Nickel-Catalyzed Cross-Coupling of Aryl Halides with Alkyl Halides: Ethyl 4-(4-(4-methylphenylsulfonamido)-phenyl)butanoate

4-Bromoaniline 
 
 
 
p-Toluenesulfonyl chloride 
 
 
 
Pyridine 
 
 
 
Dichloromethane 
 
 
 
N-(4-bromophenyl)-4-methylbenzenesulfonamide 
 
 
 
Zn powder 
 
 
 
4,4'-Dimethoxy-2,2'-bipyridine 
 
 
 
Sodium iodide 
 
 
 
1,3-Dimethylpropyleneurea 
 
 
 
Nickel (II) iodide hydrate 
 
 
 
Ethyl 4-bromobutyrate 
 
 
 
Ethyl 4-(4-(4-methylphenylsulfonamido)phenyl)butanoate 
 
 
Keywords: 
 
Nickel-catalyzed cross coupling; 
Aryl halides; 
Alkyl halides; 
Ethyl 4-(4-(4-methylphenylsulfonamido)-phenyl)butanoate; 
Hazardous chemical disposals; 
Nucleophile free cross coupling


B. Ethyl 4-(4-(4-methylphenylsulfonamido)phenyl)butanoate (2)
A 500-mL 3-necked Morton flask with 24/40 ground-glass joints is equipped with a nitrogen-gas inlet on the left neck, a glass stopper on the right neck, and the center neck is equipped for mechanical stirring (glass bearing, glass stirrer rod, 60 mm PTFE paddle, RW 20 Tekmar motor) (Note 10). NiI 2 ·xH 2 O (528 mg, 1.31 mmol, 0.051 equiv) (Note 11), 4,4′di-methoxy-2,2′-bipyridine (284 mg, 1.31 mmol, 0.051 equiv) (Note 12), sodium iodide (1.25 g, 8.34 mmol, 0.33 equiv) (Note 13), and N-(4-bromophenyl)-4methylbenzenesulfonamide (8.33 g, 25.5 mmol, 1.00 equiv) are transferred via powder funnel through the right neck of the Morton flask. To these solids, 1,3dimethylpropyleneurea (DMPU, 105 mL) (Note 14) is added from a graduated cylinder. Then pyridine (105 μL, 1.31 mmol, 0.053 equiv) (Note 5) and ethyl 4-bromobutyrate (4.0 7 Ammonium chloride (ACS certified, crystalline, Malinckrodt) was used as received. 8 Magnesium sulfate (anhydrous powder, Fisher Scientific) was used as received. 9 In the hands of the checkers the yield was greater than 99% and the product obtained as a white solid. The submitters report that in their case the yield of this procedure was consistently greater than 80%, but the color of the final product would vary from faint yellow to brown. The color of the material did not affect the outcome of the next reaction. The product exhibited the following physiochemical properties and was stable on the bench top for months: mp: 148-149 °C; 1 H NMR (400 MHz; CDCl 3 ) δ: 2.36 (s, 3 H), 6 10 The stirrer paddle must not be in contact with the bottom or sides of the flask. The stirrer paddle was generally held ~10 mm above the bottom of the flask to prevent mechanical activation of the reducing agent, which results in greater amounts of hydrodehalogenation by-products and lower product yields. PTFE sleeves (ribbed, 24/40, Fischer Scientific) were used to seal all ground glass joints, and heavy mineral oil (mineral oil white, heavy, Malinckrodt) was used to lubricate the glass stir rod inside the 24/40 standard taper adapter (see photo). The checkers used thin PTFE sleeves.
11 Nickel (II) iodide hydrate was purchased from Strem Chemicals and used as received. The submitters used elemental analysis to assess the water content to be x = 3.5, but, because a slight excess of nickel iodide does not change the outcome of these reactions, the molecular weight of the nickel (II) iodide was taken to be that of the pentahydrate (MW = 402.58). For further information, see discussion section. 12 4,4′-Di-methoxy-2,2′-bipyridine (97%, Sigma-Aldrich) was used as received. 13 Sodium iodide (puriss. p.a., ≥99%, Sigma-Aldrich) was used as received. The submitters used Strem Chemicals (anhydrous, 99%). mL, 28 mmol, 1.1 equiv) (Note 15) are added by syringe. A gas outlet adapter with tubing attached to an oil-filled bubbler is placed in the right neck before submerging the reaction vessel up to the solvent line in an oil bath pre-equilibrated to 60 °C. The vessel headspace is purged with nitrogen for 15 min while the mixture is stirred (500-600 rpm) (Note 16). After the nitrogen purge is complete, the gas outlet on the right neck is replaced with the original glass stopper and the reaction mixture is stirred at 60 °C until the reaction mixture takes on a dark green color (15-30 min) (Note 17). Next, zinc powder (6-9 μm, 3.44 g, 52.6 mmol, 2.06 equiv) (Note 18) is added through a powder funnel attached to the right neck under a positive flow of nitrogen. The flask is kept under a slight positive pressure of nitrogen during the course of the reaction. Generally within 5-15 min after the addition of zinc, the reaction undergoes a characteristic dark green to orange-brown color change, indicating the reaction has begun. The reaction is judged complete when the color changes to black (Note 19).
