Synthesis and conformational analysis of α,α-difluoroalkyl heteroaryl ethers

We report the efficient synthesis of difluoroalkyl aryl ethers from the rearrangement of heteroaryl ketones and aldehydes, mediated by xenon difluoride and HF/pyridine in methylene chloride at room temperature. Computational analysis of difluoroalkylethers shows that there is potential to allow access to conformational space not accessible to the hydrogenated parent.     

Decarboxylative C(sp3)−O Cross‐Coupling

Alkyl aryl ethers are an important class of compounds in medicinal and agricultural chemistry. Catalytic C(sp³)?O cross‐coupling of alkyl electrophiles with phenols is an unexplored disconnection strategy to the synthesis of alkyl aryl ethers, with the potential to overcome some of the major limitations of existing methods such as C(sp²)?O cross‐coupling and S_N2 reactions. Reported here is a tandem photoredox and copper catalysis to achieve decarboxylative C(sp³)?O coupling of alkyl N‐hydroxyphthalimide (NHPI) esters with phenols under mild reaction conditions. This method was used to synthesize a diverse set of alkyl aryl ethers using readily available alkyl carboxylic acids, including many natural products and drug molecules. Complementarity in scope and functional‐group tolerance to existing methods was demonstrated.     

Carbonylation of Difluoroalkyl Bromides Catalyzed by Palladium

Although important progress has been made in the fluoroalkylation reactions, the transition‐metal‐catalyzed carbonylative fluoroalkylation reaction remains challenging so far. Herein, we report the first example of a Pd‐catalyzed carbonylation of difluoroalkyl bromides with (hetero)arylboronic acids under one atmosphere pressure of CO. The reaction can also be extended to the aryl potassium trifluoroborate salts. The advantages of this protocol are synthetic simplicity, broad substrate scope, and excellent functional group compatibility. The resulting difluoroalkyl ketones can serve as versatile building blocks for the synthesis of various useful fluorinated compounds.     

Synthesis,characterization, and ion‐complexing properties of polymers displaying densely packed arrays of crown‐ethers as lateral substituents

We report the synthesis and ion‐binding properties of four poly(crown‐ethers) displaying either one or two crown‐ethers (15‐crown‐5 or 18‐crown‐6) on every third carbon alongside the backbone. The polymers were synthesized by living anionic ring‐opening polymerization of disubstituted cyclopropane‐1,1‐dicarboxylates monomers. Cation binding of the polychelating polymers and corresponding monomers to Na⁺ and K⁺ was evaluated by picrate extraction and isothermal calorimetry titration. This novel family of poly(crown‐ethers) demonstrated excellent initial binding of the alkali ions to the polymers, with a higher selectivity for potassium. © 2014 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2014 , 52, 2337–2345     

Cooperative Photoredox and N-Heterocyclic Carbene Catalyzed Fluoroaroylation for the Synthesis of α-Trifluoromethyl-Substituted Ketones

α-Trifluoromethylated ketones have attracted significant attention as valuable building blocks in organic synthesis. Such compounds are generally accessed through trifluoromethylation of ketones. Here we report an alternative disconnection approach for the construction of α-CF₃ carbonyl compounds by using aroyl fluorides as bifunctional reagents for fluoroaroylation of gem-difluoroalkenes through cooperative photoredox and N-heterocyclic carbene (NHC) catalysis. This strategy bypasses the use of expensive or sensitive trifluoromethylation reagents and/or the requirement for ketone pre-functionalization, thus enabling an efficient and general synthetic method to access α-CF₃-substituted ketones. A wide variety of gem-difluoroalkenes and aroyl fluorides bearing a diverse set of functional groups are eligible substrates. Notably, the developed methodology also provides rapid access to mono- or difluoroalkyl ketones. Mechanistic studies reveal that merging photoredox catalysis with NHC catalysis is essential for the reaction.     

