Highly-functionalised difluorinated cyclohexane polyols via the Diels-Alder reaction: regiochemical control via the phenylsulfonyl group

A difluorinated dienophile underwent cycloaddition reactions with a range of furans to afford cycloadducts which could be processed regio- and stereoselectively via episulfonium ions, generated by the reaction between their alkenyl groups and phenylsulfenyl chloride. The oxabicyclic products were oxidised to the phenylsulfonyl level and ring opened via E1(C)B or reductive desulfonative pathways to afford, ultimately, difluorinated cyclohexene or cyclohexane polyols.     

Basic and reductive sulfone-directed ring-opening reactions of difluorinated oxa[2.2.1]bicycloheptanes

Phenylsulfenyl chloride reacts with racemic endo Diels-Alder adduct 4 (DEC = CONEt(2)) to afford lactone 8, which can be reduced and protected in a series of high-yielding steps. Key sulfone 10 can be ring opened under strong base conditions to afford vinyl sulfone 11. Attempted desulfonation resulted in the formation of a monofluoroalkene, but a direct desulfonation/eliminative ring opening with strain relief delivered highly functionalized monocyclic species 16. [reaction: see text]     

Applying asymmetric dihydroxylation to the synthesis of difluorinated carbohydrate analogues: a 1,1-difluoro-1-deoxy-d-xylulose

Readily available difluoroenol iodides and stannanes undergo palladium-catalysed coupling reactions with alkenylstannanes and iodides, respectively, to afford a trial set of difluorinated 1,3- and 1,4-dienes, which were then exposed to AD conditions. A number of issues were raised including generally low reactivity of simple 1,3-butadienes, and useful reactivity of certain 1,4- and substituted 1,3-pentadienes. Though the basic conditions used for the AD resulted in the decomposition of certain diol products, enol acetal chemistry allowed the asymmetric synthesis of a difluorinated analogue of a deoxyxylulose.     

Towards novel difluorinated sugar mimetics; syntheses and conformational analyses of highly-functionalised difluorinated cyclooctenones

Highly-functionalised difluorinated cyclooctenones were synthesised from trifluoroethanol using either metallated difluoroenol acetal or carbamate chemistry, followed by a [2,3]-Wittig rearrangement or aldol reaction. Efficient RCM reactions afforded the title compounds which showed rather restricted fluxional behaviour by VT (19)F NMR. Topological characterisation by molecular modelling and NOESY/ROESY experiments offered a number of challenges, but allowed the identification of two favoured boat-chair conformers which interconverted by pseudorotation with relatively large activation barriers.     

Synthesis of difluorinated pyridinecarboxaldehyde via electrophilic fluorination

An efficient synthesis of novel 3,5-difluoropyridine-4-carboxaldehyde using N-fluoro-benzenesulfonimide (NSFi) is described. Difluorination was achieved through the reaction of 3,5-dihalo-1,3-dioxolane pyridine with n-butyllithium followed by N-fluorobenzenesulfonimide at −120 °C in good to high yields. Maintaining the low temperature during the transmetallation was found to be critical for the selective formation of the difluoro-susbstitution over the monofluoro one.     

Second-generation difluorinated cyclooctynes for copper-free click chemistry

The 1,3-dipolar cycloaddition of azides and activated alkynes has been used for site-selective labeling of biomolecules in vitro and in vivo. While copper catalysis has been widely employed to activate terminal alkynes for [3 + 2] cycloaddition, this method, often termed "click chemistry", is currently incompatible with living systems because of the toxicity of the metal. We recently reported a difluorinated cyclooctyne (DIFO) reagent that rapidly reacts with azides in living cells without the need for copper catalysis. Here we report a novel class of DIFO reagents for copper-free click chemistry that are considerably more synthetically tractable. The new analogues maintained the same elevated rates of [3 + 2] cycloaddition as the parent compound and were used for imaging glycans on live cells. These second-generation DIFO reagents should expand the use of copper-free click chemistry in the hands of biologists.     

A stereodivergent asymmetric approach to difluorinated aldonic acids

A (bromodifluoromethyl)alkyne has been deployed in a stereoselective route to difluorinated aldonic acid analogues, in which a Sharpless asymmetric dihydroxylation reaction and diastereoisomer separation set the stage for phenyl group oxidation.     

