Cover Picture: Journal of the Chinese Chemical Society 5/2011

Perflurooctanesulfonates (fluorous sulfonates) have been developed as triflates and nonaflates alternatives for Pd‐catalyzed coupling reactions to form C‐C, C‐N, C‐S, C‐H, and C‐CN bonds. They also serve as a phase‐tag for fluorous solid‐phase extraction (F‐SPE) to facilitate the product purification. The utility of fluorous sulfonate linkers in the synthesis of biologically interested library scaffolds is summarized in this short review article. This article entitled “Convertible Fluorous Sulfonate Linker for the Synthesis of Diverse Library Scaffolds“ was contributed by Prof. Wei Zhang who was invited as a Visiting Lecturer of the Chemistry Research Promotion Center, Taiwan, R.O.C. (November 23 ～ November 29, 2010). For full text, please see pp. 575～582 in this issue.     

Efficient, recoverable, copper-free Sonogashira reaction under FBS and thermomorphic mode

The solubility property of high fluorine content ligands allows us to report in this article the accomplishment under the fluorous biphasic system (FBS) the Pd-catalyzed Sonogashira reactions using novel recyclable Pd catalysts with fluorous-ponytails in the structure of 2,2′-bpy ligands that are only soluble in perfluorinated solvents at room temperature. Alternatively, without using any fluorous solvent but under the thermomorphic mode, the same Pd catalysts proceed with the Cu-free Sonogashira reactions homogeneously in DMF at 135 ± 5 °C, whereas the product mixtures after reaction remain in solution and the Pd catalysts precipitate from DMF at low temperature.     

Towards functional fluorous surfactants. Synthesis of hydrophilic fluorous 1,2,3-triazolylmethyl ethers and di(1,2,3-triazolylmethyl) ethers

Copper(I)-accelerated Huisgen–Meldal dipolar cycloaddition reactions between polyfluoroalkyl azides and propargyl ethers of n-octanol and of triethyleneglycol monomethyl ether exhibited variation in yield of 1,2,3-triazol-4-ylmethyl ethers. Microwave acceleration, and in situ generation of the azides, provided improvements in yield and efficiency. In contrast, very good yields of equivalent fluorous triazoles were obtained from a range of n-alkyl azides with propargyl ethers of perfluorohexylethanol and of perfluoroheptylmethanol through conventional copper(I)-promoted reactions. Together, the resulting substances with systematic variations in polyfluoroalkyl and alkyl substituent length and position of substitution, and degree of oxygen content, make up small libraries of hybrid fluorous 1,2,3-triazol-4-ylmethyl ethers as candidates for study as hydrophilic fluorous surfactants. In addition, a pilot sample of di(1,2,3-triazol-4-ylmethyl) ethers with 1′-octyl-1-polyfluoroalkyl-substituents and 1′-nonyl-1-perfluorooctylethyl substituents were synthesised for the first time in an effort to develop more functional, fluorous surfactants.     

Fluorous synthesis of sclerotigenin-type benzodiazepine-quinazolinones

A new synthetic protocol for sclerotigenin-type benzodiazepine-quinazolinone library scaffold is introduced. A fluorous benzyl protecting group is used for the synthesis of 4-benzodiazepine-2,5-dione intermediate and also as a phase tag for fluorous solid-phase extraction (F-SPE).     

Fluorous 2-chloropyridinium salt (Mukaiyama condensation reagent) for amide formation reactions

A new fluorous 2-chloropyridinium hexafluorophosphate was prepared as a modified Mukaiyama condensation reagent, and it was applied in amide formation reactions. Good to excellent purities of amides were obtained after fluorous solid-phase extraction of reaction mixtures without additional chromatography.     

An expeditious synthesis of bistratamide H using a new fluorous protecting group

A total synthesis of bistratamide H has been achieved using a new ‘highly’ fluorous amino protecting group, tris(perfluorodecyl)silylethoxylcarbonyl (^FTeoc) group. The synthetic intermediates were easily isolated by liquid-liquid extraction with fluorous solvent. The fluorous protecting group was demonstrated to be recycled.     