14 The submitters state that 1,3-dimethylpropylene urea (DMPU) (99%, AK Scientific, Inc.) was used as received. The DMPU can be recovered and reused for subsequent cross-coupling reactions (see Note 22). In the case of the checkers, the use of undistilled DMPU (99%, AK Scientific, Inc. or 98%, Alfa Aesar) resulted in significant amounts of a side product. According to NMR and mass analyses this contamination has been tentatively identified as 1,3,5-trimethyl-1,3,5-triazine-2,4,6-(1H,3H,5H)-trione (3) and is clearly arising from the DMPU, since it can be detected by simply extracting DMPU with water and diethyl ether. The fact that this contamination has the same R f as 2 makes it difficult to remove by column chromatography. Distillation of the commercially available DMPU as described by the submitters (Note 22) decreased the amount of this side product significantly, however there was always trace amounts (0.5 mol % for the submitters) visible in the NMR spectrum (s, 3.35 ppm).
15 Ethyl 4-bromobutyrate (98%, Alfa Aesar) was used as received. 16 The submitters used argon instead of nitrogen and a rubber septum pierced with a needle attached to the oil bubbler to purge the vessel. Oxygen does not irreversibly decompose the catalyst because the stoichiometric reducing agent can reduce any oxidized catalyst. However, reactions with too much oxygen in the headspace often suffer from long induction periods that prevent the catalyst from reacting with starting materials until the oxygen in the headspace has finished reacting with the catalyst and reducing agent. Sometimes reactions do not proceed to completion in a reasonable amount of time (< 24 h) when there is a large headspace volume of air. See discussion section below. 17 In the hands of the submitters the color change to deep green was finished in about 15 minutes. The pre-stirring allows the nickel iodide to coordinate to the bipyridine complex and form the dark-green, tetrahedral (4,4′-dimethoxy-2,2′-bipyridine)NiI 2 . 18 Zinc dust (<10 μm, ≥98%, Sigma-Aldrich) was used as received. The submitters used zinc powder (6-9 μm, 97.5% metal basis, Alfa Aesar). 19 The submitters have found the color change to be a reliable method for determining the end-point of the reaction. For this particular substrate the red-orange to black color change occurred in 4-6 h. No further product formation was observed if the reaction was allowed to stir longer (up to 48 h), and no decomposition of the product was observed either. In the hands of the checkers the color change occurred after 3-5 h. The progress of the reaction can be followed by TLC analysis (eluent: 4:1 hexanes:EtOAc, visualization with 254 nm UV light). N-(4-Bromophenyl)-4-methylbenzenesulfonamide (1) has an R f of 0.23, ethyl 4-(4-(4methylphenylsulfonamido)phenyl)butanoate (2) has an R f of 0.15 and 4-methyl-N-phenylbenzenesulfonamide (hydrodehalogenated aryl bromide) has an R f of 0.25. Since the starting material 1 and the hydrodehalogenated side product have very similar R f judging the progress of the reaction by TLC is difficult; therefore, monitoring the color change is a good alternative method.
Once the reaction mixture changes color to black, it is allowed to cool to room temperature before filtering though a pad of diatomaceous earth (15 g, wetted with 40 mL of diethyl ether and packed firmly in place) (Note 20) in a 350-mL course-fritted glass Büchner funnel. The reaction vessel is rinsed with ether (3 × 50 mL) (Note 21) and these rinses are filtered as well. The filtrate is poured into a 1 L separatory funnel containing 150 mL of 1 M NH 4 Cl (aq) . The organic layer is separated and set aside. The aqueous layer is then extracted with additional ether (3 × 60 mL). The combined organic layers are washed with water (75 mL) and brine (75 mL), then dried over MgSO 4 (15 g, ~1 min). The solids are removed by vacuum filtration through a course-fritted glass Buchner funnel and washed with ether (20 mL). The filtrate is then concentrated by rotary evaporation (30 °C, 74 mmHg) to give a colorless oil. The aqueous layers are combined and set aside for later recovery of DMPU, if desired (Note 22).

