) was added dropwise 4-methoxyphenylmagnesium bromide (1.57 mL, 0.83 M in THF), and then the Catalyst solution (0.08 ml) and 4-bromobenzophenone (261 mg, 1.00 mmol) were added. This solution was stirred for 3 hours at room temperature. The usual

Work-up and purification by column chromatography (pentane / ether 19: 1) gave 3d as a white solid (210 mg, 73%). The analytical data correspond to the literature (Andrus,

M.B. Song, C. Org. LeU.2001, 3, 3761).

Mp .: 167-168 ⁰ C.

¹ H-NMR (CDCl _3, 600 MHz, 25 ⁰ C): δ = 7.87 (d, J = 8.1 Hz, 2H), 7.83 (d, J = 8.3 Hz, 2H),

7.66 (d, J = 8.3 Hz, 2H), 7.60-7.57 (m, 3H), 7.49 (t, J = 7.6 Hz, 2H), 7.01 (d, J = 8.8 Hz, 2H),

3.86 (s, 3H).

¹³ C-NMR (CDCl _3, 151 MHz, 25 ° C): δ = 196.3, 159.9, 144.8, 137.9, 135.6, 132.4, 132.2,

130.8, 129.9, 128.4, 128.3, 126.4, 114.4, 55.4.

IR (KBr): 1651 (vs), 1600 (vs), 1529 (w), 1446 (w), 1316 (m), 1288 (s), 1276 (s), 1256 (m),

1206 (vs), 1182 (w), 1033 (w), 939 (w), 829 (s), 794 (w), 697 (m).

MS (70 eV, EI), m / z (%): 288 (100, M ⁺ ), 211 (76), 183 (6), 168 (8), 139 (8), 105 (11), 77

(10), 51 (1).

HRMS m / z: calculated for C ₂₀ Hi ₆ O ₂ : 288.1150; found: 288.1146.

3- (4-methoxyphenyl) -pyridine (3e)

Production according to AVl. To the ZnBr ₂ solution (0.67 mL, 1.5 M in THF) and NEP (0.17 mL) was added dropwise 4-methoxyphenylmagnesium bromide (1.57 mL, 0.83 M in THF), and then the Catalyst solution (0.08 ml) and 3-bromopyridine (159 mg, 1.00 mmol) or 3-chloropyridine (114 mg, 1.00 mmol). This solution was 2 hours

(12 hours for 3-chloropyridine) at room temperature. The usual workup and

Purification by column chromatography (pentane / ether 1: 1) gave 3e as a white solid

(150 mg or 81% for 3-bromopyridine and 126 mg, 68% for 3-chloropyridine). The analytical data are consistent with the literature (Cioffi, C.L., Spencer, W.T., Richards, J .;

Mr., R.J. J. Org. Chem. 2004, 69, 2210).

Mp .: 62-63 ° C.

¹ H-NMR (CDCl _3, 600 MHz, 25 ⁰ C): δ = 8.81-8.80 (m, IH), 8:53 (dd, J ₁ = 4.8 Hz, J ₂ = 1.6 Hz,

IH), 7.84-7.80 (m, IH), 7.52 (d, J = 8.8 Hz, 2H), 7.34-7.30 (m, IH), 7.01 (d, J = 8.8 Hz, 2H),

3.85 (s, 3H).

¹³ C-NMR (CDCl _3, 151 MHz, 25 ⁰ C): δ = 159.7, 148.0, 147.9, 136.3, 133.8, 130.3, 128.2,

123.5, 114.6, 55.4.

IR (KBr): 2964 (w), 1608 (s), 1578 (w), 1564 (w), 1520 (s), 1478 (s), 1434 (m), 1283 (s),

1254 (vs), 1 183 (s), 1030 (s), 838 (m), 803 (vs), 706 (m), 619 (w), 552 (w).

MS (70 eV, EI), m / z (%): 185 (100, M ⁺ ), 170 (44), 142 (46), 15 (17), 89 (11), 63 (8).

HRMS m / z: calculated for Ci ₂ H _n NO: 185.0841; found: 185.0837.

