4.8 Article

Overcoming peri- and ortho-selectivity in C-H methylation of 1-naphthaldehydes by a tunable transient ligand strategy

期刊

CHEMICAL SCIENCE
卷 13, 期 10, 页码 2900-2908

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ROYAL SOC CHEMISTRY
DOI: 10.1039/d1sc05899a

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资金

  1. National Natural Science Foundation of China [21877062]
  2. ShuangChuang research team of Jiangsu Province [20182036]
  3. Innovative and Entrepreneurial Talent program

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Methyl groups are commonly found in bioactive molecules, and site-specific methylation has become an important strategy for their structural functionalization. In this study, a highly regioselective peri- and ortho-C-H methylation of 1-naphthaldehyde was achieved using a transient ligand strategy, leading to the synthesis of various methyl-substituted naphthalene frameworks. The mechanism of peri-methylation and ortho-methylation was investigated, providing insights into the control factors and energetically favorable pathways.
Methyl groups widely exist in bioactive molecules, and site-specific methylation has become a valuable strategy for their structural functionalization. Aiming to introduce this smallest alkyl handle, a highly regioselective peri- and ortho-C-H methylation of 1-naphthaldehyde by using a transient ligand strategy has been developed. A series of methyl-substituted naphthalene frameworks have been prepared in moderate to excellent yields. Mechanistic studies demonstrate that peri-methylation is controlled by the higher electronic density of the peri-position of 1-naphthaldehyde as well as the formation of intermediary 5,6-fused bicyclic palladacycles, whereas experimental studies and theoretical calculations inferred that a 5-membered iridacycle at the ortho-position of 1-naphthaldehyde leads to energetically favorable ortho-methylation via an interconversion between the peri-iridacycle and ortho-iridacycle. Importantly, to demonstrate the synthetic utility of this method, we show that this strategy can serve as a platform for the synthesis of multi-substituted naphthalene-based bioactive molecules and natural products.

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