Highly Selective -Alkylation of Pyrazoles: Crystal Structure Evidence for Attractive Interactions.

Inspired by crystal structures, we designed and achieved a catalyst-free Michael reaction for the preparation of an N1-alkyl pyrazole in a high yield (>90%) with excellent regioselectivity (N1/N2 > 99.9:1). The scope of this protocol has been extended to accomplish the first general regioselective N1-alkylation of 1-pyrazoles to give di-, tri-, and tetra-substituted pyrazoles in a single step.

Regioselective Synthesis, NMR, and Crystallographic Analysis of N1-Substituted Pyrazoles.

A systematic study of the N-substitution reactions of 3-substituted pyrazoles under basic conditions has been undertaken. Regioselective N1-alkylation, -arylation, and -heteroarylation of 3-substituted pyrazoles have been achieved using KCO-DMSO. The regioselectivity is justified by the DFT calculations at the B3LYP/6-31G**(d) level.