6- (3-methoxyphenyl) nicotinic acid methyl ester (3f)

Production according to AVl. To the ZnBr ₂ solution (0.67 ml, 1.5 M in THF) and NEP (0.17 ml) was added dropwise 3-methoxymagnesium bromide (1.57 ml, 0.83 M in THF), and then the Catalyst solution (0.08 ml in NEP) and 6-chloronicotinic acid methyl ester (172 mg, 1.00 mmol) were added. This solution was stirred for 24 hours at room temperature. The usual work up and purification by column chromatography (CH ₂ Cl ₂ pentane 1: 1) gave 3f as a colorless solid (180 mg, 74%). Mp .: 89.5-9O ⁰ C. ¹ H-NMR (CDCl _3, 600 MHz, 25 ° C): δ = 9.24 (s, IH), 8.31 (dd, J ₁ = 8.3 Hz, J ₂ = 1.9 Hz, IH),

7.77 (d, J = 8.3 Hz, IH), 7.63-7.62 (m, I H), 7.57 (d, J = 7.9 Hz, IH), 7.38 (t, J = 8.1 Hz, IH),

6.99 (dd, J ₁ = 8.1 Hz, J ₂ = 2.4 Hz, IH), 3.94 (s, 3H), 3.88 (s, 3H).

¹³ C-NMR (CDCl _3, 151 MHz, 25 ° C): δ = 165.9, 160.7, 160.2, 151.0, 139.7, 137.9, 129.9,

124.3, 120.0, 119.7, 1 16.1, 112.5, 55.4, 52.3.

IR (KBr): 3059 (w), 3013 (w), 2954 (m), 2925 (m), 1715 (vs), 1596 (vs), 1562 (m), 1480 (s),

1433 (s), 1288 (vs), 1267 (s), 1231 (s), 1117 (s), 1030 (s), 1021 (s).

MS (70 eV, EI), m / z (%): 243 (65, M ⁺ ), 242 (100), 213 (38), 182 (9), 154 (10), 106 (11).

HRMS m / z: calculated for C] ₄ H] ₃ NO ₃ : 243.0895; found: 243.0867.

1- (3'-methoxy-biphenyl-4-yl) -ethanone (3g).

Production according to AVl. To the ZnBr ₂ solution (0.67 mL, 1.5 M in THF) and NEP (0.17 mL) was added dropwise 3-methoxymagnesium bromide (1.57 mL, 0.83 M in THF) and then the Catalyst solution (0.08 ml) and 4-bromoacetone phenone (199 mg, 1.00 mmol) were added. This solution was stirred for 2.5 hours at room temperature. The usual

Work-up and purification by column chromatography (CH ₂ Cl ₂ - pentane 1: 1) gave 3 g as a yellow solid (175 mg, 77%).

Mp .: 35-36 ° C. Hatanaka, Y .; Goda, K .; Yoshinori, O .; Hiyama, T. Tetrahedron 1994, 50, 8301

¹ H-NMR _(CDCl3, 300 MHz, 25 ° C): δ = 8:00 (ddd, J = 8.5 Hz, J ₂ = 2.9 Hz, J ₃ = 1.9 Hz, 2H),

7.65 (ddd, Ji = 8.6 Hz, J ₂ = 2.0 Hz, J ₃ = 1.9 Hz, 2H), 7:38 to 7:31 (m, IH), 7:20 to 7:17 (m, IH),

7.13-7.12 (m, IH), 6.94-6.90 (m, IH), 3.85 (s, 3H), 2.61 (s, 3H).

¹³ C-NMR (CDCl ₃ , 75 MHz, 25 ° C): δ = 198.1, 160.4, 146.0, 141.8, 136.4, 130.4, 129.3,

127.7, 120.1, 113.9, 1 13.5, 55.8, 27.0.

MS (70 eV, EI), m / z (%): 226 (56, M ⁺ ), 211 (100), 168 (14), 152 (11), 139 (21).

2- (3-pyridino) benzophenones (3h)

Production according to AVl. To the ZnBr ₂ solution (0.67 ml, 1.5 M in THF) and NEP (0.17 ml) was added 3-pyridylmagnesium bromide (Krasovskiy, A .; Knöchel, P. Angew. Chem. Int Ed., 2004 .

3333) (1.57 ml, 0.83 M in THF) was added dropwise, and then the catalyst solution

(0.08 ml) and 2-bromobenzophenone (270 mg, 1.00 mmol). This solution became 3

Hours at 5O ⁰ C stirred. The usual workup and cleaning by

Column chromatography (pentane - CH ₂ Cl ₂ 1: 1) gave 3h as a white solid (197mg, 76%).

The analytical data are consistent with the literature (Edwards, M.L., Stemerick, D.M .;

Diekema, K.A .; Dienerstein, R.J. J. Med. Chem. 1994, 37, 4357).

Mp .: 106-106.5 ⁰ C.

¹ H-NMR _(CDCl3, 300 MHz, 25 ° C): 8:56 to 8:52 (m, IH), 8:44 to 8:40 (m, IH), 7.72-7.10 (m,

H H).

