Vitalij D. Shteingarts

A new approach to polyfluoroaromatic amines with an unsubstituted position ortho to the amino group

Abstract N-acetyl derivatives of polyfluoroaromatic amines have been found to be highly selectively defluorinated by zinc in aqueous ammonia at the position ortho to the acetamido group thus affording a new approach to potential building blocks for the synthesis of polyfluorobenzheterocycles.

Reductive defluorination of polyfluoroarenes by zinc in aqueous ammonia

Abstract Aqueous ammonia has been found to be a good and versatile medium for the reductive defluorination of polyfluoroarenes by zinc. Upon the reduction of pentafluorobenzoic acid, 2,3,4,5,6-pentafluorobenzyl alcohol, pentafluoropyridine and heptafluoro-2-naphthoic acid individual products derived from the removal of one fluorine atom have been obtained.

Reactions of Polyfluoroarenes with MenE‐MMe3 Reagents (MenE = Me2As, Me2P, Me2N, and MeS; M = Si, Sn): Synthesis of Polyfluoroaryl MenE Compounds

Trimethylsilyldimethylarsane Me3SiAsMe2 was used as a reagent for the substitution of fluorine in polyfluoroarenes C6F5X (X = F, H, Cl) and C5NF5 by the Me2As group. The reactions occur between 50 — 180 °C, either in benzene or without solvent, to give as a rule 4-X-1-(dimethylarsano)tetrafluorobenzenes XC6F4AsMe2, (1—3) and 4-dimethylarsano-tetrafluoropyridine C5NF4AsMe2 (4), respectively, in yields between 43 and 94 %. In the case of C6F6, also double substitution is observed affording 1, 4-bis(dimethylarsano)tetrafluorobenzene 5 in addition to the monosubstituted derivative. The time and temperature dependencies of the reactions increase in the sequence: C6F6< C6F5H < C6F5Cl < C5NF5. The arsanes 1 and 4 were transformed to the potentially valuable bidentate ligands 1-(dimethylarsano)-4-(dimethylphosphano)tetrafluorobenzene 6 and 4-(dimethylarsano)-2-(dimethylphosphano)trifluoropyridine 8 by reaction with trimethylsilyl-dimethylphosphane Me3SiPMe2. 6reacts with oxygen to yield the corresponding phosphane oxide 7. Trimethylsilyl-dimethylamine Me3SiNMe2 also was successfully tested as a reagent for the dimethylamination of polyfluoroarenes C6F5X [X = F, H, Cl, CF3, P(S)Me2], 1-P(S)Me2-4-H-C6F4 and 4-X-C5NF4 [X = F, PMe2, P(S)Me2]. Sulfuration of the new Me2P derivatives 8 and 20 leads to the corresponding thiophosphanes 9 and 21 (Schemes 2 and 3). Furthermore, the recently reported very efficient one-pot synthesis of Me2P substituted polyfluoroarenes (e.g. XC6F4PMe2 with X = F, Me2PC6F4) was extended to the preparation of Me2As and MeS derivatives of pentafluoropyridine using a mixture of Me3SnH, As2Me4 (or S2Me2) and C5NF5 as precursors for the one-pot reaction. The expected products 4-(dimethylarsano)tetrafluoropyridine 4 and 4-(methylthio)tetrafluoropyridine 22, respectively, were obtained in 84 and 82 % isolated yields. The novel compounds were characterized by spectroscopic (NMR, MS) and analytical data. Compounds 5, 7, 9 and 21 could be isolated in form of single crystals and their structures have been studied by X-ray diffraction. Reaktionen von Polyfluorarenen mit MenE—MMe3-Reagenzien (MenE = Me2As, Me2P, Me2N, MeS; M = Si, Sn): Synthese von MenE-substituierten Polyfluorarenen Trimethylsilyl-dimethylarsan Me3SiAsMe2 wurde bei Polyfluorarenen C6F5X (X = F, H, Cl) und Perfluorpyridin C5NF5 als Reagenz fur die Substitution von Fluor durch die Me2As-Gruppe eingesetzt. Die Reaktionen wurden in Benzol oder ohne Losungsmittel bei Temperaturen zwischen 50 und 180 °C durchgefuhrt und liefern in der Regel die 4-X-1-(Dimethylarsano)tetrafluorbenzole XC6F4AsMe2 (1 — 3) bzw. 4-Dimethylarsanotetrafluorpyridin C5NF4AsMe2 (4) in Ausbeuten von 43 — 94 %. Im Fall von C6F6 wird auch Zweifachsubstitution zum 1, 4-Bis(dimethylarsano)tetrafluorbenzol 5 beobachtet. Die Reaktivitat, gemessen am Zeitbedarf und an der Temperaturabhangigkeit der Reaktionen, wird von der Art des Polyfluorarens bestimmt und nimmt in der Reihe C6F6 < C6F5H < C6F5Cl < C5NF5 zu. Die Arsane 1 und 4 wurden mit Trimethylsilyl-dimethylphosphan Me3SiPMe2 zu den heterosubstituierten Derivaten 1-(Dimethylarsano)-4-(dimethylphosphano)tetrafluorbenzol 6 bzw. 4-(Dimethylarsano)-2-(dimethylphosphano)-trifluorpyridine 8 umgesetzt, die als potenzielle zweizahnige Liganden von Interesse sind. 6 reagiert mit Sauerstoff zum entsprechenden Phosphanoxid 7. Trimethylsilyl-dimethylamin Me3SiNMe2 wurde als Reagenz fur die Dimethylaminierung der Polyfluorarene C6F5X [X = F, H, Cl, CF3, P(S)Me2], 1-P(S)Me2-4-HC6F4 and 4-X-C5NF4 [X = F, PMe2, P(S)Me2] ebenfalls untersucht. Durch Sulfurierung der Me2P-Derivate 8 und 20 werden die Thiophosphane 9 und 21 erhalten (Schemata 2 und 3). Auserdem wurde die vor kurzem entwickelte Eintopf-Synthese fur Me2P substituierte Polyfluorarene (z. B. XC6F4PMe2 mit X = F, Me2PC6F4) auf die Darstellung von Me2As- und MeS-Derivaten des Pentafluorpyridins ausgedehnt: Als Edukte fur die Eintopf-Reaktionen wurden Me3SnH, As2Me4 (oder S2Me2) und C5NF5 verwendet. Die erwarteten Produkte 4-(Dimethylarsano)tetrafluorpyridin 4 bzw. 4-(Methylthio)tetrafluorpyridin 22 wurden in 84- bzw. 82- %iger Ausbeute isoliert. Die neuen Verbindungen wurden durch spektroskopische (NMR, MS) und analytische Daten charakterisiert. Die Vertreter 5, 7, 9 und 21 konnten in Form von Einkristallen isoliert werden; ihre Strukturen wurden durch Rontgenbeugung aufgeklart.

