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Benzylic aroylation of toluenes with unactivated tertiary benzamides promoted by directed ortho-lithiation

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Abstract

The deprotonative functionalization of toluenes, for their weak acidity, generally needs strong bases, thus leading to the requirement of harsh conditions and the generation of by-products. Direct nucleophilic acyl substitution reaction of amides with organometallic reagents could provide an ideal solution for ketone synthesis. However, the inert amides and highly reactive organometallic reagents bring great challenges for an efficient and selective synthetic approach. Herein, we reported an lithium diisopropylamide (LDA)-promoted benzylic aroylation of toluenes with unactivated tertiary benzamides, providing a direct and efficient synthesis of various aryl benzyl ketones. This process features a kinetic deprotonative functionalization of toluenes with a readily available base LDA. Mechanism studies revealed that the directed ortho-lithiation of the tertiary benzamide with LDA promoted the benzylic kinetic deprotonation of toluene and triggered the nucleophilic acyl substitution reaction with the amide.

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Acknowledgements

We gratefully acknowledge the support from the Fudan University. We thank Prof. Bi-Jie Li (Tsinghua Univ.) and Prof. Qian Peng (Nankai Univ.) for their helpful discussions. This work was supported by the Natural Science Foundation of Tianjin (19JCYBJC20100).

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Authors and Affiliations

  1. College of Chemistry, Nankai University, Tianjin, 300071, China

    Can-Can Bao, Yan-Long Luo & Hui-Zhen Du

  2. Department of Chemistry, Fudan University, Shanghai, 200438, China

    Bing-Tao Guan

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  1. Can-Can Bao
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  2. Yan-Long Luo
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Correspondence to Bing-Tao Guan.

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Bao, CC., Luo, YL., Du, HZ. et al. Benzylic aroylation of toluenes with unactivated tertiary benzamides promoted by directed ortho-lithiation. Sci. China Chem. 64, 1349–1354 (2021). https://doi.org/10.1007/s11426-021-1035-5

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