Azoxy Compounds—From Synthesis to Reagents for Azoxy Group Transfer Reactions

The azoxy functional group is an important structural motif and represents the formally oxidized counterpart of the azo group. Azoxy compounds find numerous applications ranging from pharmaceuticals to functional materials, yet their synthesis remains underdeveloped with a main focus on the formation symmetric azoxy compounds. To overcome challenges in the synthesis of such unsymmetric azoxy compounds, we designed a process employing readily accessible nitroso compounds and iminoiodinanes. This method builds on the use of visible light irradiation to generate a triplet nitrene from iminoiodinanes, which is trapped by nitroso arenes to give access to sulfonyl-protected azoxy compounds with a good substrate scope and functional group tolerance. We further describe two applications of these sulfonyl-protected azoxy compounds as radical precursors in synthesis, where the whole azoxy group can be transferred and employed in C(sp³)−H functionalization of ethers or 1,2-difunctionalization of vinyl ethers. All of the reactions occurred at room temperature under visible light irradiation without the addition of any photoredox catalysts and additives. Control experiments, mechanism investigations, and DFT studies well explained the observed reactivity.     

Palladium‐Catalyzed C(sp2)−H Alkylation of Aldehyde‐Derived Hydrazones with Functionalized Difluoromethyl Bromides

A palladium‐catalyzed C(sp²)?H difluoromethylation of aldehyde‐derived hydrazones using bromodifluoromethylated compounds to afford the corresponding functionalized difluoromethylketone hydrazones has been established. It is proposed that a radical/SET mechanism proceeding via a difluoroalkyl radical may be involved in the catalytic cycle. Applications of the methodology to the synthesis of α,α‐difluoro‐β‐ketoesters and α,α‐difluoroketones (RCOCF₂H) have been illustrated.     

The synthesis of unique structures of tetra-crown ethers through Michael addition

Unique structures of tetra-crown ethers were successfully synthesized by the reaction of tetramethylolmethane tetraacrylate (TMMT) reacted with crown ethers containing primary amine functional group such as 2-aminomethyl crown ethers and 4-aminobenzo crown ethers; containing secondary amine group like 1-aza crown ethers through Michael reaction. The newly synthesized tetra-crown ethers were characterized by ¹H NMR, ¹³C NMR, FAB mass spectrum, elemental analyses, IR, respectively.     

Manganese/Cobalt Bimetallic Relay Catalysis for Divergent Dehydrogenative Difluoroalkylation of Alkenes

The involvement of manganese radical for halogen atom transfer (XAT) reactions has been esteemed as one reliable method but encountered with limited catalytic models. In this paper, a novel bimetallic relay catalysis of Mn₂(CO)₁₀ and cobaloxime has been developed for divergent dehydrogenative difluoroalkylation of alkenes using commercially available difluoroalkyl bromides. A wide range of structurally diverse terminal, cyclic and internal alkenes as well as tetrasubstituted alkenes are found to be good coupling partners to deliver difluoroalkylated allylic products and difluoromethylated cyclic products, accompanied with the production of H₂ as the by-product. This bimetallic relay strategy features broad substrate scope, mild reaction conditions and excellent functional group compatibility. Its success represents an important step-forward to expedite the construction of a rich library of difluoroalkylated products.     

Ullmann diaryl ether synthesis catalyzed by copper (I)/pyridine-functionalized silane

Ullmann-type diaryl ether synthesis was performed under mild conditions in DMF/K₂CO₃ using a pyridine-functionalized silane as a ligand. The products were obtained in good yields. This method tolerates a variety of functional groups and is effective in the synthesis of hindered diaryl ethers and heteroaryl ethers.     

Michael Addition Catalyzed by Chiral Secondary Amine Phosphoramide Using Fluorinated Silyl Enol Ethers: Formation of Quaternary Carbon Stereocenters

A chiral secondary amine phosphoramide was developed and identified as a powerful catalyst for the Mukaiyama–Michael addition of fluorinated enol silyl ethers to tetrasubstituted olefins. The resulting products are obtained with high enantioselectivities and contain a quaternary carbon stereocenter bearing either a difluoroalkyl or monofluoroalkyl group.     