Physical and electrolytic properties of difluorinated dimethyl carbonate

The physical and electrolytic properties of difluorinated dimethyl carbonate (DFDMC) synthesized using F₂ gas (direct fluorination) were examined. The dielectric constant and viscosity of DFDMC are higher than those of monofluorinated dimethyl carbonate (MFDMC) and dimethyl carbonate (DMC). The oxidative decomposition voltage of DFDMC is higher than those of DMC and MFDMC. The specific conductivity in DFDMC solution is considerably lower than those in MFDMC and DMC solutions. The ethylene carbonate (EC)-DFDMC equimolar binary solution containing 1 mol dm⁻³ LiPF₆ shows a moderate conductivity of 6.91 mS cm⁻¹ at 25 °C. The lithium electrode cycling efficiency (charge-discharge coulombic cycling efficiency of lithium electrode) in EC-DFDMC equimolar binary solution containing 1 mol dm⁻³ LiPF₆ is higher than 80%. The EC-DFDMC solution is a good electrolyte for rechargeable lithium batteries.     

Reactions of enamines with selectfluor: a straightforward route to difluorinated carbonyl compounds

[reaction: see text] Reactions of enamines, preformed from beta-dicarbonyl and monocarbonyl compounds, with Selectfluor (1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) under mild conditions (triethylamine (TEA) or molecular sieves) easily led to the corresponding difluorinated carbonyl compounds in high yields.     

Synthesis of difluorinated carbocyclic analogues of 5-deoxypentofuranoses

The synthesis of difluorinated carbocyclic analogues of 5-deoxypentofuranoses is described. The sequence involves an addition of PhSeCF₂TMS to carbohydrate-derived aldehydes followed by a radical cyclization, and provides a secure strategy for a future synthesis of pentofuranoses and nucleoside analogues.     

Preparation of 1,5-methano-2,3,4,5- tetrahydro-1H-3-benzazepine via Pd-catalyzed cyclization

[reaction: see text] A new approach to prepare 1,5-methano-2,3,4,5-tetrahydro-1H-3-benzanepine (1) is discussed. This strategy utilized a tandem Michael addition and Pd-catalyzed cyclization to afford cyanobenzofulvene acetal 13. This indene intermediate (13) was subjected to hydrogenolysis to provide an amino ester (12) and was cyclized with base to afford lactam 5. The lactam (5) was reduced with borane to afford the desired benzazepine (1).     

Executing and rationalizing the synthesis of a difluorinated analogue of a ring-expanded calystegine B2

A difluorinated analogue of a ring-expanded calystegine B(2) and some N-protected species were prepared via microwave-mediated transannular ring-opening of an epoxyketone. The diastereofacial selectivity of the epoxidation reaction, which delivers the key intermediate, and the regioselectivity of the transannular reactions were analyzed by density functional theory (DFT) methods. The epoxidation stereoselectivity arises from simple steric control, whereas the ring-closure reactions are subject to thermodynamic control.     

Photooxygenation of pyrazin-2(1h)-ones

1-Alkyl-5,6-diphenylpyra2in-2(1H)-ones (1a-b) reacted with singlet oxygen in dichloromethane to afford the stable endoperoxide (1a-b), while in methanol to afford the 1:1-adduct (3a-b) of the endoperoxide (2a-b) and methanol.     

Theoretical study on platinabenzene and mono- and difluorinated platinabenzenes: Structure, properties, and aromaticity

The electronic structures and properties of the platinabenzene and mono- and difluorinated platinabenzenes isomers have been investigated using hybrid density functional B3LYP theory. Basic measures of aromatic character were derived from structure, molecular orbital, and nuclear independent chemical shift (NICS). An energetic criterion suggests that ortho isomer of monofluorinated and F15 isomer of difluorinated platinabenzenes enjoy conspicuous stabilization. The polarizability and molecular orbital analysis are compatible with this result. NICS values calculated at several points above the ring center fail to give the result consistent with that based on relative energy, polarizability, and molecular orbital analysis. The atoms in molecules analysis indicates a correlation between NICS (1.0) and the electron density of the ring critical point (ρ_rcp) in monofluorinated platinabenzenes. There is a similar correlation in difluorinated platinabenzenes (except for F12 and F24 isomers) between NICS (0.5) and ρ_rcp.     

