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Synthesis and Tautomerism of Substituted Pyrazolo[4,3‐ c ]pyrazoles
Author(s) -
Kadam Shivaji S.,
Maier Lukáš,
Kostakis Ioannis,
Pouli Nicole,
Toušek Jaromír,
Nečas Marek,
Marakos Panagiotis,
Marek Radek
Publication year - 2013
Publication title -
european journal of organic chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.825
H-Index - 155
eISSN - 1099-0690
pISSN - 1434-193X
DOI - 10.1002/ejoc.201300606
Subject(s) - tautomer , chemistry , structural isomer , nuclear magnetic resonance spectroscopy , spectroscopy , computational chemistry , chemical shift , crystallography , stereochemistry , medicinal chemistry , physics , quantum mechanics
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.