Trifluoromethylation of Alkenes with Concomitant Introduction of Additional Functional Groups

Abstract

The trifluoromethyl group is found in many synthetic bioactive compounds, and the difunctionalization of a C=C bond, as a powerful strategy for the construction of compounds with various functional groups, has been intensively investigated. Therefore, the difunctionalizing trifluoromethylation of alkenes has attracted growing interest because of the potential of the products as building blocks for bioactive molecules. In this review, we focus on recent advances in the trifluoromethylation of alkenes with concomitant introduction of additional functional groups.

Catalytic asymmetric radical aminoperfluoroalkylation and aminodifluoromethylation of alkenes to versatile enantioenriched-fluoroalkyl amines

“…In contrast to the great success in developing nucleophilic and electrophilic fluoroalkylation reactions, the corresponding asymmetric radical fluoroalkylation versions remain scarce171819, largely because of the intrinsic reactivity of the involved odd-electron species20. On the other hand, intermolecular addition of fluoroalkyl radicals to unactivated alkenes has emerged as one of the most attractive strategies for the direct 1,2-difunctionalization of alkenes to simultaneously construct two vicinal chemical bonds by using a variety of radical fluoroalkyl precursors in racemic form21222324252627. The development of asymmetric catalytic versions of such transformations, however, still remains a formidable challenge with few successful examples.…”

“…Within the burgeoning field of radical fluoroalkyl reagents21222324252627, great progress has been made in the direct 1,2-difunctionalization-type fluoroalkylation of alkenes by employing stable fluoroalkylsulfonyl chlorides as the radical sources to in situ generate the desired fluoroalkyl radicals3536373839. For the efficient collection of fundamental yet synthetically formidable chiral β-fluoroalkyl amine-building blocks directly from readily available materials and particularly intrigued by our recent success in asymmetric radical aminotrifluoromethylation of alkenes using a dual-catalytic system of Cu(I) and CPA34, we envisaged the possibility of realizing an unprecedented asymmetric radical aminoperfluoroalkylation and aminodifluoromethylation of alkenes with various fluoroalkylsulfonyl chlorides through such a dual-catalytic system (Fig.…”

An Unconventional Mechanistic Insight into SCF3 Formation from Difluorocarbene: Preparation of 18F‐Labeled α‐SCF3 Carbonyl Compounds

“…Furthermore, in all these Cu-promoted trifluoromethylthiolation reactions, no trifluoromethylated product was observed. Since the substrates have proved to be able to undergo Cu-promoted trifluoromethylation with trifluoromethyl anion, [9, 17] these results (no trifluoromethane and no trifluoromethylation product) further confirmed that trifluoromethyl anion was not the intermediate for the generation of trifluoromethylthio anion.…”

“…A quick survey of reaction parameters finally revealed that an efficient transformation of our testing substrate, 2-bromoacetophenone with PDFA/S 8 /CsF system was achieved in 74% yield by the addition of CuBr 2 . We proposed that Cu-promoted trifluoromethylthiolation reactions occurred via ligand exchange of SCF 3 − with copper source to generate [CuSCF 3 ] complex, [17,18] followed by addition-reductive elimination to furnish final SCF 3 products. Indeed, we have observed [CuSCF 3 ] complex by 19 F NMR spectrometry in the trifluoromethylthiolation reaction systems (SI, section 5), further supporting this proposed reaction pathway.…”

Copper-catalyzed trifluoromethylation of alkenes: synthesis of trifluoromethylated benzoxazines

“…4 As a consequence, versatile methodologies are being established for the introduction of CF 3 moiety into heterocycles and related organic molecules. [5][6][7][8][9][10][11][12] Copper-catalyzed trifluoromethylation of terminal alkenes through allylic C-H bond activation has been accomplished by Fu and Liu et al exploiting copper catalyst, Umemoto's reagent, and 2,4,6-trimethyl pyridine reaction system (scheme 1, eq 1). 10a In view of recent advances in Cu-catalyzed functionalization of alkenes, 16,17 we envisioned, trifluoromethylation of terminal alkene followed by intramolecular addition of oxygen for the synthesis of trifluoromethylated benzoxazines keeping allylic C-H bond intact (eq 2).…”