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Selective α-Methylation of Aryl Ketones Using Quaternary Ammonium Salts as Solid Methylating Agents

Johanna Templ and Michael Schnürch*

*Institute of Applied Synthetic Chemistry, TU Wien, Getreidemarkt 9/163, 1060 Wien, Austria, Email:

J. Templ, M. Schnürch, J. Org. Chem., 2022, 87, 4305-4315.

DOI: 10.1021/acs.joc.1c03158

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The use of phenyl trimethylammonium iodide (PhMe3NI) as an alternative methylating agent enables a regioselective introduction of a CH3 group in α-position to a carbonyl group in good yields. Quaternary ammonium salts have the advantages of being nonvolatile, noncancerogenic, and easy-to-handle solids.

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Substrate Scope Methylation

General Procedure C: An 8 mL glass vial equipped with a magnetic stirring bar was charged with the respective diaryl ethanone (100 mg, 1 equiv.), trimethylphenyl ammonium iodide (2 equiv.), and KOH (2 equiv.). The vial was sealed with a septum screw cap. Using a cannula, the vial was evacuated and backfilled with argon three times. Anisole (2 mL, 0.2 M) was added via syringe. Evacuation and backfilling with argon were repeated three times under vigorous stirring that no boiling delay occurred. Subsequently, the septum screw cap was exchanged for a closed Wheaton® cap, and the vial was sealed tightly. The resulting inhomogeneous mixture was heated to 130 °C in a metallic heating block for 2-5 h. After complete consumption of the starting material (TLC analysis), the reaction was cooled to room temperature. 2 mL of 2 N HCl were added, and the mixture was extracted 3 times with EtOAc (5 mL each). The combined organic phases were washed twice with 2 N HCl (1 mL each) and once with brine, dried over anhydrous Na2SO4, filtered, and concentrated. The obtained crude product was purified via hand column with unmodified silica gel using a mixture of LP and EtOAc as eluent.

Monoselective N-Methylation of Amides, Indoles, and Related Structures Using Quaternary Ammonium Salts as Solid Methylating Agents

J. Templ, E. Gjata, F. Getzner, M. Schnürch, Org. Lett., 2022, 24, 7315-7319.

Key Words

alkylation of carbonyl compounds

ID: J42-Y2022