Mannich-type reactions of aromatic aldehydes, anilines, and methyl ketones in fluorous biphase systems created by rare earth (III) perfluorooctane sulfonates catalysts in fluorous media

Rare earth (III) perfluorooctane sulfonates (RE(OPf)₃) catalyze the three-component Mannich-type reactions of different ketones with various aromatic aldehydes and aromatic amines in fluorous media to give various β-arylamino ketones in good yields. By simple separation of the fluorous phase containing only catalyst, reaction can be repeated several times.     

p-Alkoxyphenyl-type heavy fluorous tag for the preparation of carbohydrate units

Carbohydrate glycosyl acceptor and donor moieties were synthesized efficiently by using the fluorous tag method. The p-alkoxyphenyl-type heavy fluorous tag was stable under all the reaction conditions used in the preparation of the various carbohydrate units. Each synthetic intermediate carrying the fluorous tag could be obtained in a simple straightforward manner by partition between fluorous and organic solvents.     

A traceless perfluorooctylsulfonyl tag for deoxygenation of phenols under microwave irradiation

The perfluorooctylsulfonyl group is introduced as a traceless tag for solution-phase palladium-catalyzed deoxygenation reactions. The synthetic efficiency is improved by microwave irradiation for reaction and fluorous solid-phase extraction for separation. Further application of this traceless tag for multistep synthesis of substituted hydantoin and pyrimidine is also described.     

Fully automated reagent peak‐free liquid chromatography fluorescence analysis of highly polar carboxylic acids using a column‐switching system and fluorous scavenging derivatization

In this study, we combined a column‐switching system with a fluorous scavenging derivatization method to develop a fully automated reagent peak‐free LC fluorescence detection protocol for the analysis of highly polar carboxylic acids. In this method, highly polar carboxylic acids were derivatized with fluorescent 1‐pyrenemethylamine in the presence of 1‐ethyl‐3‐(3‐dimethylaminopropyl)carbodiimide and 1‐hydroxy‐1H‐benzotriazole. Residual excess of the unreacted reagent was tagged with 2‐(perfluorooctyl)ethyl isocyanate and then removed selectively using a fluorous column‐switching system placed in front of an analytical reversed‐phase column. The signal of the fluorous‐tagged unreacted reagent was completely absent in the resulting chromatograms; therefore, it did not interfere with the quantification of each acid especially those eluted before 20 min. The detection limits (S/N = 3) for the examined acids were in the range from 4.0 to 22 fmol per injection. We have applied this method to comparative analysis of highly polar carboxylic acids in urine samples obtained from diabetes mellitus type‐II model mice and their control.     

An efficient, recoverable fluorous organocatalyst for direct reductive amination of aldehydes

A commercially available perfluorooctyl aniline and phenyl isothiocyanate were reacted under mild conditions to give 1-[4-(perfluorooctyl)phenyl]-3-phenylthiourea as an analogue of thiourea-based organocatalyst. This fluorous organocatalyst was successfully employed to direct reductive amination of aldehydes. It could be readily separated from reaction product by fluorous solid phase extraction for direct use.     

Rapid synthesis and fluorous-phase purification of α-perfluorohexyloligothiophenes

A high-throughput methodology that facilitates the synthesis, purification and characterisation of π-conjugated oligothiophenes has been developed. α-Perfluorohexyltetrathiophene was synthesised by sequential α-bromination and microwave promoted Stille cross-coupling reactions. Each synthetic transformation was followed by a fluorous solid-phase extraction (F-SPE) procedure to isolate the desired α-perfluorohexyloligothiophene. After a single F-SPE, each oligomer gave essentially one peak by GC-MS, which enabled stepwise growth of a tetrathiophene with no additional purification of the intermediate building blocks required. We anticipate that microwave accelerated synthesis in conjunction with fluorous-phase purification of π-conjugated systems will find generic application in the high-throughput parallel-synthesis of novel organic materials for semiconductor applications.     

The synthesis and application of fluorous boronates without perfluorinated solvents

The synthesis of a fluorous diol 4 bearing a perfluorodecyl chain was described. A series of boronic acid were attached to 4 by esterification. The purification of the products was fulfilled by facile filtration instead of expensive and environmental troublesome fluorous liquid-liquid extraction. The Suzuki cross-coupling reactions of the formed fluorous boronates 5 underwent smoothly and the fluorous diol 4 was recycled in good yields.     

