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Synthesis 2009(14): 2408-2412  
DOI: 10.1055/s-0029-1216832
PAPER
© Georg Thieme Verlag Stuttgart ˙ New York

Kumada Cross-Coupling of Aryl Grignard Reagents with Aryl Halides Catalyzed by an Immobilized Nickel Catalyst

Xiaofang Chena, Lei Wang*a,b, Jie Liua
a Department of Chemistry, Huaibei Coal Teachers College, Huaibei, Anhui 235000, P. R. of China
b State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, P. R. of China
Fax: +86(561)3090518; e-Mail: leiwang@hbcnc.edu.cn;

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Publication History

Received 22 January 2009
Publication Date:
27 May 2009 (online)

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Abstract

The Kumada cross-coupling reaction of a variety of unactivated aryl bromides and aryl chlorides with phenylmagnesium bromide has been developed. The reaction is catalyzed by an immobilized nickel(II) complex containing a pyrrolidine unit, which is part of a bidentate nitrogen ligand. The catalyst is highly efficient for the Kumada reaction, which proceeds smoothly at 10 ˚C to generate the corresponding products in good to excellent yields. In addition, the catalyst can be reused five times without significant loss of activity.

Key words

Kumada cross-coupling - immobilized nickel(II) complex - bidentate nitrogen ligands - Grignard reagents - aryl halides

The cross-coupling of Grignard reagents with aryl halides (Kumada reaction) catalyzed by a nickel complex represents a very useful and synthetic method to produce unsymmetric biaryls. [¹] Recently, a numbers of nickel and palladium complexes have been employed in the Kumada reaction with great success. [²] Ever-increasing environmental concern has resulted in much attention being directed recently toward the development of new environmentally friendly catalysts for the Kumada reaction. Initially, the catalysts have mainly been nickel complexes with phosphine ligands, e.g. [NiCl2(PPh3)2], [³] [NiCl2(PCy3)2], [4] and NiCl2L (L = dppe, dppp, dppf). More recently, new het­erogeneous nickel catalysts, such as polymer-supported nickel, [5] nickel on charcoal, [6] nickel/nanoporous carbon materials, [7] and N-heterocylic carbene-based nickel(II) complexes, have been used for this transformation. [8] Among the heterogeneous nickel catalysts, organic-inorganic hybrid-material-supported catalysts have played a great role in the area of coupling reactions and aroused great interest among chemists. Both unsupported [9] [¹0] and supported [¹¹] [¹²] bidentate nitrogen ligands have been reported to be effective in this kind of reaction. A number of papers have described that an excess of Grignard reagent can reduce nickel(II) to nickel(0) during the course of the catalytic cross-coupling reaction. [6b] [¹³] As part of our program aimed at developing selective and environmentally friendly methodologies using organic-inorganic hybrid-material-supported catalysts for the preparation of fine chemicals and in continuation of our interest in exploring novel synthetic strategies for carbon-carbon bond-formation reactions, [¹4] we have carried out the research reported herein, showing that immobilized nickel(II), coordinated by a new kind of bidentate ligand, can be a much more effective heterogenized catalyst for Kumada coupling reactions.

The synthesis of the organic-inorganic hybrid-material-immobilized nickel catalyst is illustrated in Scheme  [¹] . The desired catalyst material ‘silica-APTS-Pyr-Ni(II)’ [APTS = (3-aminopropyl)triethoxysilane; Pyr = pyrrolidin-2-ylmethyl] was readily prepared by a multistep procedure and subsequently used for Kumada reactions of aryl bromides and aryl chlorides with phenylmagnesium bromide in tetrahydrofuran. To our delight, the reactions can generate the corresponding products in good to excellent yields. It is worth noting that the silica-supported nickel(II) catalyst can be recycled by a simple filtration of the reaction solution and used for five consecutive trials without significant loss of activity.

