Synthesis and anticancer activity of fluorinated analogues of combretastatin A-4

The synthesis of a series of fluorinated benzaldehydes and their use in the Wittig synthesis of fluoro-substituted stilbenes is described. 3,5-Difluoro-4-hydroxybenzaldehyde (6) and 3-fluoro-4-methoxybenzaldehyde (11) are prepared by Duff formylation of 3,5-difluorophenol and 2-fluoroanisole, respectively. 2-Methoxy-3,4-difluorobenzaldehyde was obtained by Friedel-Crafts formylation of 2,3-difluoroanisole with α,α-dichloromethyl methyl ether. The aldehydes were used to make a series of fluorinated analogues of the anticancer combretastatins A-1, A-2 and A-4. The in vitro anticancer properties of the fluoro combretastatins are reported. The most active fluoro analogue 3-deoxy-3-fluoro-combretastatin A-4 (Z-2) retains the potent cell growth inhibitory properties of CA-4.     

Preparative enantioseparation of (±)-N-(3,4-cis-3-decyl-1,2,3,4-tetrahydrophenanthren-4-yl)-3,5-dinitrobenzamide by centrifugal partition chromatography

The racemic compound (±)-N-(3,4-cis-3-decyl-1,2,3,4-tetrahydrophenanthren-4-yl)-3,5-dinitrobenzamide ((±)-1), an analogue of increased lipophilicity of the chiral selector (CS) contained in the Whelk-O^® HPLC chiral stationary phase (CSP) has been resolved into its enantiomers by applying centrifugal partition chromatography (CPC). Considering the known enantioselectivity of the Whelk-O^® CS for naproxen, and the reciprocity concept in enantioseparation, (S)-naproxen related compounds were tested as CSs. In the search for an adequate solvent system, the partition behaviour of the two solutes, CS and racemate, has been studied using several biphasic solvent mixtures. The optimal CS concentration and sample loading capacity were determined in the chosen solvent system. The search for an appropriate CS and solvent system, the scale-up and optimization of the enantiomer separation by CPC, as well as the rationale for the unexpected elution order of enantiomers, are here described. The comparison of the preparative CPC separation achieved with that in HPLC, using a CSP containing an analogous CS, resulted favourable to the former in terms of loading capacity, solvent consumption and throughput.     

Studies on the solvent dependence of the carbamic acid formation from ω-(1-naphthyl)alkylamines and carbon dioxide

Carbamic acid formation from amine and carbon dioxide in a variety of solvents was investigated by measuring NMR (¹H, ¹³C, HMBC) and IR spectra in situ. Bubbling of CO₂ through solutions of naphthylalkylamines 1-3 in DMSO, DMF or pyridine (protophilic, highly dipolar, aprotic solvent) resulted in complete conversion of the amines to the corresponding carbamic acids 4-6. In dioxane (protophilic, dipolar, aprotic solvent), the carbamic acid and a small amount of the ammonium carbamate were formed. By contrast, in MeCN (protophobic, dipolar, aprotic solvent), in benzene or CHCl₃ (apolar, aprotic solvent), or in 2-PrOH or MeOH (dipolar, amphiprotic solvent), ammonium carbamates 7-9 rather than 4-6 were formed, although the ammonium bicarbonates/carbonates were competitively formed in MeOH. The ammonium carbamates precipitated in many cases and hence they could be separated. The selective generation of the undissociated carbamic acids in preference to the ammonium carbamates in protophilic, dipolar, aprotic solvents (DMSO, DMF, pyridine, and dioxane) is rationalized by considering the acid-base equilibria between the amines 1-3 and the carbamic acids 4-6 in nonaqueous media. The obtained selectivity is likely due to the larger pK_a values for 4-6 than the amines 1-3 in these solvents. Interestingly, the fluorescence intensities for 1-3 were dramatically enhanced (4-50 times) in DMSO or DMF upon introduction of CO₂, while they were not altered very much in dioxane, MeCN, benzene, CHCl₃, 2-PrOH, and MeOH, except small to medium increases (1.3-3 times) for 1 in dioxane, MeCN, 2-PrOH and MeOH. As a whole, the solvent effects observed in these fluorescence studies are consistent with those observed in the above NMR and IR studies. Finally, methoxycarbonylation of amine 3 into the methyl carbamate was successfully accomplished by using (trimethylsilyl)diazomethane in the presence of CO₂.     

