Accessing novel fluorinated heterocycles with the hypervalent fluoroiodane reagent by solution and mechanochemical synthesis.

A new and efficient strategy for the rapid formation of novel fluorinated tetrahydropyridazines and dihydrooxazines has been developed by fluorocyclisation of ß,γ-unsaturated hydrazones and oximes with the fluoroiodane reagent. Mechanochemical synthesis delivered fluorinated tetrahydropyridazines in similar excellent yields to conventional solution synthesis, whereas fluorinated dihydrooxazines were prepared in much better yields by ball-milling.

Fluorinations of unsymmetrical diaryliodonium salts containing ortho-sidearms; influence of sidearm on selectivity.

Activated aromatics were reacted with two different fluoroidoane reagents 1 and 2 in the presence of triflic acid to prepare only the para-substituted diaryliodonium salts. With fluoroiodane 1 the unsymmetrical diaryliodonium salts contained an ortho-propan-2-ol sidearm, whereas the alcohol sidearm was eliminated to form an ortho-styrene sidearm in the reaction with fluoroiodane 2. Only the diaryliodonium salts containing a styrene sidearm were fluorinated successfully to deliver para-fluorinated aromatics in good yields.

Activation of the hypervalent fluoroiodane reagent by hydrogen bonding to hexafluoroisopropanol.

Hexafluoroisopropan-2-ol (HFIP) is an excellent solvent for promoting fluorinations with the hypervalent fluoroiodane reagent 1 and crucially, it removes the need for transition metals or TREAT-HF activators. The fluoroiodane reagent 1 was used in HFIP to monofluorinate 1,3-ketoesters and to fluorocyclise unsaturated carboxylic acids in excellent yields under mild reaction conditions.

Intramolecular Fluorocyclizations of Unsaturated Carboxylic Acids with a Stable Hypervalent Fluoroiodane Reagent.

A new class of fluorinated lactones was prepared by the intramolecular fluorocyclizations of unsaturated carboxylic acids by using the stable fluoroiodane reagent in combination with AgBF4. This unique reaction incorporates a cyclization, an aryl migration, and a fluorination all in one step. The fluoroiodane reagent, prepared easily from fluoride, can also be used without a metal catalyst to give moderate yields within just 1 hour, thus demonstrating that it is a suitable reagent for developing new (18)F-labelled radiotracers for PET imaging.

Single-Fluorophore Detection in Femtoliter Droplets Generated by Flow Focusing.

Aqueous microdroplets with a volume of a few femtoliters are an ideal sample size for single-molecule fluorescence experiments. In particular, they enable prolonged measurements to be made on individual molecules that can diffuse freely in the surrounding medium. However, the rapid production of monodisperse droplets in a hydrodynamic flow, such as microfluidic flow focusing, will often involve volumes that are typically too large (>0.5 pL) for single-molecule studies. Desired volumes of a few femtoliters, or smaller, can be produced by either tip streaming or step emulsification in a flow-focusing device; however, in both of these methods, the aqueous droplets are dispersed in a large volume of the continuous phase, where individual droplets can diffuse perpendicular to the flow direction, and the monodispersity of droplet size produced by tip streaming is difficult to sustain for more than transient time scales. We show here that the optimized design and fabrication of microfluidic devices with shallow channel depths can result in the reliable production of stable droplets of a few femtoliters at a high rate in the dripping regime of flow focusing. Furthermore, the generated microdroplets are localized in a two-dimensional plane to enable immediate analysis. We have demonstrated the fluorescence monitoring of single molecules of encapsulated green fluorescent protein. The apparatus is straightfoward, inexpensive, and readily assembled within an ordinary laboratory environment.

Electrophilic fluorination using a hypervalent iodine reagent derived from fluoride.

The air and moisture stable fluoroiodane 8, readily prepared on a 6 g scale by nucleophilic fluorination of the hydroxyiodane 7 with TREAT-HF, has been used as an electrophilic fluorinating reagent for the first time to monofluorinate 1,3-ketoesters and difluorinate 1,3-diketones in good isolated yields.

Synthesis of α-fluoro-ß-hydroxy esters by an enantioselective Reformatsky-type reaction.