Cytotoxicity of new alkylamino- and phenylamino-containing polyfluorinated derivatives of 1,4-naphthoquinone

Fluorinated derivatives of 1,4-naphthoquinone are highly potent inhibitors of Cdc25A and Cdc25 phosphatases and growth of tumor cells. Five new N-substituted polyfluorinated derivatives of 2-amino-1,4-naphthoquinone were synthesized and their mutagenic and antioxidant properties in Salmonella cells, as well as cytotoxicity in human myeloma (RPMI 8226), human mammary adenocarcinoma (MCF-7), mouse fibroblasts (LMTK) and primary mouse fibroblast cells (PMF) were studied. 2-tert-Butylamino-3,5,6,7,8-pentafluoro-1,4-naphthoquinone (1) inhibited the growth of normal control and tumor cells at the same concentration. Three compounds: 2-diethylamino-3,5,6,7,8-pentafluoro-1,4-naphthoquinone (2), 2-ethylamino-3,5,6,7,8-pentafluoro-1,4-naphthoquinone (3), 2-phenylamino-3,5,6,7,8-pentafluoro-1,4-naphthoquinone (4) exhibited a 50% decrease in the growth of cancer cells at low and comparable concentrations (2.4-8.6 microM) while being remarkably less cytotoxic toward normal LMTK and PMF cells. Quinones (1)-(4), but not 2-phenylamino-3-methyl-5,6,7,8-tetrafluoro-1,4-naphthoquinone (5), efficiently suppressed spontaneous mutagenesis in Salmonella cells, while all compounds 1-5 decreased the mutagenic effect of H2O2 on bacterial cells. Their possible perspectives as anticancer drugs are shortly discussed.

