Tuning of Chemo- and Regioselectivities in Multicomponent Condensations of 5-Aminopyrazoles, Dimedone, and Aldehydes

Abstract

Regio- and chemoselective multicomponent protocols for the synthesis of 1,4,6,7,8,9-hexahydro-1H-pyrazolo[3,4-b]quinolin-5-ones, 5,6,7,9-tetrahydropyrazolo[5,1-b]quinazolin-8-ones, and 5a-hydroxy-4,5,5a,6,7,8-hexahydropyrazolo[4,3-c]quinolizin-9-ones starting from 5-amino-3-phenylpyrazole, cyclic 1,3-dicarbonyl compounds and aromatic aldehydes are described. Whereas the three-component coupling in ethanol under reflux conditions provides mixtures of pyrazoloquinolinones and pyrazoloquinazolinones, the condensation can be successfully tuned toward the formation pyrazoloquinolinones (Hantzsch-type dihydropyridines) by performing the reaction at 150 degrees C in the presence of triethylamine base applying sealed vessel microwave or conventional heating. On the other hand, using sonication at room temperature under neutral conditions favors the formation of the isomeric pyrazoloquinazolinones (Biginelli-type dihydropyrimidines). These products are also obtained when the three-component condensation is executed in the presence of trimethylsilylchloride as reaction mediator at high temperatures. A third reaction pathway leading to pyrazoloquinolizinones in a ring-opening/recyclization sequence can be accessed by switching from triethylamine to a more nucleophilic base such as sodium ethoxide or potassium tert-butoxide. The reaction mechanism and intermediates leading to these three distinct tricyclic condensation products are discussed.

Recent developments in aminopyrazole chemistry

“…Interest in aminopyrazole synthesis and chemistry has recently been revived. [4][5][6][7][8] The established activity of Zaleplon (1), 9 Viagra (2) 10 as well as Allopurinol (3) 11 is surely behind this interest ( Figure 1). …”

Microwave-assisted synthesis of nitrogen-containing heterocycles

“…Pyrazoloquinazolinones 279 (eight examples) were also produced (with 54-70% yield) by the same group [112] when the three-component condensation was executed in the presence of trimethylsilylchloride (Me 3 SiCl) as reaction mediator at higher temperature (170˚C) for 30 min (Scheme 76). Reaction involving the condensation of these three reactants in refluxing ethanol at 80˚C is rather unpredictable [112].…”

“…Regio-and chemoselective synthesis of 1,4,6,7,8,9-hexahydro-1H-pyrazolo [3,4- Green Chemistry Letters and Reviews 173 aromatic aldehydes 272 under MW irradiation is described by the Chebanov et al [112]. Whereas in most cases, the three-component coupling in ethanol under reflux conditions provides mixtures of both possible regioisomers pyrazoloquinolinones and pyrazoloquinazolinones in varying ratios (Scheme 75).…”

“…Reaction involving the condensation of these three reactants in refluxing ethanol at 80˚C is rather unpredictable [112].…”

Anthropogenic reaction parameters – the missing link between chemical intuition and the available chemical space

“…While the condensation reaction at reflux temperature provided the known tricyclic dihydropyridine derivative 1, sealed vessel microwave heating of the same reaction mixture to 150 °C (14 bar) favored an alternative reaction pathway that led to the hitherto unknown pyrazolo [4,3-c]quinolizinone scaffold 2. 54 While this surprising switch in selectivity is due to a simple thermal effect, 55 this example illustrates nicely that the parameter space accessible by microwave processing can sometimes lead to unexpected products, favoring reaction pathways not seen under conventional processing at lower (often reflux) temperatures. Another technique that is gaining popularity in the synthetic chemistry community is microreactor technology.…”