The design, synthesis, biological evaluation, and in vivo studies of difluoromethyl ketones as GABAB agonists that are not structurally analogous to known GABAB agonists, such as baclofen or 3-aminopropyl phosphinic acid, are presented. The difluoromethyl ketones were assembled in three synthetic steps using a trifluoroacetate-release aldol reaction. Following evaluation at clinically relevant GABA receptors, we have identified a difluoromethyl ketone that is a potent GABAB agonist, obtained its X-ray structure, and presented preliminary in vivo data in alcohol-preferring mice. The behavioral studies in mice demonstrated that this compound tended to reduce the acoustic startle response, which is consistent with an anxiolytic profile. Structure-activity investigations determined that replacing the fluorines of the difluoromethyl ketone with hydrogens resulted in an inactive analogue. Resolution of the individual enantiomers of the difluoromethyl ketone provided a compound with full biological activity at concentrations less than an order of magnitude greater than the pharmaceutical, baclofen.

Copper(II) aryl species are proposed key intermediates in Cu-catalyzed cross-coupling reactions. Novel three-coordinate copper(II) aryls [Cu]-CF supported by ancillary β-diketiminate ligands form in reactions between copper(II) alkoxides [Cu]-OBu and B(CF). Crystallographic, spectroscopic, and DFT studies reveal geometric and electronic structures of these Cu(II) organometallic complexes. Reaction of [Cu]-CF with the free radical NO results in C-N bond formation to give [Cu](η-ONCF). Remarkably, addition of the phenolate anion PhO to [Cu]-CF directly affords diaryl ether PhO-CF with concomitant generation of the copper(I) species [Cu](solvent) and {[Cu]-CF}. Experimental and computational analysis supports redox disproportionation between [Cu]-CF and {[Cu](CF)(OPh)} to give {[Cu]-CF} and [Cu](CF)(OPh) unstable toward reductive elimination to [Cu](solvent) and PhO-CF.

A variety of acyl protected phenols AcOAr participate in sp C-H etherification of substrates R-H to give alkyl aryl ethers R-OAr employing BuOOBu as oxidant with copper(I) β-diketiminato catalysts [Cu]. Although 1°, 2°, and 3° C-H bonds may be functionalized, selectivity studies reveal a preference for the construction of hindered, 3° C-OAr bonds. Mechanistic studies indicate that β-diketiminato copper(II) phenolates [Cu]-OAr play a key role in this C-O bond forming reaction, formed via transesterification of AcOAr with [Cu]-OBu intermediates generated upon reaction of [Cu] with BuOOBu.