Iodine catalyzed one-pot five-component reactions for direct synthesis of densely functionalized piperidines

2-Phenyl-pyrido[1,2-a]pyrimidin-4-one derivatives bearing a phenol or a catechol moiety in position 2 were tested as aldose reductase (ALR2) inhibitors and exhibited activity levels in the micromolar/submicromolar range. Introduction of a hydroxy group in position 6 or 9 gave an enhancement of the inhibitory potency (compare 18, 19, 28, and 29 vs 13 and 14). Lengthening of the 2-side chain to benzyl determined a general reduction in activity. The lack or the methylation of the phenol or catechol hydroxyls gave inactive (10-12, 21, 22, 25-27) or scarcely active (15, 17, 20) compounds, thus demonstrating that the phenol or catechol hydroxyls are involved in the enzyme pharmacophoric recognition. Moreover, all the pyridopyrimidinones displayed significant antioxidant properties, with the best activity shown by the catechol derivatives. The theoretical binding mode of the most active compounds obtained by docking simulations into the ALR2 crystal structure was fully consistent with the structure-activity relationships in the pyrido[1,2-a]pyrimidin-4-one series.

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Pyrido[1,2-a]pyrimidin-4-one derivatives as a novel class of selective aldose reductase inhibitors exhibiting antioxidant activity.

Publisher Summary This chapter focuses on the synthesis and applications of Pyrazol-3-ones. The chapter also highlights the reactions of the ring atoms of pyrazol-3-ones. It explores the reactivity of the ring substituents of pyrazol-3-ones. This chapter illustrates that the majority of pyrazol-3-ones have been synthesized from open chain precursors, and relatively few from5-,6-, 5,6-, 6,6-and 5,6,7-membered rings. Due to the growing use of combinatorial chemistry in various applications, use of polymer-supported methodologies have increased. The oxidation potentials as well as the hydroxyl radical scavenging activities for some pyrazol-3-ones have been detected and compared with edavarone's. The Schiff base 4-[(4-hydroxy-3-hydroxymethylbenzylidene) amino]-1,5-dimethyl-2-phenyl-1,2 dihydropyrazol-3-one retards the corrosion of steel. The chapter concludes that certain azopyrazol-3-ones may prove useful as labels for chromatographic analysis of carbohydrates.

Chapter 2 Pyrazol-3-ones. Part IV: Synthesis and Applications

Facile synthesis of C-terminal thioesters is integral to native chemical ligation (NCL) strategies for chemical protein synthesis. We introduce a new method of mild peptide activation, which leverages solid-phase peptide synthesis (SPPS) on an established resin linker and classical heterocyclic chemistry to convert C-terminal peptide hydrazides into their corresponding thioesters via an acyl pyrazole intermediate. Peptide hydrazides, synthesized on established trityl chloride resins, can be activated in solution with stoichiometric acetyl acetone (acac), readily proceed to the peptide acyl pyrazoles. Acyl pyrazoles are mild acylating agents and are efficiently exchanged with an aryl thiol, which can then be directly utilized in NCL. The mild, chemoselective, and stoichiometric activating conditions allow this method to be utilized through multiple sequential ligations without intermediate purification steps.

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Leveraging the Knorr Pyrazole Synthesis for the Facile Generation of Thioester Surrogates for use in Native Chemical Ligation

A fluorescence “turn-off” probe has been designed and successfully applied to detect cyanide (CN–) based on a Michael-type nucleophilic addition reaction and intramolecular charge transfer (ICT) mechanism. For this research, a family of 3-aryl-4-(2,2-dicyanovinyl)-1-(2-pyridinyl)pyrazoles as donor-π-acceptor (D-π-A) systems have been synthesized in 58–66% overall yield, by a three-step synthesis sequence starting from p-substituted acetophenones. The substituted p-methoxyphenyl showed good fluorescence emission and large Stokes shifts in different solvents due to its greater ICT. Likewise, this probe evidenced high selectivity and sensitivity and fast recognition for CN– with a detection limit of 6.8 μM. HRMS analysis, 1H NMR titration experiments, and TD-DFT calculations were performed to confirm the mechanism of detection and fluorescence properties of the chemodosimeter of CN–. Additionally, fluorescent test paper was conveniently used to detect cyanide in aqueous solution.

Synthesis of Dicyanovinyl-Substituted 1-(2-Pyridyl)pyrazoles: Design of a Fluorescent Chemosensor for Selective Recognition of Cyanide

5-Azido-3-benzyl-4-formyl-1-phenylpyrazoles 1a−c extrude dinitrogen upon heating in toluene to give the corresponding nitrenes, which immediately rearrange via a new ring-opening ring-closure react...

Joergen Brodersen

Papers

A Pyrazole to Furan Rearrangement. Thermolysis of 5-Azido-4-formylpyrazoles.

A Pyrazole to Furan Rearrangement. Thermolysis of 5‐Azido‐4‐formylpyrazoles.