Notes
1 This procedure is a modification of a literature method. 2 2 4-Bromoaniline (98+%, Alfa Aesar or 97%, Sigma-Aldrich) was used a received. 3 p-Toluenesulfonyl chloride (98%, Alfa Aesar) was used as received. The submitters used 1.10 equivalents of p-toluenesulfonyl chloride, but in the hands of the checkers this lead to contaminated product; therefore, the checkers decreased the amount to 1.02 equivalents. This discrepancy may be due to the use of p-toluenesulfonyl chloride of different quality since the submitters used different vendors (98%, Lancaster or ≥98% Sigma-Aldrich). 4 Dichloromethane (certified ACS grade, Fischer Scientific) was used as received. 5 Pyridine (ultrapure, spectrophotometric grade 99.5+%, Alfa Aesar) was used as received. 6 The progress of the reaction can be followed by TLC analysis (eluent: 4:1 hexanes:EtOAc, visualization with 254 nm UV light). p-Toluenesulfonyl chloride has an R f of 0.58, 4bromoaniline has an R f of 0.23, and N-(4-bromophenyl)-4-methylbenzenesulfonamide (1) has an R f of 0.28. TLC analysis was performed on pre-coated glass plates (SiliaPlate, 60Å, 250 μm, F 254 , SiliCycle). The submitters used EMD silica gel 60 F 254 pre-coated glass plates. 7 Ammonium chloride (ACS certified, crystalline, Malinckrodt) was used as received. 8 Magnesium sulfate (anhydrous powder, Fisher Scientific) was used as received. 9 In the hands of the checkers the yield was greater than 99% and the product obtained as a white solid. The submitters report that in their case the yield of this procedure was consistently greater than 80%, but the color of the final product would vary from faint yellow to brown. The color of the material did not affect the outcome of the next reaction. paddle was generally held ~10 mm above the bottom of the flask to prevent mechanical activation of the reducing agent, which results in greater amounts of hydrodehalogenation by-products and lower product yields. PTFE sleeves (ribbed, 24/40, Fischer Scientific) were used to seal all ground glass joints, and heavy mineral oil (mineral oil white, heavy, Malinckrodt) was used to lubricate the glass 27 The submitters obtained the product as faintly yellow oil in 79-93% yield. The submitters also mention that the product oil will slowly solidify after scratching the sidewall of the vessel with a metal spatula. Both the oil and the resulting white solid had identical spectral properties. In the hands of the checkers the product solidified only in one case after a prolonged time in the freezer. The product exhibited the following physiochemical properties and was stable on the bench top for months: 1 H NMR (400 MHz; CDCl 3 ) δ 11 Nickel (II) iodide hydrate was purchased from Strem Chemicals and used as received.
The submitters used elemental analysis to assess the water content to be x = 3.5, but, because a slight excess of nickel iodide does not change the outcome of these reactions, the molecular weight of the nickel (II) iodide was taken to be that of the pentahydrate (MW = 402.58). For further information, see discussion section. 12 4,4′-Di-methoxy-2,2′-bipyridine (97%, Sigma-Aldrich) was used as received. 13 Sodium iodide (puriss. p.a., ≥99%, Sigma-Aldrich) was used as received. The submitters used Strem Chemicals (anhydrous, 99%). 14 The submitters state that 1,3-dimethylpropylene urea (DMPU) (99%, AK Scientific, Inc.) was used as received. The DMPU can be recovered and reused for subsequent crosscoupling reactions (see Note 22). In the case of the checkers, the use of undistilled DMPU (99%, AK Scientific, Inc. or 98%, Alfa Aesar) resulted in significant amounts of a side product. According to NMR and mass analyses this contamination has been tentatively identified as 1,3,5-trimethyl-1,3,5-triazine-2,4,6-(1H,3H,5H)-trione (3) and is clearly arising from the DMPU, since it can be detected by simply extracting DMPU with water and diethyl ether. The fact that this contamination has the same R f as 2 makes it difficult to remove by column chromatography. Distillation of the commercially available DMPU as described by the submitters (Note 22) decreased the amount of this side product significantly, however there was always trace amounts (0.5 mol % for the submitters) visible in the NMR spectrum (s, 3.35 ppm).
