Synthesis of Pyrazolo-Fused 4-Azafluorenones in an Ionic Liquid. Mechanistic Insights by Joint Studies Using DFT Analysis and Mass Spectrometry

Abstract

A series of pyrazolo-fused 4-azafluorenones (indeno[1,2-b]pyrazolo[4,3-e]pyridines, IPP) were synthesized via the three-component reaction between arylaldehydes, 3-methyl-1H-pyrazol-5-amine and 1,3-indanedione in an ionic liquid as a catalyst at room temperature. The applied synthetic route has the advantages of easy work-up under mild reaction conditions presenting moderate yields and an environmentally benign procedure. A theoretical study based on conceptual-density functional theory has been done, bond reactivity indices have been calculated and an electrophilic and nucleophilic character of localized orbitals has been determined to analyze the possible electronic mechanisms.

Indane-1,3-Dione: From Synthetic Strategies to Applications

“…Even though these metal catalysts were highly efficient, it is always desirable not to use catalysts or to use catalysts that can operate in homogeneous phase. In this field, several examples of ionic liquids (ILs) have been proposed as green and reusable catalysts (see Scheme 33, molecules 220 and 221) [237,238]. Ionic liquids have been proposed as an interesting alternative to the traditional catalysts in a variety of chemical reactions, as these molecules are often less pollutant than metals and can also act both as solvents and catalysts [239][240][241][242].…”

“…A few years later, another interesting example was proposed with 1-hexyl-3-methyl-imidazolium iodide [HMIM]I as the ionic liquid. It may be mentioned that in this case, the reaction could be performed in water with high reaction yields (up to 95%) while using sonication as the activation mode [238]. Sonochemistry is not widely used in organic chemistry to activate a large variety of organic reactions due to its appealing features: shorter reaction times, higher reaction yields, less byproduct formed, milder reaction conditions.…”

How and Why to Investigate Multicomponent Reactions Mechanisms? A Critical Review

“…Schneider and co-workers [94] have developed a MCR that gives efficient access to [ Gutierrez and co-workers also described a three component reaction to synthesize indeno[1,2-b]-pyrazolo[4,3-e]pyridine (IPP) derivatives catalyzed by a simple imidazolium-based ionic liquid (Scheme 17) and evaluated its mechanism by ESI-MS(/MS). [95] The 1,3-dicarbonyl reagent was proposed to be activated by the noncovalent intermolecular C 2 À HÀ O=C interaction between the imidazolium-based catalyst and the 1,3-dicarbonyl reagent, thus favoring the Knoevenagel condensation with the aldehyde. The acidic hydrogen at the C2À H position of the ionic liquid (imidazolium moiety) structure was shown to have indeed a fundamental role during the catalytic cycle (Scheme 17).…”

“…[74] The positive ionic liquid effect over MCRs was also already documented elsewhere [97] and this combination has been described as "a perfect synergy". For the ESI-MS(/MS) study, [95] it was proved that the imidazolium-based catalyst had a vital role toward the C=O activation in at least two determinant steps (Scheme 17). A supramolecular aggregate formed with the imidazolium derivative and the 1,3dicarbonyl, which was also characterized via the MS experiments, was also proposed.…”

“…Gutierrez and co‐workers also described a three component reaction to synthesize indeno[1,2‐ b ]‐pyrazolo[4,3‐ e ]pyridine (IPP) derivatives catalyzed by a simple imidazolium‐based ionic liquid (Scheme 17) and evaluated its mechanism by ESI‐MS(/MS) [95] . The 1,3‐dicarbonyl reagent was proposed to be activated by the noncovalent intermolecular C 2 −H−O=C interaction between the imidazolium‐based catalyst and the 1,3‐dicarbonyl reagent, thus favoring the Knoevenagel condensation with the aldehyde.…”