Synthesis of methylene- and difluoromethylenephosphonate analogues of uridine-4-phosphate and 3-deazauridine-4-phosphate

Cytidine triphosphate synthetase (CTPS) catalyzes the formation of cytidine triphosphate from glutamine, uridine-5'-triphosphate (UTP), and adenosine-5'-triphosphate. Inhibitors of CTPS are of interest because of their potential as therapeutic agents. One approach to potent enzyme inhibitors is to use analogues of high energy intermediates formed during the reaction. The CTPS reaction proceeds via the high energy intermediate UTP-4-phosphate (UTP-4-P). Four novel analogues of uridine-4-phosphate (U-4-P) and 3-deazauridine-4-phosphate (3-deazaU-4-P) were synthesized in which the labile phosphate ester oxygen was replaced with a methylene and difluoromethylene group. The methylene analogue of U-4-P, compound 1, was prepared by a reaction of the sodium salt of tert-butyl diethylphosphonoacetate with protected, 4-O-activated uridine followed by acetate deprotection and decarboxylation. It was found that this compound undergoes relatively facile dephosphonylation presumably via a metaphosphate intermediate. The difluoromethylene derivative, compound 2, was prepared by electrophilic fluorination of protected 1. This compound was stable and did not undergo dephosphonylation. Synthesis of the methylene analogue of 3-deazaU-4-P, compound 3, was achieved by ribosylation of protected 4-(phosphonomethyl)-2-hydroxypyridine. Electrophilic fluorination was also employed in the preparation of protected 4-(phosphonodifluoromethyl)-2-hydroxypyridine which was used as the key building block in the synthesis of difluoro derivative 4. These compounds represent the first examples of a nucleoside in which the base has been chemically modified with a methylene or difluormethylenephosphonate group.     

Fluorination with xenon difluoride. Reaction with halogenated hydrocarbons

Filler and coworkers [1-5] have demonstrated the utility of xenon difluoride as a selective fluorinating agent for aromatic hydrocarbons in the liquid phase, while Mackenzie and coworker [6] have fluorinated aromatic compounds in the vapour phase. We have developed a fluorination reaction of phenyl substituted olefins resulting in high yields of vicinal difluorides [7,8] and trifluoroacetates, depending on the catalyst. In our continued interest in the use of xenon difluoride as a mild fluorinating agent for fluorination of organic compounds, we have tries to fluorinate some heterocyclic ring systems, e.g. imidazo-(1,2-b)-pyridazine, under conditions similar of those used for fluorination of phenyl substituted olefins [7,8,9] (room temperature, methylene chloride as solvent, hydrogen fluoride as catalyst). It is well known that heteroaromatic compounds are less reactive toward electrophilic substitution reactions then aromatic hydrocarbon systems. However, it has been shown that bromination of imidazo-(1,2-b) -pyridazine results in 3-bromo products [10], while in chlorination with phosphorus pentachloride [11], the entering order of chlorine atoms is at position 3 > 2, 7 > 8 > 6 (Radical reactions).     

Iron(II)‐Catalyzed Site‐Selective Functionalization of Unactivated C(sp3)−H Bonds Guided by Alkoxyl Radicals

An alkoxyl radical guided strategy for site‐selective functionalization of unactivated methylene and methine C?H bonds enabled by an Fe^II‐catalyzed redox process is described. The mild, expeditious, and modular protocol allows efficient remote aliphatic fluorination, chlorination, amination, and alkynylation of structurally and electronically varied primary, secondary, and tertiary hydroperoxides with excellent functional‐group tolerance. The application for one‐pot 1,4‐hydroxyl functionalization of non‐oxygenated alkane substrates initiated by aerobic C?H oxygenation is also demonstrated.     

Direct synthesis of 8-fluoro purine nucleosides via metalation-fluorination

A straightforward access to protected 8-fluoro nucleosides via metalation-electrophilic fluorination under heterogeneous reaction conditions is reported. This is the first synthesis of 8-fluoro-2'-deoxyribonucleoside derivatives. Phenylsulfonyl substituted nucleosides are accompanying byproducts, possibly indicating a competing radical process. Higher yields of 8-fluoro derivatives were obtained with 2'-deoxyribonucleosides, as compared to ribonucleosides. Deprotection of the hydroxyl groups leading to 8-fluoro-2'-deoxyadenosine using TASF in methylene chloride demonstrates the compatibility of desilylation with 8-fluoro substituted nucleosides. NMR data indicate a syn conformation of the 8-fluoro derivatives.     