Synthesis of aromatic tetracyclic tin compounds by template and transmetallation reactions: Alkyl vs aryl migration from tin to nitrogen

The syntheses of [bis(3,5-di-tert-butyl-2-hydroxy-2-phenyl)amine]diphenyltin (1) and [bis(3,5-di-tert-butyl-2-hydroxy-2-phenyl)amine]dichloro-phenyl-stannate (2) by template reactions using 3,5-di-tert-butylcatechol, aqueous ammonia and SnPh₂Cl₂ are reported. We also report the syntheses of compounds 2, [bis(3,5-di-tert-butyl-2-hydroxy-2-phenyl)amine]trichloro-stannate (4), [bis(3,5-di-tert-butyl-2-hydroxy-2-phenyl)methylamine]chloro-methyltin (5), and [bis(3,5-di-tert-butyl-2-hydroxy-2-phenyl)-n-butylamine]n-butyl-chlorotin (6) and [bis(3,5-di-tert-butyl-2-hydroxy-2-phenyl)amine]n-butyl-dichloro-stannate (7), performed by transmetallation reactions of the octahedral zinc coordination compound Zn[3,5-di-tert-butyl-1,2-quinone-(3,5-di-tert-butyl-2-hydroxy-1-phenyl)imine]₂ (3) with SnPhCl₃ or SnPh₂Cl₂, SnCl₄, SnMe₂Cl₂, Sn(nBu)₂Cl₂ and Sn(nBu)Cl₃, respectively. The X-ray diffraction structures of compounds 1, 2, 4 and 6 are reported. The transmetallation reactions with Sn(alkyl)₂Cl₂ afforded pentacoordinated tin compounds, where an alkyl group migrated from tin to nitrogen, while similar reactions with Sn-Ph compounds did not present any phenyl group migration.     

Effects of chemical variations on the mesophase behavior of new fluorinated poly(vinylcyclopropane)s

Several new structures of fluorinated polymers poly(1)-poly(9) were prepared by free radical ring opening polymerization of vinylcyclopropane monomers 1-9 containing different fluorinated side groups of the type (CH₂)_n(CF₂)_pF. While in poly(1)-poly(3) p varied from 6 to 10 for a fixed n=2, in poly(4)-poly(6) n increased from 3 to 5 at the given p=8. In poly(7) and poly(8) a phenyl ring was incorporated to elongate the mesogenic side group (n=2; p=6 and 8, respectively), that was further separated from the polymer backbone by a methylene spacer (m=11) in poly(9). Therefore, the effects of various chemical variations of the polymer structure on the mesophase behavior could be assessed. The polymers were in fact co-polymers comprising both 1,5-linear and cyclobutane-ring isomer units. In any case they formed smectic mesophase(s) owing to the special character of the perfluorinated chains. The order and the isotropization temperature (T_i) of the mesophase were enhanced by increasing p, but T_i lowered with increasing n. Extension of the side group by insertion of a phenyl ring improved T_i. Wide angle X-ray diffraction studies clarified the nature of the different smectic phases, the occurrence of which was discussed in terms of the ability of the fluorinated side groups to pack antiparallel in either a partly or fully interdigitated structure. Co-polymers of 3 with a non-mesogenic, not fluorinated co-monomer 10 were also prepared with different chemical compositions. Co-polymerization was found to be another effective means of modifying the mesophase behavior of the poly(vinylcyclopropane)s.     

