A metal-free strategy to construct fluoroalkyl-olefin linkages using fluoroalkanes.

We present a metal-free strategy to access fluoroalkyl-olefin linkages from fluoroalkane precursors and vinyl-pinacol boronic ester (BPin) reagents. This reaction sequence is templated by the boron reagent, which induces C-C bond formation upon oxidation. We developed this strategy into a one-pot synthetic protocol using RCFH precursors directly with vinyl-BPin reagents in the presence of a Brønsted base, which tolerated oxygen- and nitrogen-containing heterocycles, and aryl halogens.

Understanding Reactive Sulfur Species through P/S Synergy.

We investigated the differential oxidative and nucleophilic chemistry of reactive sulfur and oxygen anions (SSNO, SNO, NO, S, and HS) using the simple reducing electrophile PPhCl. In the case of SSNO reacting with PPhCl, a complex mixture of mono and diphosphorus products is formed exclusively in the P(V) oxidation state. We found that the phosphine stoichiometry dictates selectivity for oxidation to P=S/P=O products or transformation to P species.

Nucleophilic strategies to construct -CF- linkages using borazine-CFAr reagents.

Using a Lewis acid-quenched CFPh reagent, we show C-C bond formation through nucleophilic addition reactions to prepare molecules containing internal -CF- linkages. We demonstrate C(sp)-C(sp) coupling using both SAr reactions and Pd-catalysis. Finally, C(sp)-C(sp) bonds are forged using operationally simple S2 reactions that tolerate medicinally-relevant motifs.

Defluorinative Functionalization of Pd(II) Fluoroalkyl Complexes.

When subjected to arylboranes, anionic trifluoromethyl and difluorobenzyl palladium(II) complexes undergo fluoride abstraction followed by 1,1-migratory insertion. The resulting intermediate fluoroalkyl species can be induced to undergo a subsequent transmetalation and reductive elimination from either an formed fluoroboronate (FB(Ar)) or an exogenous boronic acid/ester (ArB(OR)) and nucleophilic activator, representing a net defluorinative arylation reaction. The latter method enabled a structurally diverse substrate scope to be prepared from either an isolated palladium-CF complex, or from Pd(PPh) and other commercially available reagents.

The Difluoromethyl Group as a Masked Nucleophile: A Lewis Acid/Base Approach.

The difluoromethyl group (R-CFH) imparts desirable pharmacokinetic properties to drug molecules and is commonly targeted as a terminal functional group that is not amenable to further modification. Deprotonation of widely available Ar-CFH starting materials to expose nucleophilic Ar-CF synthons represents an unexplored, yet promising route to construct benzylic Ar-CF-R linkages. Here we show that the combination of a Brønsted superbase with a weak Lewis acid enables deprotonation of Ar-CFH groups and capture of reactive Ar-CF fragments.

Borazine-CF Adducts for Rapid, Room Temperature, and Broad Scope Trifluoromethylation.

A fluoroform-derived borazine CF transfer reagent is used to effect rapid nucleophilic reactions in the absence of additives, within minutes at 25 °C. Inorganic electrophiles spanning seven groups of the periodic table can be trifluoromethylated in high yield, including transition metals used for catalytic trifluoromethylation. Organic electrophiles included (hetero)arenes, enabling C-H and C-X trifluoromethylation reactions.