Peroxide-Initiated Hydrophosphinylation of <i>gem</i>-Difluoroalkenes

The installation of fluorine and fluorinated functional groups into drug-like scaffolds can perturb the physicochemical, pharmacokinetic, and pharmacodynamic properties of compounds. However, some potentially useful fluorinated substructures reside predominantly outside the realm of the current synthetic methodologies. One such substructure, the α,α-difluorophosphine oxide, might be convergently prepared by the reaction of a gem-difluorinated alkene with a P–H bond, though such nucleophilic reactions instead proceed through a C–F substitution pathway that delivers monofluorovinyl products. In contrast, we report a peroxide-initiated hydrophosphinylation reaction of gem-difluoroalkenes that avoids C–F substitution and produces a wide range of α,α-difluorophosphine oxides and functions using readily available reagents and green solvents

Ligand-Controlled Regioselective Copper-Catalyzed Trifluoromethylation To Generate (Trifluoromethyl)allenes

“Cu–CF₃” species have been used historically for a broad spectrum of nucleophilic trifluoromethylation reactions. Although recent advancements have employed ligands to stabilize and harness the reactivity of this key organometallic intermediate, the ability of a ligand to differentiate a regiochemical outcome of a Cu–CF₃-mediated or -catalyzed reaction has not been previously reported. Herein, we report the first example of a Cu-catalyzed trifluoromethylation reaction in which a ligand controls the regiochemical outcome. More specifically, we demonstrate the ability of bipyridyl-derived ligands to control the regioselectivity of the Cu-catalyzed nucleophilic trifluoromethylation reactions of propargyl electrophiles to generate (trifluoromethyl)­allenes. This method provides a variety of di-, tri-, and tetrasubstituted (trifluoromethyl)­allenes, which can be further modified to generate complex fluorinated substructures

Copper-Catalyzed Synthesis of Trifluoroethylarenes from Benzylic Bromodifluoroacetates

Trifluoroethylarenes are found in a variety of biologically active molecules, and strategies for accessing this substructure are important for developing therapeutic candidates and biological probes. Trifluoroethylarenes can be directly accessed via nucleophilic trifluoromethylation of benzylic electrophiles; however, current catalytic methods do not effectively transform electron-deficient substrates and heterocycles. To address this gap, we report a Cu-catalyzed decarboxylative trifluoromethylation of benzylic bromodifluoroacetates. To account for the tolerance of sensitive functional groups, we propose an inner-sphere mechanism of decarboxylation

Base Catalysis Enables Access to α,α-Difluoro­alkyl­thioethers

A nucleophilic addition reaction of aryl thiols to readily available β,β-difluorostyrenes provides α,α-difluoro­alkyl­thioethers. The reaction proceeds through an unstable anionic intermediate, prone to eliminate fluoride and generate α-fluorovinylthioethers. However, the use of base catalysis overcomes the facile β-fluoride elimination, generating α,α-difluoroalkyl­thioethers in excellent yields and selectivities

Tyr¹‑ψ[(<i>Z</i>)CFCH]-Gly² Fluorinated Peptidomimetic Improves Distribution and Metabolism Properties of Leu-Enkephalin

Opioid peptides are key regulators in cellular and intercellular physiological responses, and could be therapeutically useful for modulating several pathological conditions. Unfortunately, the use of peptide-based agonists to target centrally located opioid receptors is limited by poor physicochemical (PC), distribution, metabolic, and pharmacokinetic (DMPK) properties that restrict penetration across the blood-brain barrier via passive diffusion. To address these problems, the present paper exploits fluorinated peptidomimetics to simultaneously modify PC and DMPK properties, thus facilitating entry into the central nervous system. As an initial example, the present paper exploited the Tyr¹-ψ­[(<i>Z</i>)­CFCH]-Gly² peptidomimetic to improve PC druglike characteristics (computational), plasma and microsomal degradation, and systemic and CNS distribution of Leu-enkephalin (Tyr-Gly-Gly-Phe-Leu). Thus, the fluoroalkene replacement transformed an instable in vitro tool compound into a stable and centrally distributed in vivo probe. In contrast, the Tyr¹-ψ­[CF₃CH₂–NH]-Gly² peptidomimetic decreased stability by accelerating proteolysis at the Gly³–Phe⁴ position