Highly Selective N -Alkylation of Pyrazoles: Crystal Structure Evidence for Attractive Interactions.
Natalie J NormanSi Tong BaoLynne CurtsTiffani HuiShao Liang ZhengTiffany ShouAna ZeghibeIzzy BurdickHannah FuehrerAdrian HuangPublished in: The Journal of organic chemistry (2022)
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 H -pyrazoles to give di-, tri-, and tetra-substituted pyrazoles in a single step. The resulting pyrazoles bear versatile functional groups such as bromo, ester, nitro, and nitrile, offering opportunities for late-stage functionalization. This efficient methodology will have an impact on drug discovery, as several Food and Drug Administration-approved drugs are pyrazole derivatives. A working hypothesis for the regioselectivity is proposed. X-ray crystal structures of the products that highlight the attractive interactions are discussed. This report provides a rare source for the further elucidation of the attractive interactions because the isomeric ratios and the crystal structures are directly related.
Keyphrases
- drug administration
- drug discovery
- crystal structure
- molecular docking
- ionic liquid
- randomized controlled trial
- high resolution
- room temperature
- biofilm formation
- computed tomography
- dual energy
- gold nanoparticles
- mass spectrometry
- pseudomonas aeruginosa
- climate change
- escherichia coli
- carbon dioxide
- candida albicans
- highly efficient
- molecularly imprinted
- electron transfer