¹³ C-NMR (CDCl _3, 75 MHz, 25 ⁰ C): 198.3, 149.8, 148.8, 139.5, 137.9, 137.6, 136.6, 136.3,

133.6, 131.1, 130.6, 130.3, 129.5, 128.7, 128.2, 123.3.

MS (70 eV, EI), m / z (%): 77 (27), 105 (25), 127 (20), 182 (36), 230 (100), 231 (26), 259 (19,

M ⁺ ).

5- (3-fluorophenyl) -pyrimidine (3i)

Production according to AVl. To the ZnBr ₂ solution (0.67 mL, 1.5 M in THF) and NEP (0.17 mL) was added dropwise 3-fluorophenylmagnesium bromide (1.70 mL, 0.83 M in THF), and then the Catalyst solution (0.08 ml) and 5-bromopyrimidine (159 mg, 1.00 mmol) were added. This solution was stirred for 1 hour at room temperature. The usual work up and purification by column chromatography (pentane - Et ₂ O) gave 3i as a white solid (143 mg, 82%). Mp .: 63-63.5 ° C. ¹ H-NMR _(CDCl3, 300 MHz, 25 ° C): 9.13 (s, IH), 8.85 (s, 2H), 7:44 to 7:23 (m, IH), 7:29 to 7:26

(m, IH), 7.22-7.17 (m, IH), 7.10-7.03 (m, IH).

¹³ C-NMR (CDCl ₃ , 75 MHz, 25 ° C): 163.7 (d, J = 248 Hz), 158.3, 155.2, 136.8 (d, J = 7.9 Hz),

133.5, 131.5 (d, J = 8.5 Hz), 123.0, 116.3 (d, J = 21.1 Hz), 114.3 (d, ./= 21.1 Hz).

IR (KBr): 2239 (w), 1591 (s), 1416 (s), 909 (vs), 734 (vs).

MS (70 eV, EI), m / z (%): 94 (12), 105 (25), 120 (100), 173 (21), 174 (96, M ⁺ ).

HRMS m / z: Calculated for C] ₀ H ₇ N ₂ F: 174.0593; found: 174.0577.

Ethyl 4-pyrimidin-5-yl-benzoate (3j)

Production according to AVl. To the ZnBr ₂ solution (0.67 ml, 1.5 M in THF) and NEP (0.17 ml) was added cold 4-carboethoxyphenylmagnesium bromide (prepared by iodine-magnesium exchange from 4-iodobenzoate and / PrMgCl-LiCl ( Krasovskiy, A .; ankle, P. Angew. Chem. Int. Ed. 2004, 3333) at -40 ⁰ C for 30 minutes) (1.57 ml, 0.83 M in THF) was added dropwise, and then the catalyst solution (0.08 ml) and 5-bromopyrimidine (159 mg, 1.00 mmol). This solution was stirred for 24 hours at room temperature. The usual work-up and purification by column chromatography (CH ₂ Cl ₂ -pentane) gave 3j as pale yellow crystals (137 mg, 60%). The analytical data are consistent with the literature (Kano, S. Yuasa, Y., Shibuya, S., Hibino, S. Heterocycles, 1982, 19, 1079). Mp .: 1 18-119 ⁰ C.

¹ H-NMR (CDCl _3, 600 MHz, 25 ° C): δ = 9.25 (s, IH), 8.99 (s, 2H), 8.19 (m, 2H), 7.66 (m, 2H), 4:42 (q, J - 7.2 Hz, 2H), 1.43 (t, J = 7.2 Hz, 3H).

¹³ C-NMR (CDCl _3, 150 MHz, 25 ⁰ C): δ = 164.9, 157.2, 157.0, 154.1, 154.0, 137.5, 132.4, 130.0, 129.6, 125.9, 60.3, 13.3. MS (70eV, EI), m / z (%): 228 (21, M ⁺ ), 200 (33), 183 (100), 128 (40), 101 (32).

8- (1-naphthyl) quinoline (3k)

Production according to AVl. To the ZnBr ₂ solution (0.67 mL, 1.5 M in THF) and NEP (0.17 mL) was added 1-naphthylmagnesium bromide (1.57 mL, 0.83 M in THF) dropwise, and then the Catalyst solution (0.08 ml) and 8-quinolyl nonaflate (Subramanian, LR, Garcia Martinez, A., Herrera Fernandez, A., Martinez Alvarez, R. Synthesis, 1984, 6, 481) (427 mg, 1.00 mmol). added. This solution was stirred for 24 hours at room temperature. The usual workup and purification by column chromatography (CH ₂ Cl ₂ - pentane)

3k as a white solid (224 mg, 88%).

Mp .: 163-164 ⁰ C.