N-三甲基硅基对甲苯磺酰胺与对甲苯磺酸酯的反应

报道了3-氧杂-1,5-二戊醇二对甲苯磺酸酯及1,4-丁二醇二对甲苯磺酸酯与N-三甲基硅基对甲苯磺酰胺在碱存在下反应分别得到N-对甲苯磺酰基吗啡啉和N-对甲苯磺酰基四氢吡咯这一新的有机硅胺与磺酸酯的反应,在相同条件下N-三甲基硅基-对甲苯磺酰胺与对甲苯磺酸甲酯反应后仅得到N-甲基对甲苯磺酰胺,对此反应提出了可能的反应途径。     

Change of adsorption modes of dyes on fluorinated TiO2 and its effect on photocatalytic degradation of dyes under visible irradiation

Surface-fluorinated TiO2 (F-TiO2) particles were prepared via the HF etching method. The surface characteristics of fluorinated TiO2, the adsorption modes of dyes, and the reaction pathways for the photocatalytic degradation of dye pollutants under visible light irradiation were investigated. It was found that, in the treatment of TiO2 by HF etching, F(-) not only displaces surface HO(-) but also substitutes some surface lattice oxygen. Using zwitterionic Rhodamine B (RhB) dye as a model, the change of the adsorption mode of RhB on F-TiO2 relative to that on pure TiO2 was validated by adsorption isotherms, X-ray photoelectron spectroscopy (XPS), and IR techniques for the first time. RhB preferentially anchors on pure TiO2 through the carboxylic (-COOH) group, while its adsorption group is switched to the cationic moiety (-NEt 2 group) on F-TiO2. Both the photocatalytic degradation kinetics and mechanisms were drastically changed after surface fluorination. Dyes with positively charged nitrogen-alkyl groups such as methylene blue (MB), malachite green (MG), Rhodamine 6G (Rh6G), and RhB all underwent a rapid N-dealkylation process on F-TiO2, while on pure TiO2 direct cleavage of dye chromophore ring structures predominated. The relationship between surface fluorination and the degradation rate/pathway of dyes under visible irradiation was also discussed in terms of the effect of fluorination on the surface adsorption of dyes and on the energy band structure of TiO2.     

Fluorination rates of polyolefins as a function of structure and gas atmosphere

Polyolefins and fluoropolymers were reacted with elemental fluorine under carefully controlled conditions in a thermobalance adapted to be compatible with fluorine gas. The fluorination reactions were monitored by measuring the mass increase as a result of hydrogen substitution by fluorine. The mass increase was directly proportional to the square root of the fluorination time, which indicates that fluorine gas diffusion to the unreacted surface is the rate determining step. The fluorination rate was increased by increasing the fluorine concentration and the fluorination temperature. The fluorination rate is higher when nitrogen rather than helium is used as diluting gas. The fluorination rate for the reaction in which CO₂ is used as diluting gas is the same as during fluorination with nitrogen as diluting gas, while the presence of oxygen dramatically decreased the fluorination rate. Oxygen is incorporated during fluorination with oxygen as diluting gas, while no functionalization was observed when CO₂ was employed as diluting gas. The effect of polymer structure on fluorination was studied. Poly(vinylfluoride) gained mass during fluorination, while no reaction was observed for poly(vinylidenefluoride). The reaction rate for polypropylene was higher than that of polyethylene. In celebration of the 60^th birthday of Dr. Andrew K. Galwey     

New syntheses of diaza-crown ethers using boc protecting groups

BOC-protected m-xylylenediamine was treated with tetraethyleneglycol ditosylate to form BOC-protected diazabenzo-18-crown 5 (5) in a good yield. BOC-protected diazabenzo-21-crown-6 (6) was prepared in the same manner from BOC-protected m-xylylenediamine and pentaethylene glycol ditosylate. Bis-BOC-protected diaza-17-crown-5 (12) was prepared by treating BOC-protected 1,4-diaminobutane with 1,11-diiodo-3,6,9-trioxaundecane. The BOC-protecting groups were removed in methanolic 2 N hydrogen chloride to form the corresponding diaza-crown ethers 7, 8 and 13 .     