Synthesis of 1,8- and 2,8-dihydrocycloheptapyrazol-8-one derivatives by the reactions of 3-acetyltropolone and its methyl ethers with phenylhydrazine

3-Acetyltropolone ( 1 ) reacted with phenylhydrazine to give 3-acetyltropolone phenylhydrazone ( 3 ) and 3-methyl-1-phenyl-1,8-dihydrocycloheptapyrazol-8-one ( 4 ). The former ( 3 ) cyclized to afford the latter ( 4 ). The reaction of 3-acetyl-2-methoxytropone ( 2a ) with phenylhydrazine gave 4 , 3-methyl-2-phenyl-2,8-dihydrocyclo-heptapyrazol-8-one ( 5 ), and 3-methyl-2-phenyl-2,8-dihydrocycloheptapyrazol-8-one phenylhydrazone ( 6 ). The compound ( 5 ) reacted with phenylhydrazine to afford 6 . The reaction of 7-acetyl-2-methoxytropone ( 2b ) with phenylhydrazone gave 7-acetyl-2-methoxytropone phenylhydrazone ( 7 ), 7-acetyl-2-(N′-phenylhydrazino)-tropone phenylhydrazone ( 8 ), 3-methyl-1-phenyl-1,8-dihydrocycloheptapyrazol-8-one phenylhydrazone ( 9 ), and 6 . The compound ( 7 ) was heated to afford 4 and reacted with phenylhydrazine to afford 8 and 9 . The compound ( 8 ) was also refluxed to give 9 .     

Total syntheses of conformationally locked difluorinated pentopyranose analogues and a pentopyranosyl phosphate mimetic

Trifluoroethanol has been elaborated, via a telescoped sequence involving a metalated difluoroenol, a difluoroallylic alcohol, [2,3]-Wittig rearrangement, and ultimately an RCM reaction and requiring minimal intermediate purification, to a number of cyclooctenone intermediates. Epoxidation of these intermediates followed by transannular ring opening or dihydroxylation, then transannular hemiacetalization delivers novel bicyclic analogues of pentopyranoses, which were elaborated (in one case) to an analogue of a glycosyl phosphate.     

Unexpected formation of oxetanes from a geminal difluorinated δ-lactone

A perbenzylated 3,3-difluorinated hexono-1,5-lactone was prepared in several steps. Reaction of this lactone with MeOH/p-TsOH followed by a treatment with ion-exchange resin led to the formation of an exocyclic oxetane derived vinylether. Similar reaction with ammonia gave the corresponding carboxamido substituted oxetane in good yields.     

Reactions of dimethoxycarbene with dimethyl 2,3-dicycanomaleate and fumarate

Dimethoxycarbene, in 2-fold or larger excess, reacts with dimethyl 2,3-dicyanomaleate and fumarate to afford an unstable dihydrofuran 1:1 adduct that was shown to react further with the carbene to afford a 2:1 adduct reported previously. In an astonishing process, the dihydrofuran reacts with water to afford a mixture of (d,l and meso) dimethyl 2,3-dicyanosuccinates in which both hydrogen atoms of water were used to hydrogenate a C=C bond.     

Intramolecular ester enolate-imine cyclization reactions for the asymmetric synthesis of polycyclic β-lactams and cyclic β-amino acid derivatives

Enolates of chiral N-(α-methyl-p-methoxybenzyl)-ω-imino-esters undergo intramolecular cyclization reactions to afford (syn)-aza-anions of β-amino esters in high dr that cyclize to afford N-(α-methyl-p-methoxybenzyl)-β-lactams that can be readily deprotected to afford their corresponding cyclic NH-β-lactams, β-amino esters, or β-amino acids.     

Nucleophilic addition to (3-methylpentadienyl)iron(1+) cations: counterion control of regioselectivity; application to the enantioselective synthesis of 4,5-disubstituted cyclohexenones

The regioselectivity of malonate addition to (3-methylpentadienyl)Fe(CO)3+ is controlled by the malonate-counterion association. The Li+ salt of malonate proceeds via C1 nucleophilic attack to afford the 1,3Z-diene complex 4a, while reaction of highly dissociated ion pair (i.e., Na+ or Li+/12-crown-4) salt proceeds at the C2 internal carbon to eventually afford cyclohexenone products 6. Reaction of 1a with the sodium salt of bis(8-phenylmenthyl)malonate proceeds with excellent diastereocontrol to afford a single diastereomeric cyclohexenone.