Regioselective synthesis of fluorine-containing indazolones from 2-acylcyclohexane-1,3-diones

Abstract

New regioisomeric indazolones containing fluorine atoms in the aromatic ring have been synthesized in high yield by the interaction of 2-acylcyclohexane-1,3-diones, and of their enol methyl ethers, obtained by methylating the initial β,β′-triketones with dimethyl sulfate in the presence of calcined potassium carbonate, with 4-fluorophenylhydrazine hydrochloride and with pentafluorophenylhydrazine. The structures of the synthesized compounds were confirmed by data of IR and 1 H, 13 C, and 19 F NMR spectra.At the present time methods of synthesizing various fluorine-containing polyfunctional heterocyclic structures as medicinal preparations are being developed vigorously [1,2]. Indazoles are an important class of organic compounds, many of which possess anti-inflammatory, analgesic, antiviral, and other physiological activitities [3,4].The aim of the present work was to obtain new fluorine-containing indazolones from various 2-acylcyclohexane-1,3-diones.Thanks to their polyfunctionality and depending on the structure of the acyl side chain and the cyclic portion of the molecule the 2-acylcyclohexane-1,3-diones are widely applied in the synthesis of steroids, prostaglandins, antibiotics, and other biologically active substances [5][6][7][8]. Chemical conversions of 2-acylcyclohexane-1,3-diones existing in the enolic form may also affect such reaction centers as the exo-and endocyclic carbonyl groups, and also the methylene groups adjacent to them [9].With the aim of synthesizing new derivatives of indazolones containing a fluorine atom in position 4 of the benzene ring or a completely fluorinated benzene ring we studied the interaction of 2-acylcyclohexane-1,3-diones 1a-e and their methyl ethers with 4-fluorophenylhydrazine and pentafluorophenylhydrazine.The interaction of 2-acylcyclohexane-1,3-diones 1a-e with a small excess of an equimolar mixture of 4-fluorophenylhydrazine hydrochloride and sodium hydroxide in ethanol for 8 h at room temperature led in high yield to the products of heterocyclization, indazolones 3a-e. The intermediate hydrazones 2a-e were not isolated. _______ * Dedicated to Distinguished Scientist Academician A. A. Akhrem in his 95 th Year.

Regioselective Construction and Screening of 1,3-Disubstituted Tetrahydroindazolones in Enantiomerically Pure Pairs

“…Most regioselective syntheses of tetrahydroindazolone derivatives are achieved by simple condensation of 2-acylcyclohexane-1,3-diones with substituted hydrazines through the different nucleophilicities of the two nitrogens on the substituted hydrazines. ,, In the case of arylhydrazines, the internal nitrogen atom is much less nucleophilic than the external one as a result of conjugation of the lone-pair electrons on the internal nitrogen in the aromatic ring system; this leads to the regioselective synthesis of 1,3-disubustituted tetrahydroindazolones. In the case of alkylhydrazines, however, regiochemical control in the synthesis of 1,3-disubstituted tetrahydroindazolones is quite difficult to achieve because the nucleophilicities of the two nitrogens on alkylhydrazines are indistinguishable.…”

“…The general procedure for regioselective synthesis of tetrahydroindazolones is a simple condensation of 2-acylcyclohexane-1,3-diones with substituted arylhydrazines. This is because of the inherent differences between the nucleophilicities of the two nitrogens in arylhydrazines, , but this is not the case with alkylhydrazines . To address this problem, we recently reported a regioselective pathway for the synthesis of complementary regioisomers of 1,2- and 1,3-disubstituted tetrahydroindazolones by the sequential protection and deprotection of substituted hydrazines .…”

NMR and computational studies on tautomerism of 3-hydroxy-2-(2-thienylcarbonyl)cyclohex-2-en-1-one

“…With the aim to block the keto-enol tautomerism of 1, this compound was methylated with dimethylsulfate (DMS) according to a methodology based on the Khlebnicova procedure [32], generating 3-methoxy-2-(thienylcarbonyl)cyclohex-2-en-1-one (2) (Fig. 8), which could allow to analyze the features of the thienyl group rotation.…”