Scheme 1

In our initial screening experiments, the activity of the immobilized nickel catalyst silica-APTS-Pyr-Ni(II) was tested (Table  [¹] ). It has been reported that the order of the addition of the reagents has some influence on the Kumada reaction, [¹5] and therefore we followed the following protocol for the reaction. A small Schlenk tube was charged with the silica-APTS-Pyr-Ni catalyst (48 mg, 2 mol% catalyst, loading 0.21 mmol/g), the appropriate aryl halide (0.50 mmol), and anhydrous tetrahydrofuran (2.0 mL) under an anhydrous nitrogen atmosphere. The mixture was allowed to stir at 10 ˚C for five minutes before the reaction was initiated by the dropwise addition by syringe of a phenylmagnesium bromide solution (0.75 mmol) in tetrahydrofuran (2.0 mL); the reaction was then allowed to run for 12 hours at 10 ˚C. Table  [¹] shows that when one mole-percent of catalyst was used, the reaction did not go to completion (Table  [¹] , entry 1), but that a higher loading of the catalyst of two mole-percent gave a good result (Table  [¹] , entry 2). However, with an increased loading of the catalyst of up to three mole-percent there was no increase in the isolated yield of the desired product (Table  [¹] , entry 3). Thus, two mole-percent catalyst is enough to accomplish this reaction. Although the Grignard reagent used for this reaction is very reactive, there was little side reaction. This shows that the bidentate nitrogen ligand containing the pyrrolidine unit is a good type of ligand for the Kumada cross-coupling reaction.

Table 1 Effect of Catalyst Loading on the Kumada Reactiona

Entry Catalyst loading (mol%) Yieldb (%)
1 1.0 77
2 2.0 91
3 3.0 92
a Reagents and conditions: PMPBr (0.50 mmol), silica-APTS-Pyr-Ni (cat.), PhMgBr (0.75 mmol), THF (2.0 mL), 10 ˚C, 12 h.
b Isolated yield.

Thus, the optimized reaction conditions for the Kumada reaction consist of the following: silica-APTS-Pyr-Ni (2 mol%), aryl halide (0.50 mmol), phenylmagnesium bromide (0.75 mmol), tetrahydrofuran (2.0 mL), 10 ˚C, 12 hours.

Next, the synthetic scope of the cross-coupling of various aryl bromides and aryl chlorides with phenylmagnesium bromide solution under the optimized reaction conditions was investigated (Table  [²] ). It was found that electron-neutral, electron-poor, as well as electron-rich aryl bromides react very well with phenylmagnesium bromide to generate the corresponding cross-coupling products in good to excellent yields under the established reaction conditions (Table  [²] , entries 1-9). For electron-neutral, electron-rich, as well as electron-poor aryl chlorides, moderate to good yields of the desired products were obtained (Table  [²] , entries 10-14). The position of the cyano group on the aryl bromide did not have an effect on the outcome of the reaction (Table  [²] , entries 4 and 5). However, there was an obvious positional effect of the nitro group in the aryl bromide (Table  [²] , entries 3 and 7); in comparison, the position of the nitro substituent had no influence on the Kumada reaction of aryl chlorides (Table  [²] , entries 11 and 13). It may be that the nitro-substituted aryl bromide was more active than the nitro-substituted aryl chloride. In addition, the coupling reaction of o-tolyl bromide gave lower conversion than the p-tolyl bromide as a result of steric hindrance (Table  [²] , entries 6 vs 9). It is worth noting that some substituents with electron-withdrawing groups that could have been very sensitive to the Grignard reagent also gave the desired products in good yields (Table  [²] , entries 1, 4, 5, 10, and 12).

Table 2 Effect of Substrates on the Kumada Reactiona

Entry ArX Yieldb (%)
 1 4-AcC6H4Br 74
 2 PMPBr 90
 3 4-O2NC6H4Br 93
 4 4-NCC6H4Br 81
 5 3-NCC6H4Br 83
 6 4-TolBr 91
 7 3-O2NC6H4Br 83
 8

81
 9 2-MeC6H4Br 76
10 4-AcC6H4Cl 70
11 4-O2NC6H4Cl 88
12 4-NCC6H4Cl 74
13 3-O2NC6H4Cl 86
14 4-TolCl 85
a Reagents and conditions: ArX (0.50 mmol), silica-APTS-Pyr-Ni (2 mol%, cat. loading 0.21 mmol/g), PhMgBr (0.75 mmol), THF (2.0 mL), 10 ˚C, 12 h.
b Isolated yield.

