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

The development of a highly selective N-methylation of pyrazole heterocycles using commercially available, bench-stable 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.