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

Abstract Fused 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. 1 H, 13 C, and 15 N 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 N 1‐H/ N 4‐H, N 2‐H/ N 4‐H, and N 1‐H/ N 5‐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 N 1‐H/ N 4‐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.