[2,3]-Sigmatropic rearrangement with [1.1.1]propellane

Area of Science:

• Organic Chemistry
• Synthetic Methodology
• Carbene Chemistry

Background:

• Established [1.1.1]propellane reactivity involves addition reactions at the bridge C-C bond.
• Formation of bicyclo[1.1.1]pentane derivatives is a known outcome.
• Limited methods exist for utilizing [1.1.1]propellane as a carbene precursor.

Purpose of the Study:

• To develop a novel [2,3]-sigmatropic rearrangement using [1.1.1]propellane.
• To access allenylated or allylated methylenecyclobutanes.
• To explore subsequent applications in synthesizing substituted bicyclo[2.1.1]hexanes.

Main Methods:

• [2,3]-sigmatropic rearrangement of [1.1.1]propellane with propargyl and allyl sulfides/selenides.
• Photocatalyzed radical cascade cyclization for bicyclo[2.1.1]hexane synthesis.
• Density functional theory (DFT) calculations to elucidate reaction mechanism.

Main Results:

• Efficient and scalable synthesis of allenylated/allylated methylenecyclobutanes.
• Reaction proceeds under mild conditions with broad functional group tolerance.
• Successful synthesis of substituted bicyclo[2.1.1]hexanes, potential benzene bioisosteres.
• DFT calculations indicate a copper-bound five-membered transition state.

Conclusions:

• A new synthetic route utilizing [1.1.1]propellane as a carbene precursor has been established.
• The method provides access to valuable methylenecyclobutane and bicyclo[2.1.1]hexane scaffolds.
• The developed bicyclo[2.1.1]hexane derivatives are promising bioisosteres for drug discovery.