Catalytic asymmetric nucleophilic fluorination using BF3·Et2O as fluorine source and activating reagent

Fluorination using chiral catalytic methods could result in a direct access to asymmetric fluorine chemistry. However, challenges in catalytic asymmetric fluorinations, especially the longstanding stereochemical challenges existed in BF3·Et2O-based fluorinations, have not yet been addressed. Here we report the catalytic asymmetric nucleophilic fluorination using BF3·Et2O as the fluorine reagent in the presence of chiral iodine catalyst. Various chiral fluorinated oxazine products were obtained with good to excellent enantioselectivities (up to >99% ee) and diastereoselectivities (up to >20:1 dr). Control experiments (the desired fluoro-oxazines could not be obtained when Py·HF or Et3N·3HF were employed as the fluorine source) indicated that BF3·Et2O acted not only as a fluorine reagent but also as the activating reagent for activation of iodosylbenzene.

Reaction of [18F]Fluoride at Heteroatoms and Metals for Imaging of Peptides and Proteins by Positron Emission Tomography

The ability to radiolabel proteins with [18F]fluoride enables the use of positron emission tomography (PET) for the early detection, staging and diagnosis of disease. The direct fluorination of native proteins through C-F bond formation is, however, a difficult task. The aqueous environments required by proteins severely hampers fluorination yields while the dry, organic solvents that promote nucleophilic fluorination can denature proteins. To circumvent these issues, indirect fluorination methods making use of prosthetic groups that are first fluorinated and then conjugated to a protein have become commonplace. But, when it comes to the radiofluorination of proteins, these indirect methods are not always suited to the short half-life of the fluorine-18 radionuclide (110 min). This review explores radiofluorination through bond formation with fluoride at boron, metal complexes, silicon, phosphorus and sulfur. The potential for these techniques to be used for the direct, aqueous radiolabeling of proteins with [18F]fluoride is discussed.

Mechanistic Studies of Pd-Catalyzed Fluorination of Cyclic Vinyl Triflates: Evidence for in situ Ligand Modification

<div><div><div><p>Pd-catalyzed nucleophilic fluorination reactions are important methods for the synthesis of fluoroarenes and fluoroalkenes. However, these reactions can generate a mixture of regioisomeric products that are often difficult to separate. While investigating the Pd- catalyzed fluorination of cyclic vinyl triflates, we observed that the addition of a substoichiometric quantity of TESCF3 significantly improves both the efficiency and the regioselectivity of the fluorination process. Herein, we report a combined experimental and computational study on the mechanism of this transformation focused on the role of TESCF3. We found that in the absence of additives such as TESCF3, the transmetalation step produces predominantly the thermodynamically more stable trans isomer of the key LPd(vinyl)F complex (L = biaryl monophosphine ligand). This intermediate, rather than undergoing reductive elimination, preferentially reacts through an intramolecular β-deprotonation to form a Pd-cyclohexyne intermediate. This undesired reactivity is responsible for the low efficiency (11% yield) and poor regioselectivity (1.8:1) of the catalytic reaction. When TESCF3 is added to the reaction mixture, the cis-LPd(vinyl)F complex is instead formed, through a pathway involving an unusual dearomatization of the ligand by nucleophilic attack from a trifluoromethyl anion (CF3–). In contrast to the trans isomer, this cis-LPd(vinyl)F complex readily undergoes reductive elimination to provide the vinyl fluoride product with desired regioselectivity, without the generation of Pd-cyclohexyne intermediates.</p></div></div></div>

Mechanistic Studies of Pd-Catalyzed Fluorination of Cyclic Vinyl Triflates: Evidence for in situ Ligand Modification

<div><div><div><p>Pd-catalyzed nucleophilic fluorination reactions are important methods for the synthesis of fluoroarenes and fluoroalkenes. However, these reactions can generate a mixture of regioisomeric products that are often difficult to separate. While investigating the Pd- catalyzed fluorination of cyclic vinyl triflates, we observed that the addition of a substoichiometric quantity of TESCF3 significantly improves both the efficiency and the regioselectivity of the fluorination process. Herein, we report a combined experimental and computational study on the mechanism of this transformation focused on the role of TESCF3. We found that in the absence of additives such as TESCF3, the transmetalation step produces predominantly the thermodynamically more stable trans isomer of the key LPd(vinyl)F complex (L = biaryl monophosphine ligand). This intermediate, rather than undergoing reductive elimination, preferentially reacts through an intramolecular β-deprotonation to form a Pd-cyclohexyne intermediate. This undesired reactivity is responsible for the low efficiency (11% yield) and poor regioselectivity (1.8:1) of the catalytic reaction. When TESCF3 is added to the reaction mixture, the cis-LPd(vinyl)F complex is instead formed, through a pathway involving an unusual dearomatization of the ligand by nucleophilic attack from a trifluoromethyl anion (CF3–). In contrast to the trans isomer, this cis-LPd(vinyl)F complex readily undergoes reductive elimination to provide the vinyl fluoride product with desired regioselectivity, without the generation of Pd-cyclohexyne intermediates.</p></div></div></div>

Mechanistic study of nucleophilic fluorination for the synthesis of fluorine-18 labeled fluoroform with high molar activity from N-difluoromethyltriazolium triflate

Route a: desired SN2 reaction of fluoride to form fluoroform with high molar activity; route b: side reaction to form methyl fluoride; route c: side reaction to form difluorocarbene to give fluoroform with lower molar activity.

Fluorine effect in nucleophilic fluorination at C4 of 1,6-anhydro-2,3-dideoxy-2,3-difluoro-β-D-hexopyranose

In this work, we have developed a simple synthetic approach using Et3N·3HF as an alternative to the DAST reagent. We controlled the stereochemistry of the nucleophilic fluorination at C4 of 1,6-anhydro-2,3-dideoxy-2,3-difluoro-4-O-triflate-β-ᴅ-talopyranose using Et3N·3HF or in situ generated Et3N·1HF. The influence of the fluorine atom at C2 on reactivity at C4 could contribute to a new fluorine effect in nucleophilic substitution. Finally, with the continuous objective of synthesizing novel multi-vicinal fluorosugars, we prepared one difluorinated and one trifluorinated alditol analogue.