Negishi coupling reactions with [¹¹C]CH₃I: a versatile method for efficient ¹¹C-C bond formation

Area of Science:

• Radiochemistry
• Organic Synthesis
• Computational Chemistry

Background:

• Carbon-11 ([11C]) radiolabeling is crucial for Positron Emission Tomography (PET) imaging.
• Efficient synthesis of [11C]-labeled tracers is essential for developing new diagnostic tools.
• Negishi cross-coupling offers a versatile platform for forming carbon-carbon bonds.

Purpose of the Study:

• To establish a fast, efficient, and general one-pot method for synthesizing [11C]-labeled compounds.
• To demonstrate the utility of this method by synthesizing [11C]thymidine.
• To investigate the reaction mechanism using theoretical calculations.

Main Methods:

• One-pot synthesis of [11C]-labeled compounds via Negishi cross-coupling.
• In situ generation of [11C]CH3ZnI.
• Reaction of [11C]CH3ZnI with aryl halides or triflates.
• Synthesis of [11C]thymidine.
• Density Functional Theory (DFT) calculations.

Main Results:

• A fast, efficient, and general one-pot method for [11C]-labeling was developed.
• The method successfully synthesized [11C]thymidine.
• Theoretical calculations confirmed the irreversible formation of a tetracoordinated nucleophilic 11C-Zn(ii) reagent.
• Electronic requirements for efficient Negishi coupling were elucidated.

Conclusions:

• The developed one-pot Negishi cross-coupling method is highly effective for [11C]-labeling.
• [11C]thymidine synthesis showcases the method's applicability for biologically relevant compounds.
• Understanding the reaction mechanism aids in optimizing future radiolabeling strategies.