Bis(pyrazole)- and bis(pyrazolyl)-palladium complexes as phenylacetylene polymerization catalysts

Two types of pyrazole-based palladium complexes were used to catalyze the polymerization of phenylacetylene. Catalysts with electron-withdrawing linkers, [{1,3-(3,5-R₂pzCO)₂C₆H₄}Pd₂Cl₂(μ-Cl)₂] (R = ^tBu (1), Ph (2), Me (3), [{2,6-(3,5-R₂pzCO)₂C₅H₃N)}PdCl₂] (R = ^tBu (4), Me (5)), show high conversion; whilst those with simple pyrazole ligands, [(3,5-R₂pz)₂PdCl₂] (R = H (6), Me (7), ^tBu (8)), [(3,5-^tBu₂pz)₂PdCl(Me)] (9), have much lower conversions. Conversion greatly improved when 9 was used to catalyze the co-polymerization of sulfur dioxide and phenylacetylene. Both types of catalysts produce predominantly trans–cisoidal polyphenylacetylene.     

Binuclear Salan borate compounds with three-coordinate boron atoms

A series of binuclear boron compounds supported by Salan(^tBu)H₄ ligands have been prepared. They are of the general formula Salan(^tBu)[B(OR)]₂. The compounds are Salean(^tBu)(BOR)₂ [Salean(^tBu) = (N,N′-ethylenebis(3,5-di-tert-butyl-salicylamine)), R = Me (1), SiMe₃ (4)], Salban(^tBu)(BOR)₂[Salban(^tBu) = (N,N′-butylenebis(3,5-di-tert-butyl-salicylamine)), R = Me (2), SiMe₃ (5)], and Salhan(^tBu)(BOR)₂ [Salhan(^tBu) = (N,N′-hexylenebis(3,5-di-tert-butyl-salicylamine)), R = Me (3)]. All of the compounds were characterized by spectroscopic (¹H NMR, ¹¹B NMR, IR) and physical (mp, EA) techniques. Also, 1, 2 and 4 were structurally characterized by single crystal X-ray diffraction studies.     

X-ray structural and dynamic behaviour study of allyl palladium compounds with fluorinated benzenethiolate bridges

In solution, allyl palladium homobimetallic complexes bridged by fluorinated benzenethiolates, [{Pd(μ-SR)(η³-C₃H₅)}₂] where R=C₆F₅, 1; C₆HF₄-4, 2; C₆H₄F-2, 3; C₆H₄F-3, 4 and C₆H₄F-4, 5, are found as a mixture of syn/anti and cis/trans isomers. The variable temperature ¹H and ¹⁹F NMR study of these compounds show that the four isomers undergo interconversion through two probable mechanisms, allyl rotation assisted by the solvent and inversion of the configuration at the sulphur atoms. The X-ray crystal structure determination of [{Pd(μ-SC₆F₅)(η³-C₃H₅)}₂] and [{Pd(μ-S C₆HF₄-4)(η³-C₃H₅)}₂] shown both complexes to be bimetallic with the metal centres found in a slightly distorted square planar environments.     

Hypervalent and binuclear silicon and germanium derivatives from bis-(3,5-di-tert-butyl-2-phenol)-oxamide

The reactions of bis-(3,5-di-tert-butyl-2-phenol)oxamide (1) with Cl₂SiR₂ (Me or Ph) or Cl₂GeR₂ (Me, nBu or Ph) in THF provided binuclear pentacoordinated silicon and germanium compounds: bis-(3,5-di-tert-butyl-2-oxo-phenyl)-oxamido-bis-dimethylsilane (2), bis-(3,5-di-tert-butyl-2-oxo-phenyl)-oxamido-bis-diphenylsilane (3), bis-(3,5-di-tert-butyl-2-oxo-phenyl)-oxamido-bis-dimethylgermane (4), bis-(3,5-di-tert-butyl-2-oxo-phenyl)-oxamido-bis-di-n-butylgermane (5) and bis-(3,5-di-tert-butyl-2-oxo-phenyl)-oxamido-bis-diphenylgermane (6). The mono-nuclear tetracoordinated silicon compounds N-acetyl-bis-(3,5-di-tert-butyl-2-oxo-phenyl)-amide-bis-(dimethylsilane) (8) and N-acetyl-bis-(3,5-di-tert-butyl-2-oxo-phenyl)-amide-bis-(diphenylsilane) (9) were synthesized from N-(3,5-di-tert-butyl-2-phenol)acetamide (7) and Cl₂SiR₂ (R = Me and Ph). Comparison of the ²⁹Si NMR chemical shifts of the penta- (2 and 3) and tetracoordinated (8 and 9) silicon compounds provided information about the intramolecular coordination of the carbonyl group to the silicon atom. Compounds 3 and 6 were characterized by single-crystal X-ray analyses. They have planar hexacyclic structures where the central atoms present distorted tbp geometries with one nitrogen and two carbon atoms in equatorial positions and two oxygen atoms in apical positions.     

