Continuous-Flow Hydroxylation of Aryl Iodides Promoted by Copper Tubing

Abstract

A simple and ligand-free synthesis of phenols from the corresponding aryl iodides in a continuous-flow system is described. The reaction is complete in only 4 to 20 minutes when heated between 150 to 165 °C in a reactor consisting of a commercially available copper coil. An example of trapping of the phenoxide in situ is also shown.

Key words

phenols - copper - coupling - continuous flow - hydroxylation

• References

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• 22 Phenol Synthesis; General Procedure: A solution of the aryl iodide (4.83 mmol) in a mixture of aq n-Bu₄NOH (1.5 M, 19.3 mL) and DMSO (19.3 mL, for an overall 0.125 M solution vs. aryl iodide) was prepared. The reaction solution (37 mL) was injected by using direct injection mode and the reagent stream was pumped into the 10-mL copper reactor (1.0 mm i.d.) at the desired temperature for the needed residence time, then 48 mL of the crude reaction solution was collected, acidified to pH 1 with 2 M HCl. H₂O (150 mL) was added and the mixture was extracted with Et₂O (3 × 150 mL). The combined organic layers were dried over anhydrous MgSO₄, filtered, and concentrated under vacuum. The crude mixture was purified by flash chromatography (CH₂Cl₂–hexanes gradient) to afford the desired product (see the Supporting Information for more details).
• 23 Benzyl-3-chlorophenyl Ether (3); Typical Procedure: A first solution (A) of 1-chloro-3-iodobenzene (1b; 0.50 g, 2.10 mmol) in a mixture of aq n-Bu₄NOH (1.5 M, 8.4 mL) and DMSO (8.4 mL; for an overall 0.125 M solution vs. 1-chloro-3-iodobenzene) was prepared. A second solution (B) consisting of benzyl bromide (0.62 mL, 6.30 mmol) in DMSO (8 mL) was prepared. Solution A was injected using the direct injection mode and the reagent stream was pumped into the first reactor (10 mL copper coil of 1.0 mm i.d.) at 165 °C. Then, solution B was injected by using the direct injection mode and mixed in a T-mixer with solution A after the latter had passed the first reactor. The mixture then passed the second reactor (5 mL PFA coil of 1.0 mm i.d.) at 150 °C. 23 mL of the crude reaction solution was then collected, diluted with H₂O (100 mL) and extracted with Et₂O (3 × 100 mL). The combined organic layers were dried over anhydrous MgSO₄, filtered, and concentrated under vacuum. The crude mixture was purified by flash chromatography (CH₂Cl₂–hexanes, 0–30%) to afford 3 (385 mg, 84% yield) as a yellow solid (see the Supporting Information for more details).