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

Johanna Templ, Edma Gjata, Filippa Getzner and Michael Schnürch*

*Institute of Applied Synthetic Chemistry, TU Wien, Getreidemarkt 9/163, 1060 Wien, Austria, Email: michael.schnuerchtuwien.ac.at

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

DOI: 10.1021/acs.orglett.2c02766


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Abstract

The quaternary ammonium salts PhMe3NI and PhEt3NI are safe, nontoxic, and easy-to-handle reagents for absolutely monoselective N-alkylations of amides and NH indoles. These convenient reactions offer high yields, high functional group tolerance, and especially excellent monoselectivity for amides. Late-stage methylations of a broad range of bioactive compounds are also described.

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late-stage methylations - see article for more examples



General procedure:

The starting material (100 mg, 1 equiv), the respective ammonium salt (PhMe3NI, PhEt3NI; 2.5 equiv), and Cs2CO3 (2 equiv) were placed in an 8 mL glass vial equipped with a magnetic stirring bar and a septum screw cap. Via a cannula, the vial was evacuated and backfilled with argon three times. Subsequently, toluene (0.23 M) was added via syringe, and the evacuation and backfilling cycles were repeated under vigorous stirring so that no boiling delay occurred. The septum screw cap was replaced with a closed Wheaton® screw cap. The inhomogeneous reaction mixture was heated to 120 °C in a metallic heating block for 11-23 h.

Work-up procedure for amides:

After the reaction was cooled to room temperature, 2 mL of deion. water were added, and the product was extracted 3 times with 10-15 mL EtOAc. The combined organic phases were washed once with brine, dried over Na2SO4, filtered, and concentrated to obtain a crude product which was further purified via hand column with unmodified silica gel.

Work-up procedure for indoles:

After the reaction was cooled to room temperature, 2 N HCl was added until gas evolution ceased (ca 2 mL). The product was extracted 3 times with 10-15 mL EtOAc, and the combined organic extracts were washed once twice with 3 mL 2 N HCl and once with brine, dried over Na2SO4, filtered and concentrated. The obtained crude product was purified via hand column using unmodified silica gel.


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

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


Key Words

alkylation of amides, indoles


ID: J54-Y2022