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. 2022 Mar 18;87(6):4305-4315.
doi: 10.1021/acs.joc.1c03158. Epub 2022 Mar 7.

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

Johanna Templ  1 , Michael Schnürch  1
Affiliations

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

Johanna Templ et al. J Org Chem. .

Abstract

We describe the use of phenyl trimethylammonium iodide (PhMe3NI) as an alternative methylating agent for introducing a CH3 group in α-position to a carbonyl group. Compared to conventional methylating agents, quaternary ammonium salts have the advantages of being nonvolatile, noncancerogenic, and easy-to-handle solids. This regioselective method is characterized by ease of operational setup, use of anisole as green solvent, and yields up to 85%.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1
Figure 1
Methylation strategies using quaternary ammonium salts.
Figure 2
Figure 2
Reaction time screening; conditions: Me4NBr (1.5 equiv), KOH (2 equiv), anisole (0.2 M), 130 °C.
Scheme 1
Scheme 1. Scope of α-Methylation
1 equiv PhMe3NI. PhEt3NI (2 equiv) as ammonium salt. Reaction time 6 h, addition of KOH (2 equiv) and PhMe3NI (2 equiv) after 3 h. Addition of KOH (2 equiv) and PhMe3NI (2 equiv) after 3 h and 48 h; reaction time, 4 days. BnMe3NCl (1 equiv) as ammonium salt 3 equiv KOH, reaction time 24 h. Isolated yields are shown. Standard conditions: Substrate (100 mg, 1 equiv), PhMe3NI (2 equiv), KOH (2 equiv), in anisole (2 mL, 0.2 M) at 130 °C, 2–5 h, closed vessel, inert atmosphere.
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