The first enantioselective Reformatsky-type reaction of ethyl iodofluoroacetate has been accomplished with alkyl aryl ketones. High diastereoselectivities and excellent enantioselectivities for the major diastereomer (93-95% ee) were achieved with large alkyl groups. For smaller alkyl groups the diastereoselectivities were moderate, but excellent enantioselectivities were obtained for both diastereomers (79-94% ee).

Enantioselective Reformatsky reaction of ethyl iododifluoroacetate with ketones.

Two approaches have been developed for the enantioselective Reformatsky reaction of ethyl iododifluoroacetate with ketones to form a quaternary carbon centre using (1R,2S)-1-phenyl-2-(1-pyrrolidinyl)-1-propanol as the chiral ligand. Good yields and high enantioselectivities (80-91% ee) were achieved with a range of alkyl aryl ketones in a convenient one-pot protocol using ethyl iododifluoroacetate and diethylzinc to form the difluorinated Reformatsky reagent homogeneously. In the traditional two-step Reformatsky reaction using the preformed Reformatsky reagent generated from ethyl iododifluoroacetate and zinc dust, good yields and good enantioselectivities (75-84% ee) were also obtained.

A recyclable perfluoroalkylated PCP pincer palladium complex.

A new fluorous PCP pincer ligand has been coordinated to Ni(II), Pd(II) and Pt(II). The air stable palladium complex, which promotes Heck reactions between methyl acrylate and either aryl bromides or iodides, can be recovered intact by fluorous solid-phase extraction and was reused four times in the Heck reaction between methyl acrylate and 4-bromoacetophenone without loss in catalytic activity.

Perfluoroalkylated 4,13-diaza-18-crown-6 ethers: synthesis, phase-transfer catalysis, and recycling studies.

A series of N,N'-dialkyl-4,13-diaza-18-crown-6 lariat ethers possessing two C8H17 (2), (CH2)3C8F17 (3), (CH2)3C10F21 (4), and (CH2)2C8F17 (5) side arms were synthesized in good yields by N-alkylation of 4,13-diaza-18-crown-6. Potassium picrate could be extracted from an aqueous solution into an organic phase by all of the perfluoroalkylated macrocycles demonstrating their potential to be used as phase-transfer catalysts, and preliminary studies on a classical nucleophilic substitution established that they each gave higher catalytic activities under solid-liquid than under liquid-liquid phase-transfer conditions. The light fluorous macrocycles gave similar, if not better, catalytic activity compared to the parent, non-fluorinated phase-transfer catalyst 2 under solid-liquid conditions in conventional organic solvents in both an aliphatic and an aromatic nucleophilic substitution. N,N'-Bis(1H,1H,2H,2H,3H,3H-perfluoroundecyl)-4,13-diaza-18-crown-6 (3) was recycled six times in the iodide displacement reaction of 1-bromooctane and four times in the fluoride displacement reaction of 2,4-dinitrochlorobenzene using fluorous solid-phase extraction without any loss in activity.

Rhodium catalysed hydroformylation of alkenes using highly fluorophilic phosphines.

Highly fluorophilic phosphines incorporating at least one aromatic ring containing two directly attached perfluoroalkyl groups have been synthesised, their partition coefficients (organic phase : fluorous phase) measured and their electronic properties probed using (1)J(PtP) data for their trans-[PtCl(2)L(2)] complexes. These phosphines have been used as modifying ligands for the rhodium catalysed hydroformylation of 1-octene in perfluorocarbon solvents. Catalyst activity, regioselectivity and the levels of rhodium leaching to the product phase vary with the substitution patterns of the modifying ligands that do not correlate with the electronic properties or partition coefficients of these ligands, but can be interpreted in terms of differences in the resting states of the catalysts.

Separation, recovery and recycling of a fluorous-tagged nickel catalyst using fluorous solid-phase extraction.

Highly efficient separation, recovery and recycling of the fluorous-tagged catalyst, [Ni[F13C6C(O)CHC(O)C6F13]2], can be achieved with fluorous solid-phase extraction, after the Lewis acid catalysed synthesis of enaminodiones in conventional organic solvents.

Hydroformylation in fluorous solvents.

Triaryl-phosphines and -phosphites bearing fluorous ponytails give high rates, good linear selectivity and good retention of catalyst in the fluorous phase during hydroformylation of alkenes in fluorous solvents.