¹ H-NMR _(CDCl3, 300 MHz, 25 ° C): 8.76-8.74 (m, IH); 8.16-8.13 (m, IH); 7.89-7.82 (m,

3H); 7.69-7.66 (m, IH), 7.60-7.46 (m, 3H), 7.41-7.18 (m, 4H).

¹³ C-NMR (CDCl _3, 75 MHz, 25 ⁰ C): δ = 150.9, 147.7, 140.6, 138.5, 136.6, 134.1, 133.3,

132.0, 128.9, 128.7, 128.5, 128.4, 128.3, 127.1, 126.6, 126.1, 126.0, 125.8, 121.5.

IR: (KBr) (cm ^"1 ): 3042 (w), 1593 (w), 1492 (s), 829 (s), 797 (vs), 782 (vs), 773 (vs).

MS (70eV, EI), m / z (%): 127 (9), 226 (9), 252 (14), 254 (100), 255 (47, M ⁺ ).

HRMS m / z: Calculated for C] ₉ Hi ₃ N: 255.1048; found: 255.1020.

3- (1-Methyl-1H-pyrrol-2-yl) -pyridine (31).

Production according to AVl. To the ZnBr ₂ solution (0.67 ml, 1.5 M in THF) and NEP (0.17 ml) was added 1-methyl-2-pyrryllithium (Brittain, JM; Jones, RA; Arques, JS; Saliente, TA Synth. Comm. 1982, 12, 231) (2.4 mL, 0.5 M in THF) was added dropwise and then the catalyst solution (0.08 mL) and 3-bromopyridine (158 mg, 1.00 mmol). added. This solution was stirred at 7O ⁰ C for 22 hours. The usual work up and purification by column chromatography (Et ₂ O - CH ₂ Cl ₂ 1: 1) gave 31 as a yellow oil (98 mg, 62%). The analytical data are consistent with the literature (Baxendale, I., Brusotti, M., Ley, SJ Chem. Soc. Perkin 1, 2002, 143).

¹ H-NMR _(CDCl3, 300 MHz, 25 ° C): δ = 8.66 (d, J = 1.8 Hz, IH), 8.50 (dd, J ₁ = 4.8 Hz, J ₂ = 1.6 Hz, IH), 7.70 (ddd, J ₁ = 7.9 Hz, J ₂ = 1.8 Hz, J ₃ = 1.6 Hz, IH), 7.31 (ddd, J ₁ = 7.9 Hz, J ₂ =

4.8 Hz, J ₃ = 0.8 Hz, IH), 6.74 (dd, J ₁ = 2.5 Hz, J ₂ = 1.9 Hz, IH), 6.27 (dd, J ₁ = 3.6 Hz, J ₂ =

1.9 Hz, IH), 6.20 (dd, J ₁ = 3.6 Hz, J ₂ = 2.8 Hz, IH), 3.65 (s, 3H).

¹³ C-NMR (CDCl ₃ , 75 MHz, 25 ° C): δ = 149.3, 147.8, 136.1, 131.1, 129.8, 125.2, 123.7,

110.3, 108.7, 35.5.

MS (70 eV, EI), m / z (%): 158 (100, M ⁺ ), 143 (7), 130 (19), 116 (6), 89 (5). 1- (3'-trifluoromethyl-biphenyl-4-yl) -ethanone (3m).

Production according to AVl. To the ZnBr ₂ solution (0.67 ml, 1.5 M in THF) and NEP (0.17 ml) was added 3-trifluoromethylphenylmagnesium bromide (Krasovskiy, A .; Knöchel, P. Angew. Chem.

Int. Ed. 2004, 3333) (1.57 ml, 0.5 M in THF) was added dropwise, and then the

Catalyst solution (0.08 ml) and 4-bromoacetone phenone (199 mg, 1.00 mmol) were added.

This solution was stirred at room temperature for 18 hours. The usual workup and

Purification by column chromatography (CH ₂ Cl ₂ - petane 1: 1) gave 3m as a colorless oil (180 mg, 68%). The analytical data correspond to the literature (Solodenko, W .; Schön, U .;

Messinger, J .; Glinschert, A .; Kirschning, A. Synlett 2004, 70, 1699).

¹ H-NMR _(CDCl3, 300 MHz, 25 ° C): δ = 8.06 (ddd, J ₁ = 8.6 Hz, J ₂ = 2.4 Hz, J ₃ = 2.0 Hz, 2H),

7.87-7.78 (m, 2H), 7.73-7.57 (m, 4H), 2.65 (s, 3H).

