Oxidative Nitrogen Insertion into Silyl Enol Ether C═C Bonds

Area of Science:

• Organic Chemistry
• Synthetic Methodology
• Reaction Discovery

Background:

• Silyl enol ethers are versatile nucleophilic building blocks in organic synthesis.
• Developing novel methods for nitrogen insertion into organic frameworks remains a key challenge.
• Existing methods often lack regioselectivity or require harsh conditions.

Purpose of the Study:

• To introduce a novel reactivity of silyl enol ethers involving nitrogen atom insertion.
• To develop a facile and efficient method for synthesizing alpha-amido alkylating agents.
• To enable late-stage functionalization and modification of complex organic molecules.

Main Methods:

• Utilizing an in situ-generated iodonitrene-like species to react with silyl enol ethers.
• Investigating the mechanism of nitrogen insertion and C=C bond cleavage.
• Correlating reaction efficiency with the nucleophilicity of silyl enol ethers using the Mayr N scale.

Main Results:

• A new transformation that inserts a nitrogen atom between the olefinic carbons of silyl enol ethers.
• Conversion of C-nucleophilic silyl enol ethers to C-electrophilic N-acyl-N,O-acetals.
• Demonstrated modular derivatization of the resulting acetals with various nucleophiles.
• Successful late-stage nitrogen insertion into natural product skeletons with high regioselectivity.

Conclusions:

• This work presents an unprecedented method for accessing alpha-amido alkylating agents.
• The developed methodology offers a powerful tool for late-stage carbon framework editing.
• The reaction is efficient and its scope is predictable based on enol ether nucleophilicity.
• Applications include selective 15N labeling of amides and lactams.