CATALYZED GRIGNARD COUPLING PROCESS

Abstract: A 3-chloro-2-methylphenylmagnesium halide is crosscoupled with a halobenzene in the presence of a catalyst selected from palladium metal and nickel (II) acetylacetonate, producing 3-chloro-2-methyl [1,1'-biphenyl].

Description: CATALYZED GRIGNARD COUPLING PROCESS This invention is in the field of chemical proces¬ ses; more specifically, cross-coupling an aryl Grignard reagent with a halobenzene in the presence of a catalyst to produce a biphenyl compound. Pyrethroid ester insecticides are of great commer¬ cial interest throughout the world. Both the carboxylic acid and alcohol moieties of these esters cover a wide range of structures. The alcohol, (2-methyl[1 ,1 '-bi¬ phenyl]-3-yl)-methanol, affords a series of esters having especially attractive insecticidal efficacy when combined with appropriate carboxylic acids; for example, 3-(2,2-dihaloethenyl)-2,2-dimethyrcyclopropanecarboxylic acids and 3-(2-chloro-3,3,3-trifluoro-1-propenyl)-2,2- di ethylcyclopropanecarboxylic acid. Esters of these acids combined with (2-methyl [ ., 1 '-biphenyl] -3-yl)- methanol are described in U.S. 4,214,004 and U.S. 4,238,505, respectively. Although pyrethroid esters of (2-methyl[1 ,1 '-bi¬ phenyl]-3-yl)-methanol have commercial potential, yields of the requisite (2-methyl[1 ,1 '-biphenyl]-3-yl)-methanol from known preparative techniques have been too low to warrant commercialization. For example, U.S. 4,214,004 discloses an overall yield of about 15% beginning with 2-methyl-3-nitrobenzyl alcohol. According to the multistep synthesis of which the present invention is the key step, the overall yield of (2-methyl[1 ,1 '-biphenyl]-3-yl)-methanol is about 60% utilizing a commercially available 2,6-dihalotoluene, for example, 2,6-dichlorotoluene or 2-bromo-6-chlorotoluene, in the first step to produce a 3-halo-2-methylphenylmag- nesium halide, that is, 3-chloro-2-methylphenylmagnesium chloride or bromide, by conventional techniques. The key to success of the overall process lies in the next step in which the 3-chloro-2-methylphenylmag- nesiu halide dissolved is cross-coupled with a haloben¬ zene in an inert solvent in the presence of a catalytic amount of catalyst selected from palladium metal or nickel(II) acetylacetonate, producing 3-chloro-2-methyl- [1 ,1 '-biphenyl] . It is this step ' which is the process of this invention. Coupling reactions of Grignard reagents are known to lead to mixtures of products because of the possibilities for both homo and hetero coupling between the reactants, as well as coupling between the reactants and products. The products from attempted cross-coupling of a Grignard reagent with a halocarbon compound often constitute an intractable mixture with a low yield of the desired cross-coupled product. When palladium metal is employed as catalyst, the reaction mixture is heterogeneous. Coupling reactions of Grignard reagents are not generally conducted under heterogeneous conditions. On the basis of the prior art, cross-coupling a 3-chloro-2-methylphenylmagnesium halide with a haloben¬ zene using nickel(II) acetylacetonate as catalyst under homogeneous conditions would seem best carried out by using about 1 mole percent nickel(II) acetylacetonate based on the limiting reagent and perhaps a molar excess of the Grignard reagent. One would expect to obtain a yield of 60-80% 3-halo-2-πιethyl-[1 ,1 '-biphenyl] . othing in the prior art suggests an increase in the yield to about 90% by decreasing the catalyst level one to two orders of magnitude. The 3-chloro-2-methyl-[1 ,1 '-biphenyl] cross-coupling product can be converted to the desired (2-methyl[1 ,1 '- biphenyl]-3-yl)methanol by various methods. For example, the 3-chloro-2-methyl-[1 ,1 '-biphenyl] can be converted to a second Grignard, a 2-m thyl{ [1,1 '-biphenyl]-3-yl)mag- nesium halide, which then yields the desired (2-methyl- [1 ,1 '-biphenyl]-3-yl)-methanol when treated with formal¬ dehyde, processes which are well known in the art. *f\ Although other techniques for preparing the Grignard 5 reagent are known, the 3-chloro-2-methylphenylmagnesium halide is. advantageously prepared in an inert solvent. Inert solvents suitable for use in the process include ethers, for example, tetrahydrof ran and diethyl ether, as well as liquid tertiary amines, for example, trieth- 10 ylamine. Tetrahydrofuran is preferred when preparing 3-chloro-2-methylphenylmagnesium chloride, at least two moles of tetrahydrofuran per mole of Grignard reagent. The so-prepared solution of the Grignard reagent may be added to a warm, stirred mixture of the catalyst in 15 the halobenzene, or the halobenzene may be added to a warm (50° to 80 β C preferred), stirred mixture of the catalyst and solution of the Grignard reagent. The rate of addition is not critical, but relatively fast addi¬ tion, that is, 0.5 to 1.0 hr. , is advantageously employed. 