¹³ C-NMR (CDCl _3, 75 MHz, 25 ⁰ C): δ = 197.9, 144.6, 141.1, 136.9, 132.2, 132.0, 131.6,

130.9, 130.2, 129.9, 129.5, 127.4, 125.3, 124.4, 27.1.

MS (70 eV, EI), m / z (%): 264 (35, M ⁺ ), 249 (100), 221 (6), 201 (34), 152 (21).

Ethyl 4- (1,3-benzodioxol-5-yl) benzoate (3n)

Production according to AVl. To the ZnBr ₂ solution (0.67 mL, 1.5 M in THF) and NEP (0.17 mL) was added l, 3-benzodioxol-5-yl magnesium bromide (1.57 mL, 0.83 M in THF). added dropwise, and then the catalyst solution (0.08 ml) and 4-ethyl-4-bromobenzoate (229 mg, 1.00 mmol) were added. This solution was stirred for 5 hours at room temperature. The usual workup and purification by column chromatography (pentane - ether 1: 1)

3n as a white solid (253 mg, 94%).

Mp .: 92.5-93.5 ° C.

¹ H-NMR _(CDCl3, 300 MHz, 25 ° C): δ = 8.07 (d, J = 8.7 Hz, 2H), 7:56 (d, J = 8.7 Hz, 2H),

7.11-7.07 (m, 2H), 6.89 (d, J = 8.6 Hz, IH), 5.00 (s, 2H), 4.39 (q, J = 7.1 Hz, 2H), 1.40 (d, J =

7.2 Hz, 3H).

¹³ C-NMR (CDCl ₃ , 75 MHz, 25 ° C): δ = 166.4, 148.3, 147.7, 145.1, 134.3, 130.0, 128.8,

126.6, 121.0, 108.6, 107.6, 101.3, 60.9, 14.3.

IR (KBr): 2904 (w), 1707 (vs), 1606 (m), 1522 (w), 1503 (m), 1486 (s), 1410 (s), 1274 (vs),

1256 (s), 1235 (m), 1182 (s), 1 107 (s), 1036 (s), 932 (m), 858 (m), 772 (s), 702 (w).

MS (70 eV, EI), m / z (%): 270 (100, M ⁺ ), 242 (32), 225 (70), 139 (40), 112 (5), 63 (2).

HRMS m / z: calcd. for Ci ₆ H ₁₄ O ₄ : 270.0892; found: 270.0888.

3- (1,3-benzodioxol-5-yl) pyridine (3o)

Production according to AVl. To the ZnBr ₂ solution (0.67 mL, 1.5 M in THF) and NEP (0.17 mL) was added l, 3-benzodioxol-5-yl magnesium bromide (1.57 mL, 0.83 M in THF). added dropwise and then the catalyst solution (0.08 ml) and 3-bromopyridine (158 mg, 1.00 mmol) were added. This solution was stirred for 5 hours at room temperature. The usual work-up and purification by column chromatography gave 3o as a white solid (165 mg, 83%). Mp .: 92-92.5 ° C.

¹ H-NMR _(CDCl3, 300 MHz, 25 ⁰ C): δ = 8.76 (d, J = 1.9 Hz, IH), 8:54 to 8:51 (m, IH), 7.78- 7.74 (m, IH), 7.32- 7.27 (m, IH), 7.04-7.00 (m, 2H), 6.90-6.87 (m, IH), 5.99 (s, 2H). ¹³ C-NMR (CDCl _3, 75 MHz, 25 ⁰ C): δ = 148.4, 148.1, 148.0, 147.7, 136.3, 133.9, 131.9, 123.4, 120.8, 108.8, 107.5, 101.3.

IR (KBr): 2912 (w), 1512 (s), 1479 (vs), 1420 (s), 1294 (w), 1266 (m), 1238 (s), 1111 (w), 1037 (s), 931 (m), 806 (s), 706 (m). MS (70 eV, EI), m / z (%): 199 (100, M ⁺ ), 140 (10), 1 14 (1 1), 88 (4), 63 (3). HRMS m / z: calcd. for C] ₂ H ₉ NO ₂ : 199.0633; found: 199.0602.