Semifluorinated Polymers as Ion‐selective Electrode Membrane Matrixes

Most commercially available fluorous polymers are ill suited for the fabrication of ion‐selective electrode (ISE) membranes. Therefore, we synthesized semifluorinated polymers for this purpose. Ionophore‐free ion‐exchanger electrodes made with these polymers show a selectivity range (≈14 orders of magnitude) that is nearly as wide as found previously for liquid fluorous ion‐exchanger electrodes. These polymers were also used to construct ISE membranes doped with fluorophilic silver ionophores. While the resulting ISEs were somewhat less selective than their fluorous counterparts, the semifluorinated polymers offer the advantage that they can be doped both with fluorophilic ionophores and traditional lipophilic ionophores, such as the silver ionophore Cu(II)‐I (o ‐xylylenebis[N,N ‐diisobutyldithiocarbamate]). We also cross‐linked these polymers, producing very durable membranes that retained broad selectivity ranges. K⁺ ISEs made with the cross‐linked semifluorinated polymer and the ionophore valinomycin showed selectivities similar to those of PVC membrane ISEs but with a superior thermal stability, the majority of the electrodes still giving a theoretical (Nernstian) response after exposure to a boiling aqueous solution for 10 h.     

Enantioselective carbon–carbon bond forming reactions using fluorous chiral catalysts

Fluorous chiral BINOLs and BINAP were prepared and used as the ligands for an asymmetric addition of Et₂Zn to aromatic aldehydes and an asymmetric Heck reaction, respectively. The enantioselectivities were similar in homogeneous system to those of the original non-fluorous reactions. Consecutive reactions were examined by utilizing fluorous–organic biphase and fluorous solid phase extraction techniques. Enantioselectivities in consecutive reactions were close to that attained in the non-fluorous system. The solid phase extraction method also enabled us to perform a simultaneous screening procedure.     

Total synthesis of cucurbitoside A using a novel fluorous protecting group

The first total synthesis of cucurbitoside A was achieved using a new fluorous N-phenylcarbamoyl (^FCar) protecting group. The ^FCar group was introduced into carbohydrates in high yield and was selectively removed with Bu₄NNO₂ without damaging other acyl protecting groups. The synthetic intermediates were easily isolated by fluorous solid-phase extraction.     

Fluorous thiols in oligosaccharide synthesis

A new, almost odorless fluorous thiol is synthesized, which is utilized to prepare highly fluorinated thioglycosyl donors. These thioglycosides showed excellent reactivities in glycosylation reactions. The fluorous chain, stable under esterification, etherification, deacetylation, and glycosylation conditions, allowed facile purification of the thioglycosides by solid-phase extraction through fluorous silica gel. The fluorous thiol was readily recycled.     

Rapid oligosaccharide synthesis on a fluorous support

The novel fluorous support Hfb (hexakisfluorous chain-type butanoyl) was easily prepared. The Hfb group was readily introduced into the anomeric hydroxyl group of a carbohydrate, and was recyclable after cleavage. The use of the Hfb group was applicable for the rapid oligosaccharide synthesis in which the synthetic intermediates could be purified using fluorous and normal organic solvents. Each synthetic intermediate could be monitored by TLC, NMR and mass spectrometry.     

1,1,3,3-四(全氟己基乙基)二锡氧烷二聚体在环氧化合物开环反应中的催化作用

采用氟碳-有机溶剂两相催化体系,考察了1,1,3,3-四(全氟己基乙基)二锡氧烷二聚体(1)在环氧化合物开环反应中的催化作用.结果表明,催化剂(1)在氟碳-有机溶剂两相体系中使环氧苯乙烯和甲醇的开环反应产率高达95%,¹³CNMR谱表明,开环反应的区域选择性为100%.在氟碳-有机溶剂两相催化体系中以一锅法制备了3-苯基丙酸2-甲氧基-2-苯乙醇酯,收率高,方法简便,催化剂几乎可以定量回收循环使用.     

Recyclable hafnium(IV) bis(perfluorooctanesulfonyl)amide complex for catalytic Friedel-Crafts acylation and Prins reaction in fluorous biphase system

In fluorous biphase system, hafnium(IV) bis(perfluorooctanesulfonyl)amide complex (Hf[N(SO₂C₈F₁₇)₂]₄) was found to be a highly reactive and recyclable Lewis acid catalyst for Friedel-Crafts acylation and Prins reaction at significantly low catalyst loadings (≤1 mol%). In these reactions, Hf[N(SO₂C₈F₁₇)₂]₄ is selectively soluble in the lower fluorous phase and can be recovered simply by phase separation. Furthermore, the catalyst can be reused without decrease of activity.