Thermal Ring‐Opening of Pyrazolo[3,4‐d][1,2,3]triazin‐4‐ones: An Experimental and Theoretical Study

Abstract

Several 3‐pyrazolylcarbonyl‐pyrazolo[3,4‐d][1,2,3]triazin‐4‐ones have been prepared from 5‐amino‐1H‐pyrazole‐4‐carbonitriles through a simple sequence. In the first step, diazotization of the corresponding aminopyrazoles afforded pyrazolo[3,4‐d][1,2,3]triazin‐4‐ones. Next, thermal rearrangement of these compounds through nitrogen elimination gave the final products. The proposed mechanism for the ring‐opening of the pyrazolotriazinones to give the pyrazolylcarbonyl‐pyrazolotriazinones involves the generation of an iminoketene intermediate, which reacts with a second molecule of pyrazolotriazinone. The complete mechanism of product formation involving the iminoketene intermediate, and all other reasonable pathways, have been explored in detail through DFT calculations. Furthermore, additional experiments to corroborate the presence of the iminoketene intermediate were carried out.

Uncovering the Mechanism Leading to the Synthesis of Symmetric and Asymmetric Tröger′s Bases

“…This functional was extensively challenged by us and other authors to correctly describe complex heterocycles chemistries and yielded accurate mechanistic descriptions. For example, it has already been proved that this level of theory could give practically the same energy profiles than the much more computationally expensive MP4(DQ)/6‐311+G(d,p) for the syntheses of nitrogenated heterocycles as described recently . More specifically, for a gas‐phase process (no errors introduced by the solvent model, just the electronic structure description accuracy can be judged) the level of theory used here was very close to the CCSD(T)/6‐311+G(d,p), (maximum deviation in transition states relative energies below ca.…”

“…Also for the sake of simplicity, the rapid release of water molecules will not be described (however, all intermediates and their energies are informed in the Supporting Information, SI, Table S1). This procedure has recently been fully justified in the study of a similar heterocycle synthesis, even though in that case the solvent was not as good proton donor as in this study …”

“…This scenario would be rationalized in terms of two speed determining regions [one involving ( 1 + 1 → → … 5o ) and another of ( 5o → 5TS‐o‐p → → … product)] instead of a single determinant step. This analysis of regions or determining states instead of a single determining step would be more general and has been discussed in detail in the references , , . Besides the case of 1 + 1→ 5z , and taking into account that our group is interested in obtaining a wide variety of asymmetric Tröger′s base compounds with different substituents, the possibility of going down the Path V should still be considered in this framework.…”

“…The stationary points were characterized by their Hessian matrix diagonalized to obtain the harmonic frequencies and then the zero‐point corrections to energy, enthalpy and free energy. The procedure was described previously and tested elsewhere , . The relative free energy at normal condition used in the discussions is defined as the standard free energy of the species in question minus the standard free energy of the starting reagents, taken as reference (Δ G 0 rel = 0).…”

Synthesis and anticancer evaluation of some new pyrazolo[3,4‐d][1,2,3]triazin‐4‐ones, pyrazolo[1,5‐a]pyrimidines, and imidazo[1,2‐b]pyrazoles clubbed with carbazole

“…[ 11,12 ] Earlier studies reveal that there are numerous reported methods for elaboration of substituted pyrazolotriazine system relied on the diazotization of derivatives of 3‐aminopyrazole‐4‐carboxamide [ 13,14 ] and/or 3‐aminopyrazole‐4‐carbonitriles. [ 15,16 ] These aminopyrazoles were easily obtained either by the 1,3‐dipolar cycloaddition of nitrile imines, generated in situ from treatment of hydrazonoyl halides with a base, with active methylene nitriles [ 17 ] or from treating ketene‐N,S acetals with hydrazine hydrate. [ 12,18 ] Pyrazolotriazines are also considered as deazapurine analog, since the basic skeleton of purine and pyrazolotriazine is slightly similar.…”