Transformations of conjugated enamines of the imidazolidine 1-oxide series in the Vilsmeier-Haack reaction

In some cases, the reactions of enaminones of the imidazolidine 1-oxide series with the Vilsmeier reagent afford electrophilic substitution products containing the dimethyl-aminomethylene group. In an acidic medium, these products undergo either hydrolytic elimination of the dimethylaminomethylene moiety or hydrolysis of the latter to form the aldehyde group. The reaction of nitroenamine, which is a derivative of imidazolidine 1-oxide, with the Vilsmeier reagent produces furoxane, viz., the nitroxyl biradical. Reduction of the latter affords the dioxime biradical. Dedicated to the memory of Academician N. N. Vorozhtsov on the 100th anniversary of his birth. Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 6, pp. 1165–1170, June, 2007.     

Convenient synthesis of novel sulfonamide derivatives as promising anticancer agents

Novel sulfonamide derivatives have been synthesized from the readily accessible N-(4-acetylphenyl)benzenesulfonamide (1) . Condensation of 1 with phenylhydrazine in refluxing ethyl alcohol gave the corresponding phenylhydrazone 2 , which was then added to the Vilsmeier-Haack reagent (POCl₃/DMF) to give the 4-formylpyrazole derivative 3 . Fusion of 1 with thiourea in the presence of iodine at 130°C afforded the 2-aminothiazole derivative 4 . Refluxing 1 with an excess of N, N-dimethylformamide dimethyl acetal furnished the enaminone 5 . The chemical reactivity of enaminone 5 toward some nitrogen and carbon nucleophiles has been studied to obtain polyfunctionalized heteroaromatic systems bearing a sulfonamide moiety. Besides, the enaminone 5 undergoes the Gewald reaction and reacts with ethyl cyanoacetate and elemental sulfur in the presence of morpholine to yield the 2-aminothiophene derivative 18 . Moreover, the utility of 5 for the synthesis of 4-(phenylsulfonamido)benzoic acid (19) was investigated. The synthesized sulfonamides were evaluated for their in vitro cytotoxic activities against two human cell lines, MCF-7 (breast adenocarcinoma cells) and RPE-1 (normal retina pigmented epithelium cells). The results revealed that compounds 1-3 , 6-8 , 10 , 12b , 18 , 19 , and 21 have a potent cytotoxic effect on MCF-7 and less on RPE-1 cells compared to the positive control doxorubicin®.     

Condensation of nitriles of polyhalogenated carboxylic acids and benzonitrile with 2-hydroxy-4,6-dimethylacetophenone

Condensation of 2-hydroxy-4,6-dimethylacetophenone with trifluoro- and trichloroacetonitriles gives 2-amino-5,7-dimethyl-2-trifluoro(trichloro)methyl-4-chromanones. The condensation with 2,2,3,3-tetrafluoropropionitrile, perfluorovaleronitrile, and benzonitrile stops at the stage of formation of the corresponding enamines. Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 2, pp. 362–363, February, 1998.     

An experimental and computational investigation on the fragmentation behavior of enaminones in electrospray ionization mass spectrometry

The dissociation pathways of protonated enaminones with different substituents were investigated by electrospray ionization tandem mass spectrometry (ESI‐MS/MS) in positive ion mode. In mass spectrometry of the enaminones, Ar? CO? CH?CH? N(CH₃)₂, the proton transfers from the thermodynamically favored site at the carbonyl oxygen to the dissociative protonation site at ipso‐position of the phenyl ring or the double bond carbon atom adjacent to the carbonyl leading to the loss of a benzene or elimination of C₄H₉N, respectively. And the hydrogen? deuterium (H/D) exchange between the added proton and the proton of the phenyl ring via a 1,4‐H shift followed by hydrogen ring‐walk was witnessed by the D‐labeling experiments. The elemental compositions of all the ions were confirmed by ultrahigh resolution Fourier transform ion cyclotron resonance tandem mass spectrometry (FTICR‐MS/MS). The enaminones studied here were para‐monosubstituted on the phenyl ring and the electron‐donating groups were in favor of losing the benzene, whereas the electron‐attracting groups strongly favored the competing proton transfer reaction leading to the loss of C₄H₉N to form a benzoyl cation, Ar‐CO⁺. The abundance ratios of the two competitive product ions were relatively well‐correlated with the σ_p⁺ substituent constants. The mechanisms of these reactions were further investigated by density functional theory (DFT) calculations. Copyright © 2010 John Wiley & Sons, Ltd.     

Ni(OAc)2: a highly efficient catalyst for the synthesis of enaminone and enamino ester derivatives under solvent‐free conditions

Ni(OAc)₂ was found to be an efficient catalyst for the synthesis of β‐enamino ketones or esters from β‐dicarbonyl compounds and amines under solvent‐free conditions. The reusability of the catalyst was successfully examined without noticeable loss of its catalytic activity. Copyright © 2010 John Wiley & Sons, Ltd.     

Divergent and Chemoselective Transformations of Thioamides with Designed Carbene Equivalents

The reactions of thioamides with ortho-nitro-substituted iodonium ylides proceeded under mild conditions to give enaminones or thiazoles, depending on the iodonium ylide used. This protocol allowed the use of protic solvents, including aqueous solutions, and therefore coupling reactions with complex molecules such as peptides or steroids were possible. A mild and efficient method for the synthesis of various iodonium ylides was established. DFT calculations suggested that the halogen bonding between a thioamide and iodonium ylide was important in this chemoselective coupling reaction. The potential use of enaminones conjugated with pharmaceuticals as prodrugs was also demonstrated.     

Total Synthesis of Isodaphlongamine H: A Possible Biogenetic Conundrum

Herein we describe the first synthetic efforts toward the total synthesis of isodaphlongamine H, a calyciphylline B‐type alkaloid. The strategy employs a chemoenzymatic process for the preparation of a functionalized cyclopentanol with a quaternary center. This molecule is elaborated to form an enantiopure 1‐aza‐perhydrocyclopentalene core, representing rings A and E of all calyciphylline B‐type alkaloids. Further transformations involve the formation of a cyclic enaminone, 1,4‐conjugate addition with a cyclopentenyl subunit, and intramolecular aldol cyclization to achieve a pentacyclic intermediate, ultimately forming isodaphlongamine H in a total of 24 steps from the commercially available compound 2‐carbethoxycyclopentanone. Isodaphlongamine H exhibits promising inhibitory activity against a panel of human cancer cell lines.     

Enaminones as Synthons for a Directed C−H Functionalization: RhIII‐Catalyzed Synthesis of Naphthalenes

The use of enaminones as effective synthons for a directed C?H functionalization is reported. Proof‐of‐concept protocols have been developed for the Rh^III‐catalyzed synthesis of naphthalenes, based on the coupling of enaminones with either alkynes or α‐diazo‐β‐ketoesters. Two inherently reactive functionalities (hydroxy and aldehyde groups) are integrated into the newly formed cyclic framework and a broad range of substituents are tolerated, rendering target products readily available for further elaboration.