1- (3,4-methylenedioxyphenyl) naphthalene (3p)

Production according to AVl. To the ZnBr ₂ solution or ZnCl ₂ solution (0.67 mL, 1.5 M in THF) and NEP (0.17 mL) was added 1-naphthylmagnesium bromide (1. 57 mL, 0.83 M in THF) dropwise and the catalyst solution (0.08 ml) and 3,4-methylenedioxylphenyl triflate (Echavarren, AM; Stille, JKJ Am. Chem. Soc. 1987, 109, 5478) (270 mg, 1.00 mmol) were added. This solution was stirred for 24 hours at room temperature. The usual work up and purification by column chromatography (pentane - Et ₂ O 9: 1) gave 3p as a colorless oil (196 mg, 79%, for the reaction with ZnCl ₂ was 77%). The analytical data are in accordance with the literature (Shimada, S., Yamazaki, O., Toshifumi, T .; Rao, M .; Suzuki, Y., Tanaka, M. Angew Chem Chem Int Ed 2003, 42, 1845). , ¹ H-NMR _(CDCl3, 300 MHz, 25 ° C): δ = 7.99-7.85 (m, 3H), 7:55 to 7:41 (m, 4H), 7.02-6.94 (m, 3H), 6:06 (s, 2H ).

¹³ C-NMR (CDCl ₃ , 75 MHz, 25 ° C): δ = 147.9, 174.3, 140.2, 135.1, 134.2, 132.2, 128.7, 128.0, 127.3, 126.4, 126.2, 125.8, 123.8, 11 1.1, 108.6, 101.5 , MS (70 eV, EI), m / z (%): 248 (100, M ⁺ ), 217 (19), 208 (10), 189 (52), 94 (20).

General Procedure 2 (A V2): Nickel-catalyzed reaction procedure

0.93 mL of 1.5 M ZnB ^ / THF solution (1.4 mmol) and 0.25 mL N-ethylpyrrolidinone (NEP) are placed under argon in a heated Schlenk tube. 1.2 mmol arylmagnesium halide in THF solution are added dropwise thereto. Subsequently, 1.0 mmol aryl halide, then 0.025 mL 0.08 M 4-dimethylaminopyridine (DMAP) - (EtO) ₂ P (O) H solution in THF (0.2 mol%) and 0.025 mL 0.02 M NiCl ₂ solution in NEP (0.05 mol % Ni).

After a sufficient time, the reaction is quenched with saturated NH ₄ Cl solution. The mixture is extracted with Et ₂ O, the combined organic phases are dried over MgSÜ ₄ and concentrated in vacuo. The residue is purified by chromatography (SiO ₂ ).

All of the compounds listed below in Table 1 were synthesized according to General Procedure 2.

Table 1

General Procedure 3 (A V3): Iron-catalyzed reaction procedure

Arylmagnesium bromide (1.3 mmol, in THF) is placed in a heated Schlenk tube, treated with ZnBr ₂ solution (1.3 mmol, 0.65 mL, 2.0 M in NMP) and stirred for 15 min at room temperature (RT). Subsequently, NMP (0.5 ml), Fe (DBM) ₃ (5 mol%, 36 mg) and aryl halide (1.0 mmol) was added and the reaction mixture stirred over the corresponding time at 1 10 ⁰ C. Subsequently, the reaction by addition of sat. NH ₄ Cl (aq.) And extracted with EtOAc (3x40 mL). The combined organic phases are washed with sat. NaCl (aq.) (50 ml), dried over Na ₂ SO ₄ , filtered off and the solvent distilled off under reduced pressure. Column chromatographic purification (DCM) gave the desired product.

All products of Table 2 were synthesized according to AV3, except for entry 10, which was synthesized according to the following instruction.

Preparation of ethyl 4 '-cyano-biphenyl-4-carboxylate

In a heated Schlenk tube 4-iodoethyl benzoate (1.3 mmol, 359 mg) is initially charged, at -20 ⁰ C with / PrMgCl solution (1.35 mmol, 1.38 mL, 0.98 M in THF) and stirred for 30 min. Subsequently, a ZnBr ₂ solution (1.3 mmol, 0.65 ml, 2.0 M in NMP) is added and stirred for 15 min at room temperature. Now NMP (0.5 ml), Fe (DBM) ₃ (5 mol%, 36 mg) and 4-bromobenzonitrile (1.0 mmol, 182 mg) are added and the reaction mixture is stirred for 6 hours at H ^{2 0} C. Subsequently, the reaction by addition of sat. NH ₄ Cl ( _aq . ₎ And extracted with EtOAc (3x40 ml). The combined organic phases are washed with sat. NaCl _(aq.) (50 ml), dried over Na ₂ SO _4, filtered and the solvent distilled off under reduced pressure. Column chromatographic purification (pentane-diethyl ether) gave the desired product as a colorless solid (169 mg, 67%). Table 2

Preparation of Biaryls from Arylzinc Reagents and Aryl Halides by Fe-Catalyzed Cross-Coupling:

Literature and notes:

[1] (a) Metal catalyzed cross-coupling reactions; F. Diederich; P.J. Stang Eds. Wiley-VCH, Weinheim, 1998; (b) J. Tsuji, Transition Metal Reagents and Catalysts: Innovations in Organic Synthesis; Wiley: Chichester, 1995; (c) cross-coupling reactions. A Practical Guide; N. Miyaura Ed. Top. Curr. Chem. 2002, 219, Springer-Verlag Berlin, Heidelberg, New York.

