Recent Advances in Trifluoromethylation Reactions with Electrophilic Trifluoromethylating Reagents

Abstract

Electrophilic trifluoromethylation reactions have been the latest approach to achieve the fluoroalkylation of compounds with newly-discovered reagents, such as the Togni's (1-trifluoromethyl-1,2-benziodoxol-3-(1 H)-one), Umemoto's (S-(trifluoromethyl)dibenzothiophenium tetrafluoroborate), Yagupolskii's (S-(trifluoromethyldiarylsulfonium salts), Shreeve's (S-(trifluoromethyl)dibenzothiophenium triflate), and Shibata's (trifluoromethylsulfoximine salts) reagents. All these reagents produce an electrophilic trifluoromethylating (CF3 (+) ) species that undergoes reaction with nucleophiles. In addition, these latter reactive species (i.e. CF3 (+) ) can undergo electron-transfer (ET) processes affording CF3 (⋅) radicals that expand the scope to substrates other than conventional nucleophiles that can undergo reaction. In this Review, we shall discuss the trifluoromethylation reactions of diverse families of organic substrates of biological interest as a means to comparing the reagents scope and best reaction conditions. Some, though not all, of these reactions require the assistance of metal or organometallic catalysts. Some require additives and catalysts to promote the fluoroalkylation reaction, but invariably all are initiated and carried out by electrophilic trifluoromethylating species.

Lanthanum‐Catalyzed Enantioselective Trifluoromethylation by Using an Electrophilic Hypervalent Iodine Reagent

“…[1][2][3][4][5] Indeed, the appropriate introductiono fafluorine atom or a fluorinated group can drastically affect the biological and physical properties of am olecule andi ts physiological behavior with respect to the modeo fa ction and metabolism. [10][11][12][13][14][15][16][17][18][19][20][21][22][23] The introduction of at rifluoromethylg roup in an enantioselective manner is one of the most challengings ynthetic problems. [10][11][12][13][14][15][16][17][18][19][20][21][22][23] The introduction of at rifluoromethylg roup in an enantioselective manner is one of the most challengings ynthetic problems.…”

“…Thus, individual components of the reaction were analyzed, as well as mixtures of two or more components, and finally the ongoingr eaction in its initial state and after 10 and 75 minutes, respectively (see Supporting Information). Other authors [31] have proposed as imilar activation in the presenceo fo ther Lewis acids as MgBr 2 [32] or CuI [12] .F urthermore,t he appearance of a broad signala td = À33.7 ppm in the 19 FNMR spectrum of a mixture of all the components of the reaction, namely 1a, L3, 3b and La(OTf) 3 (1:0.4:1:0.4), likely indicates the coordination of 3b to lanthanide as mixtures of binary and tertiary complexes. The ESI-MS spectrumo fas toichiometricm ixture of L3 and La(OTf) 3 showed one peak m/z = 829.9587c orresponding to ac omplex (denoted as INT1 in Figure 1 results indicatet hat in the presence of PyBOX ligands the bketo ester is in itse nolatef orm.…”

Synthetic Approaches to Trifluoromethoxy‐Substituted Compounds

“…Among the known electrophilic trifluoromethylation reagents, [15] two families have been used for the trifluoromethylation of alcohols or derivatives thereof, namely (trifluoromethyl)dibenzochalcogenophenium salts ("Umemoto reagents") [16] and hypervalent iodine reagents ("Togni reagents"). [17] However, when trifluoromethylation was attempted with Umemoto reagents, C-trifluoromethylation was found to be favored over O-trifluoromethylation.…”

Recent Developments in the Trifluoromethylation of Alkynes

“…[2] Among previousr eports, the construction of the CÀCF 3 bond has gained enormous interest due to its unique electronegativity,m etabolic stability,a nd lipophilicity. [6] However,a sa ni mportant branch of trifluoromethylation reactions, the trifluoromethylation of alkynes remains in its infancy, since crucial milestones are not yet reached. Somer eviews have summarized the recent breakthrough in this area.…”