In addition, the recyclability of the silica-APTS-Pyr-Ni catalyst was also examined after the completion of the Kumada reaction of 4-bromoanisole with phenylmagnesium bromide solution. The organic reaction solution (containing 48 mg of silica-APTS-Pyr-Ni, catalyst loading 0.21mmol/g) was filtered through a sintered glass funnel, and the solid was washed sequentially with ethanol (2 × 5 mL), dichloromethane (2 × 5 mL), and acetone (2 × 5 mL). After being dried in the oven at 60 ˚C for ten hours, the catalyst could be reused directly without further purification. The silica-APTS-Pyr-Ni catalyst could be recovered and reused for five consecutive trials without loss of activity (Figure  [¹] ). When the recycled catalyst was used for more than five times, there was a significant deactivation of the supported catalyst along with a color change to dark grayish; this is presumably the result of the formation of nickel powder and nickel oxide on the surface of the organic-inorganic hybrid support. Nickel leaching from the silica-APTS-Pyr-Ni catalyst was also determined. Atomic absorption spectroscopy analysis of the clear filtrates obtained by filtration after the reaction indicated a nickel content of less than 0.5 ppm. Also, only a trace amount of the desired product was isolated for the model reaction if substrates were added to a filtrate obtained after the filtration of the immobilized catalyst after a reaction.

Figure 1 Yields obtained with recycled silica-APTS-Pyr-Ni catalyst (model reaction under standard reaction conditions: PMPBr, PhMgBr, 10 ˚C, 12 h)

In conclusion, we have developed a highly efficient and recoverable organic-inorganic hybrid-material-immobilized nickel catalyst (silica-APTS-Pyr-Ni) for the Kumada reaction. The cross-coupling reactions of a variety of unactivated aryl bromides and aryl chlorides with phenylmagnesium bromide are catalyzed by silica-APTS-Pyr-Ni (2 mol%) in anhydrous tetrahydrofuran at 10 ˚C for 12 hours under a nitrogen atmosphere and generate the corresponding biaryls in good to excellent yields. In addition, the silica-APTS-Pyr-Ni catalyst can be used for five consecutive trials without significant loss of activity.

Melting points were recorded on a WRS-2B melting point apparatus and are uncorrected. ¹H NMR spectra were recorded on a Bruker 300-MHz, 400-MHz, or 500-MHz FT-NMR spectrometer. Chemical shifts are given relative to TMS as internal standard. IR spectra were obtained on a Nicolet NEXUS 470 spectrophotometer. Products were purified by flash column chromatography (silica gel, 230-400 mesh). The chemicals were purchased from commercial suppliers (Aldrich, USA and Shanghai Chemical Company, China) and used without further purification prior to use.

Silica-APTS

A 50-mL three-necked round-bottomed flask with a Dean-Stark trap was loaded in succession with anhyd toluene (20 mL), activated silica (3.0 g, prepared by a literature procedure [¹6] ), and (3-aminopropyl)triethoxysilane (APTS; 10 mL). The mixture was refluxed at 120 ˚C for 24 h, and then filtered; the solid was washed with acetone (10 mL) followed by CH2Cl2 (10 mL) and dried overnight under reduced pressure at 60 ˚C. Thus silica-APTS was obtained; yield: 3.36 g; loading (by CHN microanalysis): 0.512 mmol of aminopropyl groups/g (based on the nitrogen percentage).

Silica-APTS-Boc-Pro

Boc-l-proline (301 mg, 1.4 mmol) and Et3N (141 mg, 1.4 mmol) were dissolved in THF (10 mL). The resulting soln was cooled to 0 ˚C, and ClCO2Et (154 mg, 1.4 mmol) was added dropwise over 10 min. After the soln had stirred for 30 min, silica-APTS (2.735 g, 0.512 mmol aminopropyl groups/g) was added, and then the resulting mixture was stirred at 0 ˚C for 1 h, at r.t. for another 16 h, and finally refluxed for 3 h. After cooling to r.t., the mixture was filtered and successively washed with THF (10 mL), EtOH (10 mL), and EtOAc (10 mL), and then dried under vacuum. This gave silica-ATPS-Boc-Pro; yield: 2.931 g; loading (by CHN microanalysis): 0.336 mmol/g (based on the nitrogen percentage).