[2] Handbook of organopalladium chemistry for organic synthesis, Ed. E. Negishi, Wiley-Interscience, New York, 2002.

[3] (a) C. Dai, G.C. Fu, J. Am. Chem. Soc. 2001, 123, 2719; (b) A.F. Littke, G.C. Fu, J. Am. Chem. Soc. 2001, 123, 6989; (c) A.F. Littke, L. Schwarz, G.C. Fu, J. Am. Chem. Soc. 2002, 124, 6343; (d) A.F. Littke, G.C. Fu, Angew. Chem. 2002, 114, 4350; Angew. Chem. Int. Ed. 2002, 41, 4176; (e) I.D. Hills, M.R. Netherton, G.C. Fu, Angew. Chem. 2003, 115, 5927; Angew. Chem. Int. Ed. 2003, 42, 5749; (c) A.C. Frisch, A. Zapf, O. Briel, B. Kayser, N. Shaikh, M. Beller, J. Mol. Catalysis A 2004, 214, 231; (h) A. Tewari, M. Hein, A. Zapf, M. Beller, Synthesis 2004, 935; (i) F. Rataboul, A. Zapf, R. Jackstell, S. Harkal, T. Riermeier, A. Monsees, U. Dingerdissen, M. Beller, Chem. Eur. J. 2004, 10, 2983.

[4] (a) M. Tamura, J.K. Kochi, J. Am. Chem. Soc. 1971, 93, 1487; (b) M. Tamura, J.K. Kochi, Synthesis 1971, 93, 303; (c) M. Tamura, J.K. Kochi, J. Organomet. Chem. 1971, 31, 289; (d) M. Tamura, J.K. Kochi, Bull. Chem. Soc. Jpn. 1971, 44, 3063; (e) M. Tamura, J.K. Kochi, Synthesis 1971, 303; (f) J.K. Kochi, Acc. Chem. Res. 1974, 7, 351; (g) S. Neumann, J.K. Kochi, J. Org. Chem. 1975, 40, 599; (h) R.S. Smith, J.K. Kochi, J. Org. Chem. 1976, 41, 502; (i) Further: G. Molander, B. Rahn, D.C. Shubert, S.E. Bonde, Tetrahedron Lett. 1983, 24, 5449.

[5] (a) G. Cahiez, S. Marquais, Pure Appl. Chem. 1996, 68, 669; (b) G. Cahiez, S. Marquais, Tetrahedron Lett. 1996, 37, 1773; (c) G. Cahiez, H. Avedissian, Synthesis 1998, 1199; (d) K. Shinokubo, K. Oshima, Eur. J. Org. Chem. 2004, 2081; (e) MA Fakhfakh, X. Franck, R. Hocquemiller, B. Figadere, J. Organomet. Chem. 2001, 624, 131; (f) M. Hocek, H. Dvorakova, J. Org. Chem. 2003, 68, 5773; (g) B. Hölzer, RW Hoffmann, Chem. Comm. 2003, 732; (h) W. Dohle, F. Kopp, G. Cahiez, P. Knöchel, Synlett 2001, 1901; (i) M. Hojo, Y. Murakami, H. Aihara, R. Sakuragi, Y. Baba, A. Hosomi, Angew. Chem. 2001, 113, 641; Angew. Chem. Int. Ed. 2001, 40, 621; (j) M. Nakamura, A. Hirai, E. Nakamura, J. Am. Chem. Soc. 2001, 122, 978; (K) E. Alvarez, T. Cuvigny, CHdu Penhoat, M. Julia, Tetrahedron 1998, 44, 119; (1) V. Finandanese, G. Marchese, V. Martina, L. Ronzini, Tetrahedron Lett. 1984, 25, 4805. [6] (a) A. Fürstner, A. Leitner, M. Mendez, H. Krause, J. Am. Chem. Soc. 2002, 124, 13856; (b) A. Fürstner, A. Leitner, Angew. Chem. 2002, 114, 632; Angew. Int. Ed. 2002, 41, 2003, 42, 308; (c) A. Fürstner, A. Leitner, Angew. Chem. 2003, i / 5, 320; Angew. Chem. Int. Ed. 2003, 42, 308; (d) G. Seidel, D. Laurich, A. Fuerstner, J. Org. Chem. 2004, 69, 3950; (e) B. Scheiper, M. Bonnekessel, H. Krause, A. Fuerstner, J. Org. Chem. 2004, 69, 3943; (f) A. Fürstner, D. De Souza, L. Parra-Rapado, JT Jensen, Angew, Chem. 2003, 115, 5516; Angew. Chem. Int Ed. 2003, 42, 5355; (g) M. Nakamura, K. Matsuo, S. Ito, E. Nakamura, J. Am. Soc. 2004, 126, 3686; (h) T. Nagano, T. Hayashi, Org. Lett. 2004, 6, 1297; (i) R. Martin, A. Furstner, Angew. Chem. 2004, 116, 4045; Angew. Chem. Int. Ed. 2004, 43, 3955.