Radical fluoroarylation in radiochemical synthesis

In this study, we report on the radical [¹⁸F]fluoroarylation of different olefins using 4-[¹⁸F]fluorobenzenediazonium ions to provide a new route to radiopharmaceuticals containing a deactivated, 4-[¹⁸F]fluoro substituted phenyl group. This new methodology was shown to be well suited for the synthesis of ¹⁸F-labelled stilbenes. Stilbene 7 is now accessible within 80 min in 30-45% overall radiochemical yield starting from [¹⁸F]fluoride.     

Difluorocarbene-derived rapid late-stage trifluoromethylation of 5-iodotriazoles for the synthesis of 18F-labeled radiotracers

Difluorocarbene has emerged as a valuable intermediate to synthesize fluorides. However, difluorocarbene-derived synthesis of ¹⁹F/¹⁸F-trifluoromethyl triazoles has not been explored. Herein, we reported the Cu(I)-promoted difluorocarbene-derived ¹⁹F/¹⁸F-trifluoromethylation of iodotriazoles using KF/K¹⁸F as the fluorine source. This approach rapidly generated a wide range of 5-trifluoromethyl-1,2,3-triazoles in good yields showing high functional group compatibility. The reaction was effective for late-stage functionalization of bioactive molecules and ¹⁸F-trifluoromethylation of iodotriazoles. This work provides a practical synthetic methodology for the development of triazole drugs and ¹⁸F-radiotracers for positron emission tomography.     

A General Organophotoredox Strategy to Difluoroalkyl Bicycloalkane (CF2-BCA) Hybrid Bioisosteres**

Here, we report a general approach to the synthesis of the difluoroalkyl bicycloalkanes (CF₂-BCAs), as structural surrogates of aryl ketones and ethers. The chemistry is driven by a dihydrobenzoacridine photocatalyst, that engages in a catalytic electron-donor acceptor (EDA) complex, or directly reduces the fluorinated substrate. These two convergent manifolds lead to the generation of the R-CF₂ radical, that reacts with the [1.1.1]- or [3.1.1.]-propellane. The method is extremely general, and extendable to complex bioactive molecules (30 examples, up to 87 % yield). The structural features of the CF₂-BCP hybrid bioisostere were investigated by single crystal X-ray. Finally, we synthesised a CF₂-BCP analogue of a Leukotriene A₄ hydrolase inhibitor, replacing the original aryl ether motif. In silico docking studies indicated that this new analogue maintains the same arrangement within the enzyme pocket, profiling the use of the CF₂-BCA hybrid bioisostere in medicinal chemistry settings.     

“Design” of Boron‐Based Compounds as Pro‐Nucleophiles and Co‐Catalysts for Indium(I)‐Catalyzed Allyl Transfer to Various Csp3‐Type Electrophiles

We have recently uncovered a general indium(I)‐catalyzed method for allylations and propargylation of acetals and ketals with a water‐ and air‐stable allyl boronate. By using a more reactive allyl borane, we have successfully extended this methodology to the more challenging C C coupling with ethers. Herein, we report an improved methodology for the indium(I)‐catalyzed allylation of acetals and ethers, through combination of the allyl boronate with a commercially available “hard” Lewis acid, B‐methoxy‐9‐BBN (BBN=borabicyclo[3.3.1]nonane), as an effective co‐catalyst. Significantly, our work highlights for the first time the correlation between the Lewis acidity of “electrophilic” boron‐based compounds and their “nucleophilic” reactivity in Csp³–Csp³ couplings, catalyzed by a “soft” low‐oxidation main group metal. In addition, we also report several applications of these methodologies to the selective synthesis of various carbohydrate derivatives.     

