Trifluoromethyl ethers and -thioethers as tools for medicinal chemistry and drug discovery.

The ever-growing number of fluorinated compounds in medicinal and agrochemical applications has led to a remarkable positive emulation in research. The last few years have been the witness of several advances in the search of more effective and user-friendlier methods for the introduction of fluorine as substituent or of fluorinated groups on various structures. In particular, the synthesis of trifluoromethyl ethers and thioethers is receiving increasing attention due to the peculiar properties of the OCF3 and SCF3 groups. This review will cover the different methods for the preparation of trifluoromethyl ethers and thioethers, and will emphasize on the most recent developments, including the use of catalytic methods or of methodologies for trifluoromethylation or trifluoromethanesulfanylation.

Recent advances in transition metal-catalyzed Csp(2)-monofluoro-, difluoro-, perfluoromethylation and trifluoromethylthiolation.

In the last few years, transition metal-mediated reactions have joined the toolbox of chemists working in the field of fluorination for Life-Science oriented research. The successful execution of transition metal-catalyzed carbon-fluorine bond formation has become a landmark achievement in fluorine chemistry. This rapidly growing research field has been the subject of some excellent reviews. Our approach focuses exclusively on transition metal-catalyzed reactions that allow the introduction of -CFH2, -CF2H, -C n F2 n +1 and -SCF3 groups onto sp² carbon atoms. Transformations are discussed according to the reaction-type and the metal employed. The review will not extend to conventional non-transition metal methods to these fluorinated groups.

Synthesis and growth inhibition activity of fluorinated derivatives of tamoxifen.

The design and synthesis of 11 fluorinated derivatives of tamoxifen are described. Growth inhibition values (GI50) on human HT-29, M21, MCF7, and MDA-MB-231 tumor cells are also reported. In general, the GI50 values are similar or slightly higher than tamoxifen with the most active compound on MCF7 cell line having a GI50=3.6µM. Surprisingly, as opposed to tamoxifen, both geometrical isomers behave similarly. We hypothesize that this behavior is due to in vitro isomerization of the compounds.

Synthetic approaches to monofluoroalkenes.

Monofluoroalkenes are an important fluorinated class of compounds with applications in medicinal chemistry, material sciences and organic chemistry. An overview of methods allowing synthetic access to these fluorinated building blocks is provided. In particular, this critical review, which covers publications up to October 2010, will be divided according to the substitution pattern of the monofluoroalkenes, i.e. di-, tri- or tetra-substituted. Within each group, the various synthetic approaches will be divided according to the reaction type (282 references).

Stereoselective synthesis of both stereoisomers of ß-fluorostyrene derivatives from a common intermediate.

The stereoselective synthesis of both cis- and trans-ß-fluorostyrene derivatives from a common intermediate, (Z)-1-aryl-2-fluoro-1-(trimethylsilyl)ethenes, is described. The trans isomers are obtained by a stereospecific replacement of the silyl group in the presence of water and a fluoride source, whereas the preparation of the cis isomers is achieved by a bromination/desilicobromination sequence followed by reduction of the newly created C-Br bond. A stereoselective transformation of both stereoisomers of ß-fluorostyrene is also presented.

Stereocontrolled access to unsymmetrical 1,1-diaryl-2-fluoroethenes.

A simple and effective method for stereocontrolled preparation of 1,1-diaryl-2-fluoroethenes is reported. First, 1-aryl-1-bromo-2-fluoroethenes are generated using an addition/elimination reaction of hydride to silylated beta,beta-difluorostyrene derivatives followed by a bromination/desilicobromination reaction. Subsequent Suzuki-Miyaura coupling with a variety of boronic acids gives access to the desired 1,1-diaryl-2-fluoroethenes.

Stereocontrolled approach to bromofluoroalkenes and their use for the synthesis of tri- and tetrasubstituted fluoroalkenes.

An addition/elimination reaction of organolithium reagents to silylated beta,beta-difluorostyrene derivatives followed by a bromination/desilicobromination reaction provides a simple and effective synthetic approach to a wide range of bromofluoroalkenes (up to >97/3). In addition, the bromofluoroalkenes can be used in Pd-catalyzed transformations giving access to both tri- and tetrasubstituted fluoroalkenes.