Advancing Boron Mediated Fluoroalkylation Reactions

Abstract

Discovering new methods to form carbon-fluorine bonds is of great interest to the scientific community. Fluorinated motifs play a key role in medicinal chemistry specifically because they exhibit desirable properties: increased lipophilicity, metabolic stability and biological activity compared to their non-fluorinate counterparts. Chemists have developed two general routes to install C–F bonds: direct fluorination and installation of preassembled larger fluoroalkyl units. The work in this dissertation focuses on the second route, more generally referred to as fluoroalkylation. We use boron Lewis-acids to form stable adducts with reactive fluoroalkyl anions. These adducts can subsequently release potent fluoroalkyl nucleophiles to further react with organic and inorganic electrophiles including palladium(II). We employ the palladium(II)-fluoroalkyl complexes in both catalytic cross-coupling and defluorinative functionalization reactions. In Chapter 2, we discuss how hexamethylborazine-CF3 adducts and potassium trimethoxyl(trifluoromethyl)borate both operate through dissociative -CF3 transfer. Alkali metal additives enhance the rate of CF3 transfer from borazine, while the opposite effect is observed for (MeO)3BCF3K which is likely due to the Lewis-basic methoxide groups on the later. In order to generate fluoroalkylation reagents that are more specifically suited towards catalysis, we synthesized and characterized 3 neutral fluoroalkyl borane species (PinBCF2Ph, B3N3Me5CF2Ph and B3N3Me5CF2Ph). PinBCF2Ph was showed to be competent in a stoichiometric Suzuki cross coupling, demonstrating the important proof of principle that these reagents have catalytic application. More chemically complex polyfluoroethane substrates also formed adducts with borazine in the presence of base, however β-fluoride elimination was operative, forming polyfluorovinyl borazine adducts. Finally, we assessed the generality of fluoroalkyl anions stabilized by borazine and their ability to transfer -RF to vinyl BPin compounds. Iodine and base could be used to induce metal-free C–C coupling of these fluoroalkylated vinyl boronate species. In Chapter 3, we demonstrated that 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 in situ formed fluoroboronate (FB(Ar3)-) or an exogenous boronic acid/ester (ArB(OR)2) and nucleophilic activator, representing a net defluorinative arylation reaction. The latter method enabled a structurally diverse substrate scope to be prepared in one pot from a representative aryl palladium-CF3 complex either discretely isolated or generated in situ from Pd(PPh3)4 and other commercially available reagents. In Chapter 4, we demonstrate C–C bond formation through nucleophilic addition reactions to prepare molecules containing internal –CF2– linkages using a hexamethylborazine-CF2Ph reagent. We were able to achieve metal-free C(sp2)-C(sp3) coupling with electron-deficient nitroarenes using an SNAr strategy. Palladium catalyzed C(sp2)-C(sp3) cross-coupling allowed for access of electron-rich and neutral aryl iodides to provide a complimentary scope of diaryl difluoromethyl products. Finally, C(sp3)-C(sp3) bonds are forged using operationally simple SN2 reactions that tolerate medicinally-relevant motifs and functional groups that are amenable to further functionalization. To demonstrate the utility of the method, allyl bromide could undergo nucleophilic substitution and with an experimentally facile intermediate removal of solvent and unreacted starting materials subsequent rhodium catalyzed hydroboration reaction.