20 The reaction generally is completed in a few hours. Whereas the halobenzene may be bromobenzene or iodobenzene, bromobenzene is preferred. At least a 10% molar excess of halobenzene is preferably used to mini¬ mize coupling of the Grignard reagent to the product. 25 The use of iodobenzene leads to more self-coupling to biphenyl, with a corresponding decrease in cross-coupling yield, than if bromobenzene is used. Generally, a catalytic amount of palladium metal catalyst sufficient to contain about 0.01-1.0, preferably 30 0.02-0.5, mole percent palladium metal based on the Grignard reagent is sufficient, and larger amounts may actually lead to lower yields of the desired product. Although palladium metal, for example, as commercially available palladium black, can be used, the small amounts 35 required are difficult to weigh and handle, so it is usually desirable to employ palladium metal carried on a solid support such as carbon, alumina, silica, or clay. Palladium metal on either carbon or alumina as solid supports are available commercially and preferred for that reason. At the catalyst levels employed in this invention, catalyst recovery and recycling are not necessary. If the nickel catalyst is selected, a catalytic amount of nickel(II) acetylacetonate, greater than 0.01 mole percent, but not more than 0.1 mole percent based on the Grignard reagent should be used, with the 0.02-0.04 mole percent range being preferred for maximum yields. The procedure for preparing the Grignard reagent and conducting the cross-coupling reaction of this invention are illustrated in the following Examples. Example 1 Palladium Metal Catalysis A. Palladium On Carbon As Catalyst Bromobenzene (7.58 g, 48.3 mill ' imoles) and 5% palladium on carbon (0.01 g, 4.83 micromole of palladium metal) was stirred under nitrogen at 100°C. To this was added dropwise during a 15 hour period 3-chloro-2-methyl- phenylmagnesium chloride (4.48 g, 24.2 milli oles) in dry tetrahydrofuran (15 ml), which had been prepared by the method of Mitchell and Yan, Can. J. Chem. , _8, 2584 (1980). The reaction mixture was stirred for two hours and then analyzed by vapor phase chromatography, which indicated 95.8% of the Grignard reagent had reacted. Of the products .which formed, 86.1% was 3-chloro-2-methyl- [1 ,1 '-biphenyl] , a yield of 82.5% based on the Grignard reagent. Other similar experiments utilizing palladium on carbon under conditions within the scope of this inven¬ tion are summarized as follows: Reagents Addition Reaction A B c - Time Time Temp Yield Example ( moles) (mmoles) (mole%) (hr) (hrs) ( β C) (%) 2 24.2 120.8 0.5 1.5 4.0 80 73.7 3 24.2 60.4 0.1 20.0 20.0 80 77.6 4 24.2 48.3 0.1 2.5 2.5 100 81.3 5 24.2 48.3 0.01 5.5 5.5 120 54.6 Mole % based on Grignard reagent. The reaction time is the total of the addition time, plus the time the reaction was stirred at the reaction temperature after complete addition. 33 • Palladium On Alumina As Catalyst Bromobenzene (18.9 g, 120.7 millimoles) and 5% palladium on alumina (0.25 g, 0.12 millimole of palladium metal) was stirred under nitrogen at 80 β C. A solution of 3-chloro-2-methylphenylmagnesium chloride (4.48 g, 24.2 millimoles) in dry tetrahydrofuran (15 ml) was added dropwise to the reaction mixture during a 1.25 hour period. After complete addition the mixture was analyzed by vapor phase chromatography. Analysis of the reaction mixture indicated 98% of the Grignard reagent had reacted. Of the products formed, 75.2% was 3-chloro-2-methyl[1 ,1 *- biphenyl], a yield of 73.5% based on the Grignard reagent added. Example 2 Nickel (II) Acetylacetonate Catalysis Under a dry nitrogen atmosphere, a stirred mixture of magnesium turnings (97.3 g, 4.00 moles) in approxi¬ mately 65 ml of dry tetrahydrof ran was heated to 65 β C. To the warm mixture was added one ml of 1 ,2-dibromoethane. While maintaining the > temperature at about 65 β C, a solution of 2,6-dichlorotoluene (322 g, 2.00 moles) in dry tetrahydrofuran (600 ml) was added to the mixture during a 45 minute period. After complete addition, the reaction mixture was stirred at 65°C for three hours. Analysis of the reaction mixture indicated each milli- liter of the solution contained 1.698 milliequivalents of 3-chloro-2-methylphenylmagnesium chloride. under a dry nitrogen atmosphere, 50 ml of the above-described reaction mixture, containing 0.085 mole 3-chloro-2-methylphenylmagnesium chloride, was stirred and heated at 50 β C. Nickel(II) acetylacetonate hydrate (0.00825 g, 0.00003 mole) was added to the mixture. During a one hour period bromobenzene (18.8 g, 0.120 mole) was added dropwise to the warm reaction mixture. After complete addition, the mixture was stirred at 50 β C for 23 hours. The mixture was cooled to room temperature and 20.0 ml of n-tetradecane added as an OMPI internal standard for GLPC analysis. The resultant mixture was washed with 25 ml of a 0.1 N hydrochloric acid solution. Analysis of the washed mixture by GLPC indicated 20.73% by weight of 3-chloro-2-methyl-[1 ,1 '- biphenyl], an 88.9% yield. Other similar experiments, arranged in order of increasing amount of catalyst, are summarized as follows: Reagents Addition Reaction A B c*- Time Time Temp Yield Example ■ (moles) . ' (moles) (πole%) (hr) (hrs) ( β C) (%) 2 0.10 0.11 0.01 0.17 22.0 89 66.6 3 0.085 0.12 0.024 2.0 24.0 65 84.3 4 0.085 0.12 0.024 1.5 24.0 80 85.0 5 0.085 0.12 0.024 1.5 24.0 50 86.2 6 0.085 0.12 0.024 1.0 24.0 65 86.2 7 C 0.048 0.0528 0.02 0 d 9.0 80 87.8 8 C 1.0 1.1 0.02 0.17 3.0 25-80 88.2 9 C 0.032 0.0352 0.02 0.75 4.0 80 89.2 1 0.085 0.12 0.035 1.0 24.0 50 88.9 10 0.085 0.12 0.035 1.0 24.0 80 84.8 11 0.085 0.12 0.035 1.5 24.0 65 85.1 12 0.085 0.12 0.035 1.5 24.0 65 86.0 13 0.085 0.12 • 0.035 1.5 24.0 65 86.6 14 0.085 0.12 0.035 2.0 24.0 80 86.5 15 0.085 0.12 0.035 2.0 24.0 50 86.2 16 0.085 0.12 0.047 1.0 24.0 65 85.5 17 0.085 0.12 0.047 1.5 24.0 50 85.7 18 0.085- 0.12 0.047 1.5 24.0 80 84.1 19 0.085 0.12 0.047 2.0 24.0 65 82.6 20 C 0.048 0.0528 0.1 o d 5.0 90 85.4 21 0.T0 0.15 0.11 2.25 22.0 65 58.0 22 0.10 0.15 0.11 2.25 22.0 65 57.8 23 0.10 0.15 0.11 2.25 22.0 65 61.8 24 0.10 0.20 0.2 0,5 22.0 50 68.2 25 0.10 0.10 0.2 4.0 22.0 50 43.7 26 0.10 0.20 0.2 4.0 22.0 80 27.3 27 0.10 0.10 0.2 0.5 22.0 80 35.0 28 C 0.093 0.466 1.0 2.0 2.0 25-45 68.4 29 C 0.0246 0.246 1.0 2.3 2.3 80 77.0 a Mole % based on Grignard reagent. b The reaction time is the total of the addition time, plus the time the reaction was stirred at the reaction temperature after complete addition. Grignard reagent added to bromobenzene/catalyst mixture. No internal standard in GLPC analysis. Added at once. X c "-<_? "

Claims: Claims: 1. A process for producing 3-chloro-2-methyl-[1,1 '- biphenyl] characterized by cross-coupling a halobenzene with a 3-chloro 2-methylphenylmagnesium halide in an inert solvent in the presence of a catalytic amount of catalyst selected from palladium metal or nickel (II) acetylacetonate. 2. The process according to claim 1 characterized in that the catalyst is palladium metal. 3. The process of claim 2 characterized in that the palladium metal is carried on a solid support. 4. The process of claim 2 characterized in that said solid support is carbon. 5. The process of claim 2 characterized in that said solid support is alumina. 6. The process of claim 2 characterized in that said catalytic amount of palladium metal is 0.02-0.5 mole percent based on 3-chloro-2-methylphenylmagnesium halide. 7. The process according to claim 1 characterized in that the catalyst is nickel (II) acetylacetonate. 8. The process of claim 7 characterized in that said catalytic amount is greater than 0.01 mole percent, but not more than 0.1 mole percent, based on the 3-chloro- 2-methylphenylmagnesium halide. 9. The process of claim 7 characterized in that said catalytic amount is 0.02-0.04 mole percent. 10. The process of any of claims 1-9 characterized in that the halobenzene is bromobenzene. 11. The process of any of claims 1-10 characterized in that the 3-halo-2-methylphenylmagnesium halide is 3-chloro-2-methylphenylmagnesium chloride. 12. The process of any of claims 1-11 characterized in that the inert solvent is tetrahydrofuran.

Inventors: DELMAR ERIC GEORGE, DELMAR, ERIC, GEORGE
Applicants: FMC CORP, FMC CORPORATION
Application year: 1984
Main classification: C07C17
IPC codes: C07C17