Alkyl Carbagermatranes Enable Practical Palladium-Catalyzed sp²-sp³ Cross-Coupling

Area of Science:

• Organic Chemistry
• Organometallic Chemistry
• Catalysis

Background:

• Palladium-catalyzed cross-coupling reactions are vital in synthesis.
• C(sp3)-hybridized nucleophiles present challenges due to slow transmetalation compared to C(sp2) counterparts.
• Limited progress exists for C(sp3) nucleophiles in traditional two-electron cross-coupling mechanisms.

Purpose of the Study:

• To develop novel C(sp3) nucleophiles for efficient palladium-catalyzed cross-coupling.
• To investigate the reactivity and mechanism of alkyl carbagermatranes in cross-coupling reactions.
• To explore applications in complex molecule synthesis, such as stapled peptides.

Main Methods:

• Synthesis of unique alkyl carbagermatranes.
• Development of electron-deficient phosphine ligands.
• Palladium-catalyzed cross-coupling reactions utilizing alkyl carbagermatranes.
• Mechanistic studies including stereochemical analysis.

Main Results:

• Alkyl carbagermatranes demonstrate high reactivity in cross-coupling reactions.
• Secondary alkyl carbagermatranes show comparable activity to tin analogues.
• Primary alkyl carbagermatranes exhibit high activity and stability, compatible with various reactions.
• Chiral secondary benzyl carbagermatrane coupling proceeds with full inversion, indicating an "S_E2(open) Inv" pathway.
• Base/additive-free cross-coupling of primary alkyl carbagermatranes shows excellent functional group tolerance.

Conclusions:

• Alkyl carbagermatranes are effective and versatile nucleophiles for palladium-catalyzed cross-coupling.
• The developed system overcomes previous limitations associated with C(sp3) nucleophiles.
• These findings open avenues for applications in synthesizing complex structures, including stapled peptides.