Convenient Procedure for the α-Methylation of Simple Pyridines

Abstract

A convenient and straightforward laboratory procedure is presented for a highly selective mono-α-methylation of pyridines without reactive functional groups. The methylating agent is probably carbon monoxide/dihydrogen generated in situ from a high-boiling alcohol on a metal surface. The reaction is catalyzed by a Raney nickel catalyst at ambient pressure, which renders the protocol practicable in standard organic laboratories. The intrinsically high reaction temperature and long reaction times restrict the application to pyridine derivatives with less reactive substituents. The outcome of the reaction can be rationalized by the assumption of a simple heterogeneous mechanism.

Keywords:

• Electrophilic substitution
• α-methylation
• pyridines
• Raney nickel catalyst

ACKNOWLEDGMENTS

Support for this work by the Deutsche Forschungsgemeinschaft (DFG) is gratefully acknowledged. We thank Holger Pletsch and Jens Stellhorn for helpful assistance in the laboratory. We express our gratitude to Prof. Dr. Gerhard Hilt for help performing the GC-MS analyses.

Notes

Note. Conditions are described in “Procedure for Screening Experiments” except for entry 2 “Preparation of 2-Methylpyridine,” entry 4 (“Procedure for Screening Experiments”), and entry 5 (“Procedure for Screening Experiments”: 0.4 eq nickel, 2.4 ml/mmol solvent).

Note. Conditions are described in “Procedure for Screening Experiments.”