Advances in Asymmetric Di‐and Trifluoromethylthiolation, and Di‐ and Trifluoromethoxylation Reactions

Abstract

Methods to introduce fluorine atoms or fluoroalkyl groups are highly valuable to the design and development of biologically active compounds. To date, majority of fluorinated pharmaceuticals and agrochemicals bear a fluorine atom or CF3 group at a non‐stereogenic center. The development of methods for the construction of new, emerging fluorinated motifs, in particular those combining a heteroatom and a fluorocarbon moiety have witnessed tremendous advancement in recent years; however, a challenging problem is the stereocontrol of a carbon center featuring such fluorinated motifs. This review aims to summarize the advancement in the asymmetric construction of trifluoromethylthio‐ and trifluoromethoxy compounds as well as their difluoromethyl analogues. Both the direct installation of the O−Rf and S−Rf groups (Rf=CF3, CF2H) and the exploitation of building blocks featuring these groups are detailed.

Nucleophilic trifluoromethoxylation of alkyl halides without silver

“…In recent years, the latestage and selective fluorination reaction of organic molecules has received significant attention, especially the trifluoromethoxylation reaction, which is one of the most important research hotspots, as the trifluoromethoxy group's electron-withdrawing effects and high lipophilicity (Hansch parameter π x = 1.04) [6][7][8][9][10] . However, the trifluoromethoxylation reaction remain limitations and challenges, such as limited trifluoromethoxylation reagents and instability of trifluoromethoxide anion, which impede its development and application [11][12][13][14] .…”

Extension to the SCF 2 H , SCH 2 F , and SCF 2 R Motifs ( R = PO ( OEt ) 2

“…More recently, the same group developed a diastereoselective difluoromethylthiolation of indanone-based ketoesters thanks to the use of the ylide 3d by means of a chiral auxiliary (Scheme 3.6-9) [18]. One acyclic enamino ester was also functionalized albeit in a poor 12% ee [19]. Besides, the quest for new electrophilic SCF2H sources emerged over the last years and original sources were developed, especially starting from the HCF2SO2Cl, HCF2SO2Na and HCF2SOCl reagents.…”

Markovnikov-Type Hydrotrifluoromethylchalcogenation of Unactivated Terminal Alkenes with [Me4N][XCF3] (X = S, Se) and TfOH

“…Recently, the special stereoelectronic and physicochemical properties originating from the association of the trifluoromethyl (CF 3 ) moiety with chalcogens (e.g., oxygen, sulfur and selenium) have been well documented [ 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 ]. The OCF 3 and SCF 3 groups possess strong electronegativity, considerable steric hindrance, and high lipophilicity, which can significantly change the bioactivity of a molecule [ 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 ]. The least-studied SeCF 3 group represents another important functionality, exhibiting a valuable stereoelectronic nature and lipophilicity, and has immense potential to modulate the potency of agrochemicals and pharmaceuticals [ 11 , 12 , 13 ].…”

“…Although selenium substances have shown very useful biological activities and have been widely utilized in drug design and development [ 14 , 15 , 16 , 17 , 18 ], to our knowledge, the uses of SeCF3-containing compounds have rarely been explored in comparison with those non-fluorinated analogues. This may be attributed to the lack of structural diversity, sufficient synthetic methods, and imperative biological investigation of the trifluoromethylselenolated compounds [ 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 ]. Thus, continuously developing efficient approaches for the construction of different types of SeCF 3 -containing organic scaffolds for future function studies is highly sought-after.…”