15 Ethyl 4-bromobutyrate (98%, Alfa Aesar) was used as received. 16 The submitters used argon instead of nitrogen and a rubber septum pierced with a needle attached to the oil bubbler to purge the vessel. Oxygen does not irreversibly decompose the catalyst because the stoichiometric reducing agent can reduce any oxidized catalyst. However, reactions with too much oxygen in the headspace often suffer from long induction periods that prevent the catalyst from reacting with starting materials until the oxygen in the headspace has finished reacting with the catalyst and reducing agent. Sometimes reactions do not proceed to completion in a reasonable amount of time (< 24 h) when there is a large headspace volume of air. See discussion section below. 17 In the hands of the submitters the color change to deep green was finished in about 15 minutes. The pre-stirring allows the nickel iodide to coordinate to the bipyridine complex and form the dark-green, tetrahedral (4,4′-dimethoxy-2,2′-bipyridine)NiI 2 . 18 Zinc dust (<10 μm, ≥98%, Sigma-Aldrich) was used as received. The submitters used zinc powder (6-9 μm, 97.5% metal basis, Alfa Aesar). 19 The submitters have found the color change to be a reliable method for determining the end-point of the reaction. For this particular substrate the red-orange to black color change occurred in 4-6 h. No further product formation was observed if the reaction was allowed to stir longer (up to 48 h), and no decomposition of the product was observed either. In the hands of the checkers the color change occurred after 3-5 h. The progress of the reaction can be followed by TLC analysis (eluent: 4:1 hexanes:EtOAc, visualization with 254 nm UV light). N-(4-Bromophenyl)-4-methylbenzenesulfonamide (1) has an R f of 0.23, ethyl 4-(4-(4-methylphenylsulfonamido)phenyl)butanoate (2) has an R f of 0.15 and 4-methyl-Nphenylbenzenesulfonamide (hydrodehalogenated aryl bromide) has an R f of 0.25. Since the starting material 1 and the hydrodehalogenated side product have very similar R f judging the progress of the reaction by TLC is difficult; therefore, monitoring the color change is a good alternative method. 20 Filter agent, Celite® 545 was purchased from Sigma-Aldrich and used as received. The submitters used "Celite 545 filter aid" from Fischer Scientific. 21 Diethyl ether (certified ACS grade, 7 ppm BHT stabilizer, Fisher Scientific) was used as received. 22 To the combined aqueous layers from the workup, sodium chloride (Aldrich) was added until the solution was saturated (generally ~ 5 g, some undissolved salt does not pose a problem). DMPU was extracted from the salted aqueous layer with dichloromethane (3 × 75 mL). The combined organic layers were dried over magnesium sulfate (15 g, ~1 min), and the magnesium sulfate was removed by vacuum filtration through a course-fritted glass Büchner funnel. The filtrate was concentrated by rotary evaporation (35 °C, 73 mmHg) to give 90-95 mL (86%-90% recovery) of faintly yellow liquid. This material was then distilled from calcium hydride (Sigma-Aldrich, reagent grade, 95%) (60-61 °C, 0.05 mmHg) 3 , dried to <1000 ppm water over 4 Å molecular sieves, and reused in subsequent cross coupling reactions. The submitters repeated the title cross coupling reaction on identical scale and obtained 8.63 g (94%) of ethyl 4-(4-(4methylphenylsulfonamido)phenyl)butanoate (2) using DMPU recycled by this method. 23 Silica gel (SiliaFlash® P60, 230-400 mesh, SiliCycle) was used as received. The submitters used EMD silica gel 60 (mesh 230-400) 24 Hexanes (certified ACS grade, 4.2% various methylpentanes, Fisher Scientific) were used as received. 25 Ethyl acetate (EtOAc, certified ACS grade) was purchased from Fischer Scientific and used as received. 26 The separation between product and hydrodehalogenated aryl bromide is small (ΔR f = 0.1). The submitters point out, therefore, that the yield may vary 5-15% depending on the number of mixed fractions. The checkers obtained only few mixed fractions, not calculating the possible yield loss. 27 The submitters obtained the product as faintly yellow oil in 79-93% yield. The submitters also mention that the product oil will slowly solidify after scratching the sidewall of the vessel with a metal spatula. Both the oil and the resulting white solid had identical spectral properties. In the hands of the checkers the product solidified only in one case after a prolonged time in the freezer. The product exhibited the following physiochemical properties and was stable on the bench top for months  13

