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. 2021 Sep 17;23(18):7059-7063.
doi: 10.1021/acs.orglett.1c02458. Epub 2021 Aug 31.

Deaminative Reductive Methylation of Alkylpyridinium Salts

Olivia P Bercher  1 , Shane Plunkett  1 , Thomas E Mortimer  1 , Mary P Watson  1
Affiliations

Deaminative Reductive Methylation of Alkylpyridinium Salts

Olivia P Bercher et al. Org Lett. .

Abstract

Methyl groups can imbue valuable properties in organic molecules, often leading to enhanced bioactivity. To enable efficient installation of methyl groups on simple building blocks and in late-stage functionalization, a nickel-catalyzed reductive coupling of secondary Katritzky alkylpyridinium salts with methyl iodide was developed. When coupled with formation of the pyridinium salt from an alkyl amine, this method allows amino groups to be readily transformed to methyl groups with broad functional group and heterocycle tolerance.

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Figures

Scheme 1.
Scheme 1.
C(sp3) Methylation
Scheme 2.
Scheme 2.
Scope of Methylationa a Conditions: alkylpyridinium salt (1.0 mmol, 1.0 equiv), NiBr2(1-bpp) (10 mol %), Mn (2.0 equiv), CH3I (1.2 equiv), DMA (5 mL), rt, 1 h. Average yield of duplicate experiments (±8%), unless noted otherwise. b Single experiment. c 24 h. d Diastereomeric ratio (dr) of crude reaction mixture determined by 1H NMR. e Glassware was not dried. f Minimal precautions to protect from air and moisture. See Supporting Information.
Scheme 3.
Scheme 3.
Late-stage Methylation of Pharmaceutically Relevant Compounds
Scheme 4.
Scheme 4.
Mechanistic Experiments
See this image and copyright information in PMC

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