Lecture Notes: Alternative Synthetic Routes to Cubane

Introduction

• Focus on alternative methods for synthesizing cubane.
• Avoids the classical UV [2+2] cycloaddition as used in the Eaton route.

1. Sensitized Thermal Cycloaddition

Triplet Energy Transfer Approach

• Goal: Replace UV excitation with visible-light sensitization and thermal activation.
• Process:
  • Start with Eaton's endo-diene ketal precursor.
  • Add a triplet sensitizer (e.g., Ir(ppy)_3).
  • Irradiate with blue LED light (~450 nm) at room temperature.
  • Allow thermal cyclization via a stepwise diradical mechanism.
  • Monitor formation of cage-like isomer 4 by NMR or GC-MS.
  • Proceed with Favorskii rearrangement.
• Note: Exclude oxygen to prevent quenching._

2. Electrochemical or Photoredox Cycloaddition

Electrochemical Synthesis

• Goal: Induce [2+2] via electrochemical or visible-light-driven radical cation mechanisms.
• Process:
  • Dissolve endo-diene in anhydrous acetonitrile with Bu4NBF4.
  • Apply constant current electrolysis in a divided cell with platinum electrodes.
  • Anodic oxidation forms a radical cation, leading to isomer 4 through cyclization.

Photoredox Variant

• Add photocatalyst (e.g., Ir[dF(CF3)ppy]_2(dtbbpy)PF6).
• Irradiate with visible light under inert atmosphere.
• Oxidize alkene to radical cation, initiate intramolecular closure.
• Note: Suitable for scale-up via flow electrolysis or using photoreactors._

3. Transition-Metal-Catalyzed [2+2] Cycloaddition

• Goal: Use metals like Ni(0), Ti(II), or Fe(II) for catalysis.
• Process:
  • Use endo-diene with directing group.
  • Add Ni(COD)_2 with phosphine ligand (e.g., PPh3).
  • Stir at room temperature or gently heat under inert gas.
  • Nickel mediates formation of metallacyclobutane, reductively eliminating to yield isomer 4.
  • Proceed to cubane via Favorskii rearrangement.
• Note: Requires optimization to prevent over-reaction._

4. Radical Cascade or Coupling Strategy

• Goal: Use intramolecular radical reactions for CC bond formation in cubane.
• Example Process:
  • Design dihalogenated intermediate with tethered alkene and radical initiator site.
  • Treat with Bu3SnH/AIBN or photoredox catalyst.
  • Generate radical, add to tethered alkene.
  • Terminate via H-abstraction or radical rebound, forming cage structure.
  • Proceed to oxidation or rearrangement.
• Note: Compatibility with radical chemistry confirmed by Barton photochemical steps.

5. Rearrangement-Based Cubane Formation

• Goal: Build a cuneane precursor and rearrange it to cubane.
• Process:
  • Synthesize cuneane derivative via Diels-Alder or similar method.
  • Functionalize to direct rearrangement.
  • Heat with Lewis acid or irradiate to trigger bond shift.
  • Drive rearrangement thermodynamically or through small group elimination.
  • Isolate cubane and functionalize.
• Note: Reverse of known cubane-cuneane rearrangements, challenges exist but feasible with computational assistance.

Conclusion

• Alternative routes provide safer, modern, and scalable lab conditions.
• Each method requires further optimization based on equipment and materials.