N1-Selective Methylation of Pyrazoles via α?Halomethylsilanes as Masked Methylating Reagents

Emma Yang and Derek M. Dalton

Department of Small Molecule Process Chemistry, Genentech, Inc., South San Francisco, United States;

—J. Org. Chem., 2024, 89, 4221?4224.

Recommended by Bing Han_MC3

ABSTRACT: The development of a highly selective N-methylation of pyrazole heterocycles using commercially available, benchstable α-halomethylsilanes as masked methylating reagents is described. Sterically bulky α-halomethylsilanes significantly improve the selectivity of N-alkylation over traditional methylating reagents and readily undergo protodesilylation in the presence of a fluoride source and water to give N-methyl pyrazoles. Selectivities of 92:8 to >99:1 N1/N2 regioisomeric ratios were achieved with a range of pyrazole substrates in good yields.

N-alkylation of pyrazoles with methyl iodide and α-halomethylsilanes

Optimization of reaction conditions

Reaction profile of N-alkylation and protodesilylation of pyrazole 1a

Summary and Comments

Derek M. Daltona and co-workers reported sterically bulky α-halomethylsilanes significantly improve the selectivity of N-alkylation over traditional methylating reagents and readily undergo protodesilylation in the presence of an aqueous fluoride source. Selectivities of 92:8 to >99:1 N1/N2 were achieved with a range of pyrazole substrates in good yields. The N-alkylation proceeded to completion within 2h despite the steric bulk of the α-halomethylsilane. Similarly, protodesilylationproceeded smoothly and finished in a similar time frame.