Synthesis and Tautomerism of Substituted Pyrazolo[4,3‐c]pyrazoles

Abstract

AbstractFused five‐membered nitrogen heterocycles comprise a very important group of compounds frequently utilized in pharmaceutical applications. In this study, we report the first systematic synthesis of substituted pyrazolo[4,3‐c]pyrazoles and three regioisomers of their N‐methyl derivatives. All compounds were fully characterized by NMR spectroscopy in solution and selected compounds also were studied by X‐ray diffraction in the solid state. 1H, 13C, and 15N NMR spectroscopic data for all isomers were interpreted by DFT calculations of nuclear shielding constants and indirect spin–spin coupling constants. The N‐methyl isomers were used in the following steps as model compounds to investigate a potential N1‐H/N4‐H, N2‐H/N4‐H, and N1‐H/N5‐H tautomerism of 3,6‐substituted pyrazolo[4,3‐c]pyrazoles by using low‐temperature NMR spectroscopy. All bases were shown to occur predominantly in the N1‐H/N4‐H tautomeric form and the structure of minor form was governed by the substituents at positions 3 and 6. Stabilities of individual tautomeric forms are calculated by DFT methods and discussed. A relationship between the tautomeric populations and the ratios among N‐methyl isomers obtained upon methylation of selected bases in solution are investigated.