Synthesis and 13C-NMR spectroscopic investigations of rhamnobioses

A convenient method has been developed for the synthesis of all mono- and di-O-benzyl ethers of methyl α-L-rhamnopyranoside applying a new stereoselective method for the hydrogenolytic ring-cleavage of benzylidene acetals. Using the prepared dibenzyl ethers as aglycones, the (1→2)-, (1→3)- and (l→4)-linked rhamnosyl-rhamnose derivatives (13–15) were synthesised. Hydrogenolysis of the latter compounds and subsequent acetylation gave the pentaacetates (16–18) of methyl dirhamnosides, which on saponification furnished the free methyl dirhamnosides (19–21). Acetolysis of 16–18 gave the corresponding dirhamnose-hexaacetates which were transformed into the three disaccharides by saponification. The structure of each product was investigated by ¹³C-NMR spectroscopy, and for the purpose of ¹³C-NMR studies the mono-O-methyl ethers of methyl α-L-rhamnopyranoside, the diacetates and di-O-benzyl ethers of the latter compounds, and, also the diacetates of methyl α-L-rhamnopyranoside were synthesised.It has been established that, for ¹³C-NMR investigations of oligosaccharides, the benzyl ethers of monosaccharides are more suitable model compounds than the currently used monosaccharide methyl ethers.     

Stability constants of complexes formed by new Schiff-base lariat ethers derived from 4,13-diaza-18-crown-6 with Ag+, Pb2+, Cu2+ cations determined by competitive potentiometry

The stability of complexes formed by a series of Schiff-base lariat ethers, derived from 4,13-diaza-18-crown-6, 1 with Ag⁺, Pb²⁺, Cu²⁺ cations, has been comparatively determined, in methanol: dichloromethane solution. We present here the synthesis and an interesting competitive potentiometry method useful for the stability constant determination for a new family of Schiff-base bibracchial lariat ethers. The stability constants and the selectivity in competitive complexation of Ag⁺, Pb²⁺ and Cu²⁺ cations by macrocyclic receptors 1–7 (L), can be accurately evaluated and species distribution diagrams can be calculated for individual system. In all cases further functionalization of bibracchial lariat ethers 2–7 is accompanied by an increasing of the selectivity, relative to the complexes of the initial 4,13-diaza-18-crown-6 macrocycle 1.     

Symmetrical Ketones from Aldehyde Trimethylsilyl Enol Ethers on Storage: A Cautionary Note

The widespread use of trialkylsilyl enol ethers has dramatically increased the utility of enolate anion chemistry.¹ These enol ethers are readily prepared, reactive, and in many instances are stable enough to be commercially available. We have been using trimethylsilyl enol ethers as aldehyde enolate precursors and wish to report some observations regarding storage of these 1-alkyl-2-trimethylsilyloxyethenes. We have noted that after 2–3 months in sealed glass ampuoles these trimethylsilyl enol ethers contained significant amounts of symmetrical ketones.     

A Highly K+‐Selective Phenylaza‐[18]crown‐6‐Lariat‐Ether‐Based Fluoroionophore and Its Application in the Sensing of K+ Ions with an Optical Sensor Film and in Cells

Herein, we report the synthesis of two phenylaza‐[18]crown‐6 lariat ethers with a coumarin fluorophore ( 1 and 2 ) and we reveal that compound 1 is an excellent probe for K⁺ ions under simulated physiological conditions. The presence of a 2‐methoxyethoxy lariat group at the ortho position of the anilino moiety is crucial to the substantially increased stability of compounds 1 and 2 over their lariat‐free phenylaza‐[18]crown‐6 ether analogues. Probe 1 shows a high K⁺/Na⁺ selectivity and a 2.5‐fold fluorescence enhancement was observed in the presence of 100 mM K⁺ ions. A fluorescent membrane sensor, which was prepared by incorporating probe 1 into a hydrogel, showed a fully reversible response, a response time of 150 s, and a signal change of 7.8 % per 1 mM K⁺ within the range 1–10 mM K⁺. The membrane was easily fabricated (only a single sensing layer on a solid polyester support), yet no leaching was observed. Moreover, compound 1 rapidly permeated into cells, was cytocompatible, and was suitable for the fluorescent imaging of K⁺ ions on both the extracellular and intracellular levels.