The introduction of light molecular weight aliphatic substituents into biologically active molecules can lead to significant changes to their biological properties. This property is illustrated in the literature by the introduction of the smallest substituent - methyl. At the moment this phenomena even is named "Magic Methyl", and a number of reviews is published on this issue. There are two available strategies for the solving this problem, i.e. introduction of an alkyl substituent into a biomolecule. Introduction at the final stage (late stage functionalization) or insertion at the stage of synthesis of a building block.<br/>We have chosen a synthetic pathway based on the sequence of reactions: the introduction of dialkylamino acetal - selective hydrogenation, which can combine both strategies (scheme 1). Despite the apparent simplicity of the approach, there is only one example of such "methylation" of acetophenones using DMADMF as a source of "methyl" in the literature. In this example, only acetophenones were used, and the reducing step was non-selective and very problematic.<br/>In this report, the synthetic methodology for 2 steps selective methylation is described. The evaluation of its for both building blocks formation and the late stage functionalization is shown. The scope and limitation of the methodology are determined. And the perspective of the using of this method for introduction other alkyls are discussed.

Selective methylation of α-methylene ketones

2019 Fall National Meeting

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