Effects of TiO<Subscript>2</Subscript> surface fluorination on photocatalytic degradation of methylene blue and humic acid

Photocatalytic degradation (PCD) reactions of cationic methylene blue (MB) and anionic humic acid (HA) were studied in naked TiO₂ and fluorinated TiO₂ (F-TiO₂) suspensions in order to investigate how the modification of the TiO₂ surface functional group influenced PCD reactions. Adsorption behaviors of MB and HA in the naked TiO₂ followed a typical pH-dependent electrostatic interaction mechanism. On the other hand, those in the F-TiO₂ were markedly changed and even showed a reversed dependence in specific pH ranges due to surface fluoride interrupting the interaction of substrates and surface titanol groups. PCD rates of MB (k _MB) and its N-demethylation (Δλ _max) were significantly increased by surface fluorination below circum-neutral pH range, in particular, by a factor of 12 and 54 at pH 2, respectively. In the case of HA, the fluorination had an insignificant effect on its degradation rate but appeared to change its degradation behavior. It has been suggested that, although the primary effect of fluorination enhances the photocatalytic production of hydroxyl radicals, the change in electrostatic interaction with substrates could affect PCD as well.     

New synthesis methods for fluorinated carbon nanofibres and applications

Several new synthesis methods of fluorinated carbon nanofibres, such as controlled fluorination using fluorinating agent (TbF₄ or XeF₂), or assisted fluorination under UV and gamma irradiation, are reviewed and compared with the direct fluorination using undiluted fluorine gas. The results highlight the different fluorination mechanisms for the direct fluorination and the new methods. The other advantage of those alternative fluorination routes is the possibility to provide fine tuning of the fluorination level, i.e. from F/C atomic ratio close to zero, as a functionalization, to the unity (CF₁) according to the required application, electrochemical or tribological. Two applications are described in this paper as a function of the fluorine content: protection against ozonation and use as solid lubricants.     

Low temperature fluorination of sulphur compounds with elemental fluorine

Low temperature fluorination technique is adopted for fluorination of the following sulphur compounds in freon-11 medium (1) Sulphur dioxide (2) Thionyl chloride (3) Sulphuryl chloride (4) Tetrasulphur tetra nitride and (5) Sulphur bromide. All the compounds undergo oxidative fluorination to give rise to sulphur-fluorine compounds except sulphuryl chloride which resists fluorination. Sulphuryl chloride thus behaves as a good solvent medium for fluorination of other reactive compounds like elemental sulphur. Details of the experimental procedures adopted and the identification of the products will be presented.     

新的酚型开链冠醚及由其衍生的二苯并冠醚的合成

将水杨醛与碱和氯甲基甲基醚反应, 再经过NaBH4还原, 即制得邻(甲氧基甲氧基)苯甲醇, 然后将其在DMF中与NaH和二(或三)甘醇二对甲苯磺酸酯反应, 得开链冠醚1a和1b。1a和1b经稀酸水解, 即脱保护而分别生成新的酚型开链冠醚2a和2b。用2a与二甘醇二对甲苯磺酸酯和NaH在DMF溶液中反应, 合成顺型二苯并-20-冠-6(3); 而2a与环氧氯丙烷在NaOH水溶液中反应, 则合成了17-羟基二苯并-18-冠-5(4)。     

电化学部分氟化芳基研究进展

含氟芳香化合物具有生物活性好、稳定性高、易被生物体代谢等优点,在医药和农药领域有着广泛的用途.目前芳基部分氟化的方法主要分为依赖于氟化试剂的亲电氟化方法以及反应条件苛刻甚至需要过渡金属催化的亲核氟化方法,这些方法操作繁琐并且污染环境.电化学氟化将"电能"作为一种"强氧化剂"来实现氟化反应,是一种直接、绿色且温和的氟化手...     

含氟卟啉的研究进展

综述了近几年国内外含氟卟啉的合成及其研究进展. 含氟卟啉合成方法分为直接氟化法和间接氟化法. 直接法主要采用无机氟化试剂直接对卟啉环进行氟化; 间接法主要采用含氟砌块法引入氟基团. 由于合成卟啉环比较复杂, 目前氟化学家主要采用间接氟化法合成含氟卟啉化合物.     