Claims

PATENT APPLICATIONS

1. Process for the preparation of a compound of general formula (3)

R'-Ar'-Ar ² -R ² (3)

by a compound of the general formula (1)

R'-Ar'-ZnY (1)

with a compound of the general formula (2)

R ² -Ar ² -X (2)

is reacted under the action of a Ni or Fe catalyst in a solvent, wherein

X is a leaving group suitable for nucleophilic substitution; Y is Cl, Br, I, R ¹ COO, Vi SO ₄ , NO ₃ , R ¹ SO ₃ ;

R ¹ and R ² independently represent one or more substituents selected from H; substituted or unsubstituted aryl or heteroaryl containing one or more heteroatoms; straight, branched or cyclic, substituted or unsubstituted alkyl, alkenyl, alkynyl; or derivatives thereof;

Ar ¹ and Ar ^{2 are} independently an aryl, fused aryl, heteroaryl or fused heteroaryl containing one or more heteroatoms; an alkenyl or alkynyl; or derivatives thereof; could be.

2. The method of claim 1, wherein the catalyst is a Ni (II) complex, a Ni (II) salt or a Ni (0) complex, or a reduced form of a Ni salt or complex, preferably a Ni ( II) -SaiIz in addition to DMAP and / or (EtO) ₂ P (O) H includes.

3. The method according to one or more of the preceding claims, wherein the reaction under the action of a Ni catalyst at a temperature between 0 ⁰ C and 150 ⁰ C, preferably between 10 ° C and 12O ⁰ C, more preferably between 20 ⁰ C and 100 ⁰ C and most preferably between 25 ° C and 8O ⁰ C is performed.

The process of claim 1, wherein the catalyst is a Fe (III) complex, a Fe (III) salt, a Fe (II) complex, a Fe (II) salt, or a reduced form of an Fe salt or complex, preferably Fe (acac) ₃ or Fe (DBM) ₃ .

5. The method according to one or more of the preceding claims, wherein the catalyst is a complex with aza heterocycles, polyaza heterocycles and / or (R ^a O) ₂ P (O) H, wherein R ^{a is} a straight-chain, branched or cyclic, substituted or unsubstituted alkyl, as ligands.

6. The method according to one or more of the preceding claims, wherein X is preferably I, Br, Cl, OTf, N ₂ ⁺ , OSO ₂ R ^S , OP (O) (OR ^S ) ₂ , where R ^{s is} straight-chain, branched or cyclic, substituted or unsubstituted alkyl, fused aryl, substituted or unsubstituted aryl or heteroaryl, more preferably I or Br, even more preferably I.

7. The method according to one or more of the preceding claims, wherein the compound (1) in a molar ratio of 0.2 to 5, preferably in a molar ratio of 1 to 3, more preferably in a molar ratio of 1.1 to 2 , 5 is added based on the molar amount of compound (2).

8. The method according to one or more of the preceding claims, wherein R ¹ and R ^{2 are} independently a substituted or unsubstituted C ₄ -C ₂₄ aryl or C ₃ -C ₂₄ heteroaryl containing one or more heteroatoms such as B, O, N, S , Se, P contains; a straight or branched, substituted or unsubstituted C ₁ -C ₂₀ alkyl, C ₂ -C ₂ 0 alkenyl, C2-C20 alkynyl; or a substituted or unsubstituted C ₃ -C ₂₀ cycloalkyl; or derivatives thereof.

A process according to one or more of the preceding claims, wherein the catalyst is present in a molecular ratio of 0.00001 to 10%, more preferably 0.001 to 1 mol%, more preferably from 0.02 to 0.2 mol%, based on the compound of the formula (1) or (2).

10. The method according to one or more of the preceding claims, wherein as solvent, a polar solvent or solvent mixture, preferably an ethereal solvent, a dipolar, aprotic solvent or their solvent mixtures, and most preferably a solvent selected from the group consisting of THF, DME, NEP, DMPU, DMI, NMP, DMAC and mixtures thereof.