Synthesis and properties of novel fluorinated polynaphthalimides derived from 1,4,5,8-naphthalenetetracarboxylic dianhydride and trifluoromethyl-substituted aromatic bis(ether amine)s

A series of novel fluorinated polynaphthalimides (PNIs) (2a-g) were synthesized from 1,4,5,8-naphthalenetetracarboxylic dianhydride (NTDA) and trifluoromethyl (CF₃)-substituted aromatic bis(ether amine)s (1a-g) by high-temperature solution polycondensation in m-cresol using isoquinoline as catalyst. Almost all the PNIs were readily soluble in polar solvents such as N-methyl-2-pyrrolidone (NMP) and N,N-dimethylacetamide (DMAc) and could be solution-cast to transparent and tough films with high tensile strengths. The PNIs exhibited high thermal stability, with glass-transition temperatures of 262-383 °C, 10% weight loss temperatures above 528 °C in nitrogen or air, and char yields at 800 °C in nitrogen higher than 50%. In comparison with analogous PNIs without the -CF₃ substituents, these fluorinated PNIs revealed an enhanced solubility and better film-forming capability.     

Synthesis of fluorinated malonamides and use in L/L extraction of f-elements

Synthesis of new fluorinated tertiary malonamides (F-malonamides) was accomplished, and their liquid/liquid (L/L) extraction properties with f-elements were investigated. These molecules are fluorinated analogues of well known extractants used in several processes designed towards the treatment of nuclear wastes, and the efficient separation of lanthanides from minor actinides; however, the synthesis of F-malonamides deserved a modification of the general synthetic route commonly employed to prepare H-malonamides. Extraction of neodymium from various aqueous media into both fluorous and classical solvents was studied, which revealed an opposite trend between F-malonamides and H-malonamides: L/L extraction ability is very sensitive to the nitrogen atoms substitution pattern, and the most efficient F-malonamide is compound 3 (R₁ = Me), whereas the best H-malonamide is compound 5 (R₁ = Bu, DMDBTDMA).     

From bis(silylamino)tin dichlorides via di(1-alkynyl)-bis(silylamino)tin to new heterocycles by 1,1-organoboration

Bis(silylamino)tin dichlorides 1 [X₂SnCl₂ with X=N(Me₃Si)₂ (a), N(9-BBN)SiMe₃ (b), N(^tBu)SiMe₃ (c), and N(SiMe₂CH₂)₂ (d)] were prepared from the reaction of two equivalents of the respective lithium amides (Li-a-d) with tin tetrachloride, SnCl₄, or from the 1:1 reaction of the respective bis(amino)stannylene with SnCl₄. The compounds 1 react with two equivalents of lithium alkynides LiCCR¹ to give the di(1-alkynyl)-bis(silylamino)tin compounds X₂Sn(CCR¹)₂, 2 (R¹=Me), 3 (R¹=^tBu), and 4 (R¹=SiMe₃). Problems were encountered, mainly with LiCC^tBu as well as with 1b, since side reactions also led to the formation of 1-alkynyl-bis(silylamino)tin chlorides 5-7 and tri(1-alkynyl)(silylamino)tin compounds 8 and 9. 1,1-Ethylboration of compounds 2-4 led to stannoles 10, 11, and in the case of propynides, also to 1,4-stannabora-2,5-cyclohexadiene derivatives 12. The molecular structure of the stannole 11b (R¹=SiMe₃) was determined by X-ray analysis. The reaction of 2a and d with triallylborane afforded novel heterocycles, the 1,3-stannabora-2-ethylidene-4-cyclopentenes 14. These reactions proceed via intermolecular 1,1-allylboration, followed by an intramolecular 1,2-allylboration to give 14, and a second intramolecular 1,2-allylboration leads to the bicyclic compounds 15.     