Silica-APTS-Pyr

A 10-mL round-bottomed flask was successively loaded with TFA (5 mL) and CH2Cl2 (5 mL), and then the mixture was stirred. After addition of silica-APTS-Boc-Pro (2.7 g), the mixture was stirred for 2.5 h in an ice bath. The mixture was filtered and the solid was washed with CH2Cl2 (10 mL) and dried under vacuum; this gave the corresponding Boc-deprotected product silica-APTS-Pro; yield: 2.5 g.

In a 50-mL round-bottomed flask were introduced successively the thus obtained Boc-deprotected product (2.5 g), NaBH4 (127 mg), and anhyd THF (25 mL), and then the mixture was cooled to 0 ˚C overnight. After a soln of I2 (160 mg) in THF (5 mL) had been added, the soln was refluxed for 48 h. Then it was cooled to r.t., the mixture was filtered, and the solid was washed successively with THF (10 mL), EtOH (10 mL), and EtOAc (10 mL), and then it was dried under reduced pressure until the weight remained constant. This gave the organic-inorganic hybrid material silica-APTS-Pyr; yield: 2.4 g; loading (by CHN microanalysis): 0.218 mmol/g (based on the nitrogen percentage).

IR (KBr): 1101 (Si-O), 2937 (C-H), 3330 (N-H) cm-¹.

Silica-APTS-Pyr-Ni Catalyst

In a small Schlenk tube, NiCl2 (26 mg, 0.2 mmol) was dissolved in anhyd DMF (10 mL), and then silica-APTS-Pyr (920 mg) was added and the suspension was stirred for 10 h under a N2 atmosphere at r.t. The soln was filtered and the solid was successively washed with DMF (5 mL) and acetone (5 mL), and then dried under reduced pressure at r.t. overnight; this gave the silica-APTS-Pyr-Ni catalyst as a pale yellow powder; yield: 945 mg; 1.24 wt% Ni (based on atomic absorption spectroscopy analysis).

IR (KBr): 1081 (Si-O), 2936 (C-H), 3327 (N-H) cm-¹.

Kumada Cross-Coupling Reaction; General Procedure

A small Schlenk tube was charged successively with the silica-APTS-Pyr-Ni catalyst (25 mg; 0.005 mmol Ni), the aryl halide (0.25 mmol), and anhyd THF (1.0 mL). The mixture was stirred for 5 min before the catalytic reaction was initiated by the dropwise addition by syringe of the Grignard reagent (0.375 mmol) in THF (1.0 mL) at 10 ˚C. The reaction was quenched by the addition of MeOH (1.0 mL). The crude product was purified by column chromatography.

Recycling the Silica-APTS-Pyr-Ni Catalyst

After the reaction had been carried out, the mixture (containing 25 mg of silica-APTS-Pyr-Ni) was filtered through a sintered glass funnel and washed successively with EtOH (2 × 5 mL), CH2Cl2 (2 × 5 mL), and acetone (2 × 5 mL). After being dried in an oven at 60 ˚C for 10 h, the catalyst can be reused directly without further purification.

4-Phenylacetophenone

Mp 120-121 ˚C (Lit. [¹7] mp 119 ˚C).

¹H NMR (300 MHz, CDCl3): δ = 2.63 (s, 3 H), 7.42 (m, 1 H), 7.47 (m, 2 H), 7.63 (m, 2 H), 7.68 (m, 2 H), 8.03 (m, 2 H).

¹³C NMR (75 MHz, CDCl3): δ = 26.7, 127.2, 127.3, 128.2, 128.9, 129.0, 133.9, 139.9, 145.7, 197.7.

4-Nitrobiphenyl

Mp 113-114 ˚C (Lit. [¹8] 113-114 ˚C).