Highly selective electrochemical fluorination of organic compounds in ionic liquids

Recent studies on electrochemical partial fluorination in ionic liquid fluoride salts are reviewed. At first, historical background and some problems of electrochemical fluorination in organic solvents are briefly mentioned. Solvent-free electrochemical fluorinations in ionic liquids are explained as follows. Ultrasonication was found to improve both the yield and current efficiency for electrochemical fluorination of α-phenylthioacetate, which is mainly attributable to marked mass transport promotion of the substrate and the suppression of anode passivation. Highly regioselective and efficient fluorination of cyclic ethers, lactones, and cyclic carbonate was achieved in Et₄NF·4HF and Et₃N·5HF. Selective fluorination of hardly oxidizable phthalide was realized using a combination of imidazolium and fluoride ionic liquids. The unique effect of imidazolium ionic liquids on electrochemical fluorodesulfurization of 3-phenylthiophthalide was explained. Reuse of ionic liquids for electrochemical fluorination is also possible.     

Selective Radical Fluorination of Tertiary Alkyl Halides at Room Temperature

Direct fluorination of tertiary alkyl bromides and iodides with Selectfluor is described. The halogen‐exchange fluorination proceeds efficiently in acetonitrile at room temperature under metal‐free conditions and exhibits a wide range of functional group compatibility. Furthermore, the reactions are highly selective in that alkyl chlorides and primary and secondary alkyl bromides remain intact. A radical mechanism is proposed for this selective fluorination.     

Elemental fluorine in organic chemistry (1997-2006)

The use of elemental fluorine as a reagent over the period 1997-2006 for carbon-fluorine bond formation in organic synthesis is reviewed. Recent advances in the exhaustive fluorination of ethers and esters to give perfluorinated systems, selective direct fluorination of aliphatic, aromatic, heterocyclic and carbonyl systems and the application of microreactor techniques to direct fluorination are discussed.     

高价碘试剂介导的8-氨基喹啉C(5)位碳-氢键亲核氟化反应

8-氨基喹啉的C(5)位碳-氢键氟化反应近年来受到广泛关注,但大多需要使用过渡金属催化剂和亲电氟化试剂来实现.在高价碘试剂的介导下实现了无过渡金属催化条件下的8-氨基喹啉C(5)位碳-氢键亲核氟化反应.使用廉价易得且安全稳定的氟化银作为亲核氟化试剂,反应无需惰性气体保护,条件简单,操作方便,区域选择性好,底物范围较广,为喹啉类化合物的氟化提供了一种有潜在应用价值的新方法.     

Electrophilic fluorination with N,N′-difluoro-2,2′-bipyridinium salt and elemental fluorine

N,N′-Difluoro-2,2′-bipyridinium bis(tetrafluoroborate) (MEC-31) was shown to be a highly reactive electrophilic fluorinating agent with the highest effective fluorine content in its class. We have developed the perfect recycled fluorination system with MEC-31 for the lower-cost industrial fluorination and for an environment. MEC-31 can be completely recycled including the counter-anion. We found the fluorination of 2-naphthol in liquid CO₂ with MEC-31 in the presence of catalytic amount of NaOTf proceeded quantitatively without the generation of by-product.

In the fluorination of 1,3-dicarbonyl compounds with elemental fluorine, we found the introduction method of fluorine gas would be very important in order to make a reaction efficient. As fluorination goes on, the quantity of 1,3-dicarbonyl compounds of the starting material is reduced gradually, and therefore the quantity of fluorine must be reduced by the method to control the flow rate or the concentration of fluorine gas diluted with nitrogen, together the fluorination to proceed efficiently.     

Elemental fluorine. Part 18. Selective direct fluorination of 1,3-ketoesters and 1,3-diketones using gas/liquid microreactor technology

1,3-Ketoesters and 1,3-diketones react with fluorine gas, using Durham multichannel modular microreactor technology, on a preparatively useful scale. High conversions and yields of monofluorinated products were obtained. A consideration of the mechanism of fluorination of dicarbonyl systems provides a rationale of the scope and limitations of the use of microreactor technology for such direct fluorination processes. We conclude that it is especially appropriate for the fluorination of diketones and ketoesters that exist mainly in the enol form at equilibrium and/or undergo rapid keto-enol interconversion. A one-stage route to fluoroketones from ketoesters was achieved by allowing the crude product mixture obtained from the fluorination of the ketoesters to stand for a period of time before reaction work-up.