The dual role of thiourea in the thiotrifluoromethylation of alkenes

Alkenes substituted with a thiourea undergo C-CF3 followed by intramolecular C-S bond formation with the Togni reagent and trifluoroacetic acid (TFA) at room temperature; thiols and thioamides are not suitable S-sources for this reaction. This anti-addition process involves a CF3 radical, and affords CF3-substituted thiazolines and thiazines for medicinal applications. A metal or photoredox catalyst is not required as the thiourea acts as a reductant, as well as serving as an S-source capable of adding to a C-centered radical. Mechanistic work comparing the reactivity of thiourea, urea, thioamide and thiol in the context of alkene trifluoromethylation demonstrates that in this series, the thiourea is unique for its ability to release CF3 radical from the Togni reagent, and to orchestrate trifluoromethylation followed by S-cyclization with both activated and unactivated alkenes

Regio- and stereoretentive synthesis of branched, linear (E)- and (Z)-allyl fluorides from allyl carbonates under Ir-catalysis

This paper describes a new catalytic method for the regio- and stereocontrolled fluorination of allylic carbonates. This transformation uses TBAF·4tBuOH as the fluoride source and [Ir(COD)Cl]2 as the catalyst; the most commonly used [Ir(COD)Cl]2/phosphoramidite system is ineffective. Synthetically, this reaction is characterized by a high degree of structural conservation in going from substrates to the products. The fluorination of (E)-allylic carbonates leading to linear (E)-allylic fluorides (l : b > 20 : 1, E : Z > 20 : 1) is unprecedented and a unique feature of fluoride as the nucleophile. The first examples of transition metal catalyzed fluorination affording (Z)-allyl fluorides (Z : E ratio >20 : 1) are disclosed along with the successful fluorination of branched, linear (E)- and (Z)-allyl carbonates with [18F] fluoride in the presence of [Ir(COD)Cl]2. 18O-Labeling of the reactant reveals internal return during the allylic ionization step, and pathways for effective intra- and intermolecular isotope exchange. © 2013 The Royal Society of Chemistry

The dual role of thiourea in the thiotrifluoromethylation of alkenes

Alkenes substituted with a thiourea undergo C-CF3 followed by intramolecular C-S bond formation with the Togni reagent and trifluoroacetic acid (TFA) at room temperature; thiols and thioamides are not suitable S-sources for this reaction. This anti-addition process involves a CF3 radical, and affords CF3-substituted thiazolines and thiazines for medicinal applications. A metal or photoredox catalyst is not required as the thiourea acts as a reductant, as well as serving as an S-source capable of adding to a C-centered radical. Mechanistic work comparing the reactivity of thiourea, urea, thioamide and thiol in the context of alkene trifluoromethylation demonstrates that in this series, the thiourea is unique for its ability to release CF3 radical from the Togni reagent, and to orchestrate trifluoromethylation followed by S-cyclization with both activated and unactivated alkenes

Silver-Mediated ¹⁸F-Labeling of Aryl-CF₃ and Aryl-CHF₂ with ¹⁸F-Fluoride

We report the synthesis of [18F]arylCF3 and [18F]arylCHF2 derivatives from arylCF2Br and arylCHFCl precursors applying a silver-mediated halogen exchange with [18F]fluoride. In the absence of Ag(I)OTf, no reaction takes place at room temperature for both classes of substrates; this result demonstrates the beneficial role of silver(I) as a means to induce 18F-incorporation under very mild conditions

18F-trifluoromethylation of unmodified peptides with 5-18F-(trifluoromethyl)dibenzothiophenium trifluoromethanesulfonate

The 18F-labeling of 5-(trifluoromethyl)-dibenzothiophenium trifluoromethanesulfonate, commonly referred to as the Umemoto reagent, has been accomplished applying a halogen exchange 18F-fluorination with 18F-fluoride, followed by oxidative cyclization with Oxone and trifluoromethanesulfonic anhydride. This new 18F-reagent allows for the direct chemoselective 18F-labeling of unmodified peptides at the thiol cysteine residue

Synthesis and reactivity of (18)F-labeled α,α-Difluoro-α-(aryloxy)acetic acids.

In this work, we describe the (18)F-labeling of α,α-difluoro-α-(aryloxy)acetic acid derivatives and demonstrate that these building blocks are amenable to post-(18)F-fluorination functionalization. Protodecarboxylation offers a new entry to (18)F-difluoromethoxyarene, and the value of this approach is further demonstrated with coupling processes leading to representative (18)F-labeled TRPV1 inhibitors and TRPV1 antagonists

Synthesis and reactivity of (18)F-labeled α,α-Difluoro-α-(aryloxy)acetic acids.

In this work, we describe the (18)F-labeling of α,α-difluoro-α-(aryloxy)acetic acid derivatives and demonstrate that these building blocks are amenable to post-(18)F-fluorination functionalization. Protodecarboxylation offers a new entry to (18)F-difluoromethoxyarene, and the value of this approach is further demonstrated with coupling processes leading to representative (18)F-labeled TRPV1 inhibitors and TRPV1 antagonists

Catalytic hydrotrifluoromethylation of unactivated alkenes.

A visible-light-mediated hydrotrifluoromethylation of unactivated alkenes that uses the Umemoto reagent as the CF(3) source and MeOH as the reductant is disclosed. This effective transformation operates at room temperature in the presence of 5 mol % Ru(bpy)(3)Cl(2); the process is characterized by its operational simplicity and functional group tolerance

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

Although great success has been achieved in asymmetric fluoroalkylation reactions via nucleophilic or electrophilic processes, the development of asymmetric radical versions of this type of reactions remains a formidable challenge because of the involvement of highly reactive radical species. Here we report a catalytic asymmetric radical aminoperfluoroalkylation and aminodifluoromethylation of alkenes with commercially available fluoroalkylsulfonyl chlorides as the radical sources, providing a versatile platform to access four types of enantioenriched α-tertiary pyrrolidines bearing β-perfluorobutanyl, trifluoromethyl, difluoroacetyl and even difluoromethyl groups in excellent yields and with excellent enantioselectivity. The key to success is not only the introduction of the CuBr/chiral phosphoric acid dual-catalytic system but also the use of silver carbonate to suppress strong background and side hydroamination reactions caused by a stoichiometric amount of the in situ generated HCl. Broad substrate scope, excellent functional group tolerance and versatile functionalization of the products make this approach very practical and attractive