Preparation of cobalt-containing bulky monodentate phosphines with electron-withdrawing/donating substituents on bridged arylethynyl and their applications in Suzuki coupling reactions

Several cobalt-containing bulky monodentate phosphines (μ-PPh₂CH₂PPh₂)Co₂(CO)₄(μ,η-(^tBu)₂PCC(C₆H₄R)) (4a: R=H; 4b: R=p-F; 4cp: R=p-CF₃; 4cm: R=m-CF₃; 4d: R=p-OMe) were prepared from the reactions of (^tBu)₂PCC(R-C₆H₄) (2a: R=H; 2b: R=p-F; 2cp: R=p-CF₃; 2cm: R=m-CF₃; 2d: R=p-OMe) with Co₂(CO)₆(μ-PPh₂CH₂PPh₂) 3. Further reactions of 4a, 4b, 4cp, 4cm, and 4d with Pd(OAc)₂ yielded unique palladium complexes (μ-PPh₂CH₂PPh₂)Co₂(CO)₄(μ,η-(^tBu)₂PCC(C₆H₃R)-κC¹)Pd(μ-OAc) (5a: R=H; 5b: R=p-F; 5cp: R=p-CF₃; 5cm: R=m-CF₃; 5d: R=p-OMe, respectively). The strong electron-withdrawing substituents, -F and -CF₃, assist the ortho-metalation process during the formation of 5b, 5cp, and 5cm. The more positively charged palladium center in 5b (or 5cp, 5cm) enhances the probability for PhB(OH)₃⁻ to attack the metal center and the rate of reduction thereafter. DFT studies on the charges of these palladium centers support this assumption. The enhancement of the reaction rates of the Suzuki-Miyaura cross-coupling reactions using 5b, 5cp, and 5cm is thereby attributed to this effect.     

Pyridine mediated supramolecular assemblies of 3,5-dinitro substituted benzoic acid, benzamide and benzonitrile

Synthesis and characterization of molecular assemblies of pyridine adducts, 1a, 2a and 3a, of 3,5-dinitrobenzoic acid, 1, 3,5-dinitrobenzamide, 2 and 3,5-dinitrobenzonitrile, 3, respectively, have been reported. All these adducts were obtained by crystallization of 1, 2 and 3 from pyridine. However, crystallization of 1 from pyridine in the presence of benzene resulted in the formation of a pyridinium adduct, 1b, along with a water molecule. All the adducts crystallize in a 1:1 molecular ratio except 1a, which forms a 1:2 adduct, as characterized by single crystal X-ray diffraction method. The adducts crystallize in different space groups—1a, orthorhombic, Pna2₁; 1b, monoclinic, P2₁; 2a, monoclinc, C2/c; 3a, triclinic, . In two-dimensional arrangement, 1a, 1b and 3a form sheet structures. In 1a, within the two-dimensional sheets, large cavities are formed, which are occupied by pyridine molecules. In 1b, the sheets are catenated to form a chicken-wire network. However, 2a formed a crossed ribbon packing pattern with empty channels in the three-dimensional structure.     

Synthesis and structures of π-allylpalladium(II) complexes containing bis(1,2,4-triazol-5-ylidene-1-yl)borate ligands. An unusual tetrahedral palladium complex

Four air stable, neutral π-allylpalladium(II) complexes containing bis(1,2,4-triazol-5-ylidene-1-yl)borate ligands [H₂B(RBTz)₂Pd(π-allyl)] (R = ⁿBu, 2a; ^tBu, 2b; 2,6-diisopropylphenyl, 2c; cyclohexyl, 2d) have been prepared and characterized. The molecular structures of 2c and 2d have been confirmed by single-crystal X-ray diffraction. To our surprise, the coordination geometry about the palladium atom in 2d is distorted tetrahedron, in which the allyl group is nearly perpendicular to the plane defined by the Pd and the carbene C atoms. To our knowledge, such configuration has not been reported for a four-coordinated palladium allyl complex.     