Handling and Disposal of Hazardous Chemicals
The procedures in this article are intended for use only by persons with prior training in experimental organic chemistry. All hazardous materials should be handled using the standard procedures for work with chemicals described in references such as "Prudent Practices in the Laboratory" (The National Academies Press, Washington, D.C., 2011 www.nap.edu). All chemical waste should be disposed of in accordance with local regulations. For general guidelines for the management of chemical waste, see Chapter 8 of Prudent Practices.
These procedures must be conducted at one's own risk. Organic Syntheses, Inc., its Editors, and its Board of Directors do not warrant or guarantee the safety of individuals using these procedures and hereby disclaim any liability for any injuries or damages claimed to have resulted from or related in any way to the procedures herein.

Discussion
Very recently, our group reported a new nickel-catalyzed method to directly couple haloalkanes (iodides or bromides) with haloarenes (iodides, bromides, or electron-poor chlorides). [4][5] A distinguishing feature of this method is that the only organometallic intermediates are catalytic organonickel species -no organozinc or organomanganese reagents are involved. Previous transition metal-catalyzed methods to synthesize alkylated aromatic compounds have relied on the coupling of pre-formed aryl nucleophiles with alkyl electrophiles, 6-8 aryl electrophiles with pre-formed alkyl nucleophiles, 9 or in situ formation of a carbon nucleophile. 10-15 A major advantage of this new approach is that most carbon nucleophiles are synthesized from the corresponding organic halides, 16 and thus a synthetic step can be eliminated. Additionally, the absence of stoichiometric strong nucleophiles or bases to aid trans-metalation imparts excellent functional group compatibility. Concurrent with our work, Gosmini and Amatore developed a similar cobalt-catalyzed method, though the mechanism remains unclear. 17 Following our studies, Peng has studied the use of a simplified catalyst for inter-and intramolecular couplings under similar conditions 18 and Gong noted that the addition of MgCl 2 can improve yields with secondary alkyl halides. 19 Acidic groups, such as N-arylsulfonamides (pKa similar to acetic acid in DMSO), 20 are well tolerated (title compound 2). Substrates that are prone to β-elimination when metalated (6) couple cleanly with aryl bromides containing acidic protons (5) ( Table 1, entry 1) in stark contrast to the difficulties conventional cross-coupling methods have with these types of substrates. 21 Carbon nucleophiles used for Suzuki, 22 Stille, 23 and Hiyama-Denmark 24 crosscoupling reactions are not reactive under these conditions, allowing for the straightforward synthesis of poly-substituted aromatic compounds (Table 1, entries 4-6). Electrophilic groups, such as alkyl-aryl ketones, trifluoromethanesulfonic acid esters, and acetylated phenols, are compatible with our method as well (Table 1, entries 7-9). Lastly, the coupling of 26 with 27 is the synthetic equivalent of the α-arylation of acetaldehyde (Table 1, entry  10).
Scaling our recent procedures from 1 mmol to 25 mmol required addressing two difficulties, the heterogeneous nature of the reduction and variable induction periods that resulted in unpredictable reaction times.
The best results are obtained with mechanical stirring, but care must be taken to avoid grinding the zinc dust with the stirrer. Mechanical activation of metal powders is well known [25][26][27] and in the present reaction results in hydrodehalogenation products. This is presumably due to direct insertion of the zinc into the starting materials. Keeping the stirrer above the bottom surface and using a Morton flask 28 to ensure turbulent mixing results in reliable, high yields on large scale. Zinc powder from Alfa Aesar has proven more reliable than from other suppliers. If very deactivated zinc must be used, then brief activation with hydrochloric acid can be effective. 5 As we discovered when conducting kinetic studies on the present reaction, 5 oxygen in the headspace leads to long induction periods. Although the reactions proceed as expected after this induction period on small scale, in some large scale reactions we observed that the starting materials would decompose or the catalyst would become inactivated before reactions could complete. Sweeping most of the oxygen out with argon (or nitrogen) enables consistent reaction times and higher yields. These reactions are oxygen tolerant in that trace oxygen is not a concern, but large amounts of oxygen should be avoided.
Finally, although DMPU is routinely used on scale, its price is higher than other dipolar aprotic solvents routinely used in the lab. In order to conserve resources in our own lab, we worked out a simple procedure for recovering the DMPU that allows for efficient recycling of the solvent.

Supplementary Material
Refer to Web version on PubMed Central for supplementary material.

Table 1
Scope of Nucleophile Free Cross Coupling a Organic Synth. Author manuscript; available in PMC 2014 May 07.