Current Organic Synthesis - Volume 7, Issue 5, 2010

From the organic synthesis point of view, major reviews concerning the uses and applications of the trifluoromethyl group in chemistry appeared in the 90's by Kiselyov [1] and McClinton [2]. Despite fluorine atoms are extremely rare in natural compounds, they have a valuable importance in drug synthesis and agrochemicals. Particularly, the trifluoromethyl group is very common in drug compounds (i.e marketed pharmaceutical compounds such as the anti-depressant fluoxetine 1 (Prozac), the COX-2 inhibitor celecoxib 2 (Celebrex), the antimalarial drug mefloquine 3 and the HIV protease inhibitor tipranavir 4 (Aptivus)). Trifluoromethyl compounds are also valuable intermediates in synthesis, for the preparation of pharmaceuticals, agrochemicals and ionic liquids. Since Moisson's elemental F2 discovery in 1886, fluorine had attracted the attention of chemists due to its properties as a reagent for the direct preparation of several organic and inorganic compounds; however, its extreme reactivity limits its widespread laboratory use. The 1970's decade marked the development of new safer and selective fluorinating agents, compatible with ordinary laboratory equipment, and thus permitted a growing field for the fluorination of organic key molecules. Recent developments in the synthetic methodology toward trifluoromethyl containing organic molecules have given rise to a great interest in the scientific community, from both academy and industry. This special Issue of Current Organic Synthesis covers some interesting aspects of the trifluoromethyl group in organic synthesis, such as the trifluomethylation of carbonyl compounds, stereoselective construction of an assymetric center containing a trifluoromethyl group, preparation of trifluorometyl-substituted fused bicycled-heterocycles and the trifluoacetylation of organic molecules, including its application for the preparation of trifluomethyl heterocycles.

This paper reviews the recent findings on trifluoromethylation of carbonyl compounds. Emphasis was given to the description of the trifluoromethylating agents, their activation mode, their reaction with carbonyl compounds, as well as applications in organic synthesis.

This review covers the trifluoroacetylation reaction in organic synthesis and its importance for the construction of trifluoromethylated compounds. Developed reagents for trifluoroacetylation are described, as well as their characteristics and preparation, giving emphasis on their applications and limitations in organic synthesis. Trifluoroacetylation, although commonly employed for the protection of functional groups (amines, alcohols, thiols), may be a useful tool for the further introduction of a trifluoromethyl group into an organic molecule. Its application, mainly in the synthesis of trifluoromethyl-heterocycles such as benzothiadiazines, pyrazoles, benzodiazepines, thieno-thiazines, isoxazoles and pyrimidines, is also covered.

Development of efficient routes to many kinds of fluorine-containing heterocycles is an attractive area of research since these compounds are now widely recognized as important organic materials for their potential use in medicinal and agricultural scientific fields. This review survey research works on trifluoromethyl- substituted fused bicyclic heterocycles and their corresponding benzo-fused analogues over the last ten years. Different approaches for the synthesis of such systems are discussed.

Stereoselective synthetic methods for the construction of the tertiary or quaternary asymmetric carbon centers having a trifluoromethyl group and carbon substituent(s) or hydrogen atom, not heteroatom substituent(s), are described.

The literature concerning amination of electron rich arenes with azodiesters using catalytic amount of Lewis acids as ZnI2, ZnCl2, CF3SO3H or CF3COOH and reports focused on application of diprotected hydrazine derivatives as versatile intermediates in the synthesis of several important compounds are reviewed. The reports concerning reactions of different olefins with diethyl azodicarboxylate (DEAD) and 4-phenyl-1,2,4-triazoline-3,5-dione (PTAD) carried out as spontaneous ene-additions or reactions catalyzed by Lewis acids as Et2AlCl, Me2AlCl, BF3, Et2BBr, Ti(OPr)4 and SnCl4 are presented. The catalysis by lithium perchlorate of ene reactions as well as the reactions of organotin phenoxides and electron rich arenes with bis(trichloroethyl) azodicarboxylate, (DEAD) and (PTAD) is discussed in this review.

Since past few decades, Room Temperature Ionic Liquids (RTILs) have extensively been used in organic synthesis as solvents, catalysts and catalyst/solvents in chemical as well as enzymatic reactions, whereas their interest in various different branches of science is expanding exponentially. RTILs show an enhanced performance in a number of syntheses involving carbohydrates when compared to the conventional organic solvents owing to their very interesting and attractive features, viz. simple handling, high yield, less reaction time, benign environmental character, ease of synthesis and excellent recyclability. Carbohydrates are not known only for their vital commercial applications as foods, drugs and chemical feed stocks etc., but sugar based molecules are also identified to play pivotal roles in various pathologically and physiologically important biological processes including cellular recognition, adhesion, migration, invasion, communication, bacterial/viral infection, tumor metastasis etc. The clear understanding of role of sugars in these important biological events has led to the increased demand for significant amounts of carbohydrate based molecules for complete chemical, biological, medicinal, and pharmacological investigations. Therefore, tremendous efforts have been made to develop novel and facile procedures for the synthesis of sugar based molecules of great biological interest and their modification. With an increasing focus on the glycomics, the RTILs solvent may offer promising solutions in carbohydrate chemistry. However, there is lack of recent and concise reports dealing with the RTILs in the field of carbohydrate chemistry particularly, in relevance to dissolution and functionalization, and their further modifications including glycosylation. This review highlights the application of RTILs that have been extensively used in carbohydrate chemistry.