Synthesis, structures, and catalytic properties for ethylene polymerization of bridged [η,η-C5H4CHPhArO]TiCl2 complexes

A number of bridged half-sandwich titanium complexes [η⁵:η¹-2-C₅H₄CHPh-4-R¹-6-R²C₆H₂O]TiCl₂ [R¹ = H (5), Me (6), ^tBu (7, 8); R² = H (6, 7), ^tBu (5, 8)] were synthesized from the reaction of their corresponding trimethylsilyl substituted ligand precursors 2-Me₃SiC₅H₄CHPh-4-R¹-6-R²C₆H₂OSiMe₃ [R¹ = H (1), Me (2), ^tBu (3, 4); R² = H (2, 3), ^tBu (1, 4)] with TiCl₄ in hexane. All new complexes were characterized by ¹H and ¹³C NMR spectroscopy. Molecular structures of complexes 5 and 8 were determined by single crystal X-ray diffraction analysis. Upon activation with AlⁱBu₃/Ph₃CB (C₆F₅)₄, complexes 5-8 exhibit reasonable catalytic activity for ethylene polymerization and copolymerization with 1-hexene, producing polyethylene and poly(ethylene-co-1-hexene) with moderate molecular weights.     

Fluorinated alcohol directed formation of dispiro-1,2,4,5-tetraoxanes by hydrogen peroxide under acid conditions

The oxidative system MTO/30%H₂O₂/HBF₄/fluorous alcohol is promising for the selective synthesis of biologically important antimalarial dispiro-1,2,4,5-tetraoxanes by direct acid-catalysed cyclisation of various 4-substituted cyclohexanones (1, R=Me, Et, tBu, Ph, COOEt, CF₃). The role of the substitutent at the 4-position was important in the selectivity of formation of tetraoxane (2, TO) with respect to hexaoxonane (3, HO). By the use of fluorinated alcohols and under the right reaction conditions, tetraoxanes 2 were selectively formed and synthesised in 46-86% isolated yield from 4-substituted cyclohexanones 1.     

Synthesis and redox properties of novel ferrocenes with redox active 2,6-di-tert-butylphenol fragments: The first example of 2,6-di-tert-butylphenoxyl radicals in ferrocene system

Novel Schiff bases of ferrocenecarboxaldehyde bearing 2,6-di-tert-butyphenol fragments N-(3,5-di-tert-butyl-4-hydroxyphenyl)iminomethylferrocene (1) and N-(3,5-di-tert-butyl-4-hydroxybenzyl)iminomethylferrocene (2) have been synthesized and characterized. The oxidation of the compounds 1 and 2 by PbO₂ in solution leads to the formation of stable phenoxyl radicals 1′ and 2′ studied by EPR spectroscopy. The redox properties of ferrocenes 1 and 2 were studied using cyclic voltammetry.     

Solvent-dependent effect by carbon dioxide on the photoreactions of (9-anthryl)alkylamines

The effect of CO₂ on a photoreaction was first studied systematically by using (9-anthryl)alkylamines (APA, AEA, and AMA) as the starting compound. From close scrutiny of the results, the CO₂ effect was clearly observed and was well rationalized by the previously reported novel solvent dependence of the amine-CO₂ reversible reactions. For instance, the yield of the dimer (h-t from APA or AEA, h-t+h-h from AMA) obtained in MeOH or DMSO was higher under CO₂ than under argon and this was ascribed to formation of either ammonium bicarbonate/carbonate in MeOH or carbamic acid in DMSO, which will prevent the nitrogen lone pair from being involved in electron-transfer reactions. In fact, the electron-transfer side reactions producing 1-3 in DMSO were strongly inhibited under CO₂. Also, due to formation of noncovalent linkage between the ammonium cation and the carbamate anion in 2-PrOH, the proportion of h-h relative to h-t produced from AMA in 2-PrOH was increased by carrying out the reaction under CO₂.     

Indium trichloride catalyzed efficient one-pot synthesis of highly substituted furans

A one-pot synthesis of the substituted furans 3 could be achieved in good yields by reacting but-2-ene-1,4-diones 1 with acetoacetates 2 in the presence of a catalytic amount of InCl₃ (20 mol %) using i-PrOH as solvent at 80-90 °C for 4-8 h. InCl₃ was observed to give the optimum results among the various Lewis acids examined.