Cytotoxicity of new polyfluorinated 1,4-naphtoquinones with diverse substituents in the quinone moiety

Fluorinated derivatives of 1,4-naphthoquinones are highly potent inhibitors of Cdc25A and Cdc25B phosphatases and growth of tumor cells. Eight new derivatives of polyfluoro-1,4-naphthoquinone were synthesized and their cytotoxicity in human myeloma, human mammary adenocarcinoma, mouse fibroblasts and primary mouse fibroblast cells as well as their mutagenic and antioxidant properties in a Salmonella tester strain were studied. The efficiency of suppressing the growth of two lines of tumor cells decreased in the order: 2-(2-hydroxy-ethylamino)-3,5,6,7,8-pentafluoro-1,4-naphthoquinone (1), 2,3-dimethoxy-5,6,7,8-tetrafluoro-1,4-naphthoquinone (2), 2-[2-hydroxyethyl(methyl)amino]-3,5,6,7,8-pentafluoro-1,4-naphthoquinone (3), 2-morpholino-3,5,6,7,8-pentafluoro-1,4-naphthoquinone (4), 2-[bis-(2-hydroxyethyl)amino]-3,5,6,7,8-pentafluoro-1,4-naphthoquinone (5), 2-[(2-hydroxy)ethylsulfanyl)]-5,6,7,8-tetrafluoro-1,4-naphthoquinone (6), 2-methoxy-3,5,6,7,8-pentafluoro-1,4-naphthoquinone (7), and 1,4-dioxo-3-(1-pyridinio)-1,4-dihydro-5,6,7,8-tetrafluoronaphthalene-2-olate (8). Taking into account these data together with the better cytotoxic effect against cancer cells as compared with normal mammalian cells, protecting of bacterial cells from spontaneous and H(2)O(2)-dependent mutagenesis, and lower general toxicity of the compounds towards different cells, one can propose that compounds 3-5 may be considered as useful potential inhibitors of growth of tumor cells.

On the difference in the results of reductive defluorination of pentafluorobenzoic acid by sodium and zinc in liquid ammonia medium

Under the reduction of pentafluorobenzoic acid in liquid ammonia by sodium the deep defluorination with removal of three or more fluorine atoms has been observed, whereas with zinc only the product of para-defluorination has been obtained.

Synthesis of 2,3′,4′-tricyanobiphenyl derivatives and tetraphenylphthalocyanines based thereon

The nitration of 2,3′,4′-tricyanobiphenyl with subsequent transformations of the obtained product provided 4-X-2,3′,4′-tricyanobiphenyls (X = NO2, NH2, NHCOCH3, Br, I). The condensation of the initial biphenyl or its 4-X-derivatives (X = NO2, NHCOCH3, Br, I) in the presence of zinc acetate afforded the corresponding zinc complexes of tetra(4-X-2-cyanophenyl)phthalocyanines.

Synthesis of 2-aminopentafluoro-1,4-naphthoquinone derivatives

Potential biologically active derivatives of 2-aminopentafluoro-1,4-naphthoquinone modified at the amino group were synthesized in 32–96% yield by reactions of hexafluoro-1,4-naphthoquinone with nitrogen-centered nucleophiles.

Evidence for the transition from SN to ET mechanism in the reaction of arene radical anion with alkyl halide evoked by the introduction of an electron withdrawing substituent into radical anion

The interaction of potassium salts of benzonitrile and 1.4-dicyanobenzene radical anions with cyclopropylmethyl bromide provides benzylcyclopropane, in the first case, and 4-alkyl- benzonitriles together with 2-alkyl-1,4-dicyanobenzenes containing both cyclopropylmethyl and its isomeric 3-butenyl fragment, in the second case. These results provide evidence for the change of reaction mechanism from SN to ET.

The Influence of Nucleophile Substituents on the Orientation in the Reaction between 2,4-Difluoronitrobenzene and Lithium Phenoxides in Liquid Ammonia

The dependence of the orientation of aryloxydefluorination of 2,4-difluoronitrobenzene (1) (o/p ratio) by the action of X-substituted lithium phenoxides 2 (X = p-OMe, p-Me, p-Et, p-iPr, p-tBu, m-Me, H, p-F) in liquid ammonia in the temperature range from −55 to −35 °C has been investigated. The enthalpic preference for ortho-fluorine substitution decreases with weakening substituent electron-donating capability in the order: p-OMe > p-Me ≈ p-Et > m-Me > H ⩾ p-F. The predominant fluorine substitution at the ortho position for X = p-Me, p-Et turns into a preference for substitution at the para position when X = p-iPr, and this increases further on going to X = p-tBu. PM3, AM1 and MNDO MO calculations showed greater stability of the intermediate anionic σ-complexes formed on nucleophile addition at the para position, thus suggesting that the predominant ortho substitution manifested for X = p-OMe, m-Me, H, p-F and p-Alk = Me, Et is due to control over orientation by the charge distribution in the substrate. The substrate electronic structure, as a controlling factor, is probably changed by the relative stability of intermediate anionic σ-complexes on going to p-Alk = iPr, tBu, as a consequence of an enhancement of the substituent’s electron-withdrawing nature with the increase in alkyl group polarizability in the order: p-Me ≈ p-Et < p-iPr < p-tBu.