Benzylic Aroylation of Toluenes Mediated by a LiN(SiMe3)2/Cs+ System

Chemoselective deprotonative functionalization of benzylic C-H bonds is challenging, because the arene ring contains multiple aromatic C(sp(2))-H bonds, which can be competitively deprotonated and lead to selectivity issues. Recently it was found that bimetallic [MN(SiMe3)(2) M = Li, Na]/Cs+ combinations exhibit excellent benzylic selectivity. Herein, is reported the first deprotonative addition of toluenes to Weinreb amides mediated by LiN(SiMe3)(2)/CsF for the synthesis of a diverse array of 2-arylacetophenones. Surprisingly, simple methyl benzoates also react with toluenes under similar conditions to form 2-arylacetophenones without double addition to give tertiary alcohol products. This finding greatly increases the practicality and impact of this chemistry. Some challenging substrates with respect to benzylic deprotonations, such as fluoro and methoxy substituted toluenes, are selectively transformed to 2-aryl acetophenones. The value of benzylic deprotonation of 3-fluorotoluene is demonstrated by the synthesis of a key intermediate in the preparation of Polmacoxib.

Automated summary

The chemoselective deprotonative functionalization of benzylic C-H bonds using LiN(SiMe3)(2)/CsF combination has been found to exhibit excellent benzylic selectivity, leading to the synthesis of a diverse array of 2-arylacetophenones. Surprisingly, even simple substrates like methyl benzoates can react under similar conditions to form the desired products with high selectivity.