¹H NMR (300 MHz, CDCl3): δ = 7.44 (m, 3 H), 7.61 (m, 2 H), 7.73 (d, J = 8.9 Hz, 2 H), 8.29 (d, J = 8.9 Hz, 2 H).

¹³C NMR (75 MHz, CDCl3): δ = 124.1, 127.4, 127.8, 129.0, 129.2, 138.8, 147.7.

4-Cyanobiphenyl

Mp 85-86 ˚C (Lit. [¹9] 84-86 ˚C).

¹H NMR (300 MHz, CDCl3): δ = 7.44-7.48 (m, 3 H), 7.60 (m, 2 H), 7.67-7.75 (m, 4 H).

¹³C NMR (75 MHz, CDCl3): δ = 110.8, 118.9, 127.2, 127.7, 128.7, 129.1, 132.6, 139.1, 145.6.

4-Methylbiphenyl

Mp 45-46 ˚C (Lit. [¹9] 44.5-46.5 ˚C).

¹H NMR (300 MHz, CDCl3): δ = 2.38 (s, 3 H), 7.24 (d, J = 8.1 Hz, 2 H), 7.32 (m, 1 H), 7.41 (t, J = 7.5 Hz, 2 H), 7.48 (d, J = 8.1 Hz, 2 H), 7.56 (d, J = 7.5 Hz, 2 H).

¹³C NMR (75 MHz, CDCl3): δ = 21.2, 127.1, 128.8, 129.6, 137.1, 138.5, 141.3.

3-Nitrobiphenyl

Mp 58-60 ˚C (Lit. [²0] 61 ˚C).

¹H NMR (300 MHz, CDCl3): δ = 7.52 (m, 3 H), 7.63 (m, 3 H), 7.95 (m, 2 H), 8.46 (s, 1 H).

¹³C NMR (75 MHz, CDCl3): δ = 122.6, 127.5, 129.0, 129.7, 133.4, 136.8, 137.6, 148.7.

3-Cyanobiphenyl

Pale yellow solid. [²¹]

¹H NMR (500 MHz, CDCl3): δ = 7.42-7.59 (m, 7 H), 7.65 (m, 1 H), 7.77 (dd, J = 1.0, 8.0 Hz, 1 H).

¹³C NMR (125 MHz, CDCl3): δ = 111.1, 118.6, 127.9, 128.7, 130.3, 133.2, 133.6, 138.4, 145.8.

4-Methoxybiphenyl

Mp 90-92 ˚C (Lit. [²²] 89-90 ˚C).

¹H NMR (400 MHz, CDCl3): δ = 3.86 (s, 3 H), 6.98 (d, J = 9.0 Hz, 2 H), 7.31 (t, J = 7.5 Hz, 1 H), 7.42 (t, J = 7.8 Hz, 2 H), 7.54 (t, J = 8.4 Hz, 4 H).

¹³C NMR (100 MHz, CDCl3): δ = 55.5, 114.4, 126.8, 126.9, 128.3, 128.8, 133.9, 141.0, 159.3.

3-Phenylpyridine

Yellow oil. [²³]

¹H NMR (400 MHz, CDCl3): δ = 7.43-7.35 (m, 2 H), 7.49 (t, J = 7.2 Hz, 2 H), 7.60 (d, J = 8.4 Hz, 2 H), 7.88 (d, J = 12.0 Hz, 1 H), 8.59 (d, J = 6.4 Hz, 1 H), 8.85 (s, 1 H).

¹³C NMR (100 MHz, CDCl3): δ = 123.0, 127.1, 128.1, 129.0, 134.3, 136.6, 137.8, 148.3, 148.4.

2-Methylbiphenyl

Oil. [²4]

¹H NMR (400 MHz, CDCl3): δ = 2.29 (s, 3 H), 7.36-7.27 (m, 9 H).

¹³C NMR (100 MHz, CDCl3): δ = 20.5, 125.7, 126.7, 127.3, 128.1, 129.2, 129.9, 130.3, 135.2, 141.8.

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Scheme 1

Figure 1 Yields obtained with recycled silica-APTS-Pyr-Ni catalyst (model reaction under standard reaction conditions: PMPBr, PhMgBr, 10 ˚C, 12 h)