Screening of ligands for the Ullmann synthesis of electron-rich diaryl ethers

In the search for new ligands for the Ullmann diaryl ether synthesis, permitting the coupling of electron-rich aryl bromides at relatively low temperatures, 56 structurally diverse multidentate ligands were screened in a model system that uses copper iodide in acetonitrile with potassium phosphate as the base. The ligands differed largely in their performance, but no privileged structural class could be identified.


General procedure A for synthesis of oxime ethers:
According to a modified procedure of MacNevin [5] et al., methoxyamine hydrochloride (1.1 equiv) is suspended in anhydrous methanol. Anhydrous pyridine is added (pyridine/methanol = 1:1) and the aldehyde (1.0 equiv) is added dropwise. The reaction mixture is stirred for 13 h at room temperature. After complete conversion the reaction mixture is taken up in dichloromethane and is washed with 5% citric acid aqueous solution Methoxyamine hydrochloride (500 mg, 5.90 mmol, 2.2 equiv) is suspended in anhydrous methanol (2 mL). Anhydrous pyridine (2 mL) is added and cyclohexane-1,2-dione (0.3 mL, 300 mg, 2.68 mmol, 2.2 equiv) is added dropwise. The reaction mixture is stirred for 8 h and another portion of methoxyamine hydrochloride (250 mg) is added. After complete conversion of starting material, the reaction mixture is taken up in dichloromethane and is washed with 5% citric acid aqueous solution (3 × 50 mL
The precipitate is filtered, and the filtrate is extracted with diethyl ether (3 × 50 mL). The combined organic phases are dried over Na 2 SO 4 , filtered and the solvent is removed in vacuo.

S13
According to a procedure of Zhao [14]
According to a procedure of Zhao [14]     According to a procedure of Clarke [19] and Rahal [20]  According to a procedure of Clarke [19] and Rahal [20]   Potassium hydroxide (440 mg, 7.87 mmol, 2.2 equiv), dissolved in ethanol (6 mL), is added dropwise. Then, bromoacetic acid (520 mg, 3.73 mmol, 1.0 equiv) is added. The reaction mixture is cooled and is stirred for 15 h at room temperature. The precipitated solid is filtered and washed with cold ethanol. The colorless solid is dissolved in a few drops of water, and conc. hydrochloric acid is added dropwise. The precipitate is filtered and washed with cold ethanol and diethyl ether. The product (0.64 g, 2.67 mmol, 74%) is obtained as a yellow solid.

S18
The solvent is removed in vacuo, and the obtained crude product (1.60 g, 51% w/w, 0.81g,
According to a procedure of Baati [29] et al., picolinic acid (2.00 g, 16.25 mmol, 1.0 equiv) is dissolved in methanol (40 mL) and conc. sulfuric acid (1 mL) is added. The reaction mixture is heated under reflux for 48 h. The reaction mixture is neutralized with solid potassium S20 carbonate (adjusted to pH [8][9], and then it is extracted with ethyl acetate (3 × 50 mL). The combined organic phases are dried over Na 2 SO 4 , and the solvent is removed in vacuo. The crude product (1.92 g, 14.00 mmol, 86%, (lit.: 80%) [29]) is obtained as a pale yellow oil and is sufficiently pure for further use.       According to a procedure of O'Connell [39] et al., sarcosine (2.50 g, 28.00 mmol, 1.0 equiv) is suspended in anhydrous methanol (50 mL) and it is cooled to 0 °C. Thionyl chloride S26 (2.14 mL, 3.51 g, 29.46 mmol, 1.05 equiv) is added dropwise, it is stirred for 30 min at 0 °C, and then the mixture is heated under reflux for 3 h. The solvent is removed in vacuo. The solid residue is dissolved in methanol (10 mL), diethyl ether (40 mL) is added, and the solution is cooled to 0 °C. The precipitate is filtered and dried in vacuo. The product (3.60 g, 25.79 mmol, 92%, (lit.: 90%) [39]) is obtained as a colorless solid.    The reaction mixture is stirred for 1.5 h at 0°C and is warmed then to room temperature. After complete conversion, water is added cautiously (30 mL), and the mixture is extracted with diethyl ether (3 × 50 mL). The combined organic phases are dried over Na 2 SO 4 and filtered, and the solvent is removed in vacuo. The crude product (1.32 g, 7.46 mmol, 93%, (lit.: 89%) [41]) is obtained as pale yellow oil and is sufficiently pure for further use. S31 chloride (0.14 ml, 150 mg, 0.64 mmol, 1.0 equiv) is added dropwise at 0 °C. The reaction mixture is warmed to room temperature and is stirred for 8 h at room temperature. n-Pentane is added and the mixture is stored at −27 °C for 48 h to precipitate nonconverted 8-hydroxyquinoline. The supernatant is taken off and is evaporated in vacuo. The resulting pale yellow oily residue is directly used in the Ullmann model reactions.