Current Organic Chemistry - Volume 19, Issue 16, 2015

As both trifluoromethylthio (CF3S) and trifluoromethoxy (CF3O) moieties have proved to be valuable functionalities in pharmaceutical chemistry, trifluoromethylthiolation and trifluoromethoxylation have received a great deal of attention. For the trifluoromethylthiolation reaction, a variety of efficient methods have been developed. Among these methods, C-H trifluoromethylthiolation avoids the need to prefunctionalize substrates, meaning that this straightforward protocol is quite attractive and promising. The first section of this review summarizes recent advances in this field, including Csp3-H, Csp2-H and Csp-H trifluoromethylthiolation and the asymmetric Csp3-H trifluoromethylthiolation reactions. Trifluoromethoxylation with safe trifluoromethoxylation reagents remains a significant challenge. The second section of this review summarizes the recent progress in trifluoromethoxylation reaction.

Because of the lack of naturally occurring pathways to form C-F bonds, and the high toxicity and/or explosive nature of the fluorination reagents (HF and F2), chemists have to seek alternative reagents and relevant fluorination and fluoroalkylation methods to construct oragnofluorides that we widely use today. The direct transition-metal mediated/catalyzed trifluoroethylation of organic scaffolds, such as arylboronic acids or esters, aryl iodides, arene, alkynes, and alkenes, has been encouragingly established. This review narrates the recent progress of the reactions with using CF3CH2X (X = I, OTs, NH2) as the trifluoroethyl reagents in the past few years. Given the high potential of trifluoroethyl-containing compounds as bioactive agents, these synthetic methodologies will find wide applications in the life-science-related fields. To overcome the negative intrinsic factors of the current trifluoroethylation reagents in these reactions, future research work will doubtlessly focus on the development of effective catalytic systems, the design of new reagents, and the investigation of the possible CF3CH2-metal intermediates.

The difunctionalization of unsaturated carbon-carbon double bond is a powerful strategy for the construction of compounds with various functional groups. The present review aims to highlight the recent developments in the fluorination of alkenes with concomitant introduction of additional functional groups. Various methods are described for both intramolecular and intermolecular fluorofunctionalization of alkenes. These fluorofunctionalization processes should find broad applications in pharmaceutical and material industries.

During recent 30 years, successful efforts have been made to develop useful electrophilic fluorinating and fluoroalkylating reagents in spite of the difficulty of generating fluorine cation (F+) and fluoroalkyl cation (F-C+). With this advancement, a wide variety of reactions between these reagents and organometallics have been reported as one of the most straightforward ways to introduce fluorinated functional groups. This review focuses on the progress of the fluorination and fluoroalkylation of organolithium, magnesium, and zinc reagents, including trifluoromethylation, difluoromethylation, bromodifluoromethylation, fluoro(di)halomethylation, perfluoroalkylation, carbonylfluoromethylation, and miscellaneous fluoroalkylations.

The utility of pentafluorosulfanyl (SF5)-containing compounds has been limited because the chemistry has not been fully explored. While significant attention has been focused on the incorporation of fluorine in C-F bonds, or the introduction of a trifluoromethyl (CF3) groups, our attention has been focused on the SF5 group. The SF5 group has a similar electron withdrawing effect as the CF3 group yet the SF5 group is significantly more lipophilic. Combining these properties results in the proclivity of SF5-containing arenes to undergo displacement reactions. The hydrophobicity of the SF5-group was used to direct the conformation of SF5-containing peptides. The profound dipole associated with pentafluorosulfanylation has been successfully used to direct the stereochemistry of the Staudinger reaction. The greater steric demand of the SF5 group relative to the CF3 group has dramatically effected the conformation of small molecules by encumbering rotational freedom. The influence of the SF5-group on the reactions of alkanes, alkenes, alkynes, arenes and various functional groups is reviewed below.

Synthetic methods for the enantioselective constructions of trifluoromethylated stereogenic centers are described. In particular, this review focuses on recent examples of catalytic enantioselective transformations with trifluoromethyl alkenes. These reactions efficiently synthesized chiral compounds with trifluoromethylated stereogenic centers.

Impressive progress has been achieved during the past decade in the incorporation of various fluroinecontaining groups, especially lightly fluorinated groups, into organic compounds. Among them, the introduction of difluoromethyl group into a compound commonly brings about many special and important effects. Two major strategies have been developed: (1) direct transfer of a CF2H group into target molecules (direct difluoromethylation); (2) the introduction of a functionlized moiety into organic substrates followed by subsequent transformation of the functional group into hydrogen or fluorine atoms (stepwise difluoromethylation). This mini review summarizes the recent developments in the selective direct and stepwise difluoromethyaltion methods during the past six years.