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.
1 A study was made of the effects of 5-hydroxytryptamine (5-HT) on pressor response induced in vivo by electrical stimulation of the sympathetic outflow from the spinal cord of pithed rats. All animals had been pretreated with atropine. Intravenous infusion of 5-hydroxytryptamine at doses of 10 and 20 jig kg-' min-' reduced the pressor effects obtained by electrical stimulation at intervals of 10 min over the 1 h of infusion. 2 This inhibitory action of 5-HT was depressed by cyproheptadine and methiothepin but was not modified by ketanserin or MDL-72222. By contrast, the inhibitory action of 5-HT was lost in pithed rats that had been pretreated with exogenous noradrenaline.3 The 5-HT, receptor agonist 5-carboxamidotryptamine (5-CT) caused an inhibition of the pressor response, whereas the 5-HT3 receptor agonist, 1-phenylbiguanide, produced a variable but significant increase in the pressor response. The 5-HT2 receptor agonist, m-CPP, did not modify the pressor sympathetic response. 4 Our results suggest that 5-hydroxytryptamine interferes with sympathetic neurotransmission by inhibiting pressor effects as a result of stimulation of the complete sympathetic outflow, and that this inhibition is mainly through a presynaptic 5-HT1 mechanism.
This report describes the development of a photochemical method for C(sp2)−H pyridination that leverages the photoexcitation of electron donor–acceptor (EDA) complexes. Experimental and DFT studies show that black light (λmax≈350 nm) irradiation of solutions of protonated pyridines (acceptors) and aromatic C−H substrates (donors) results in single electron transfer to form aryl radical cation intermediates that can be trapped with pyridine nucleophiles under aerobic conditions. With some modification of the reaction conditions, this EDA activation mode is also effective for promoting the oxidatively triggered SNAr pyridination of aryl halides. Overall, this report represents an inexpensive and atom‐economical approach to photochemical pyridination reactions that eliminates the requirement of an exogenous photocatalyst.
A bioinspired synthesis of Pinoxaden
metabolites 2–5 is described herein. A site-selective
C–H oxidation strategy
validated by density functional theory (DFT) calculations was devised
for preparing metabolites 2–4. Oxidation of the
benzylic C–H bond in tertiary alcohol 7 using
K2S2O8 and catalytic AgNO3 formed the desired metabolite 2 that enabled access
to metabolites 3 and 4 in a single step.
Unlike most metal/persulfate-catalyzed transformations reported for
the C–C and C–O bond formation reactions wherein the
metal acts as a catalyst, we propose that Ag(I)/K2S2O8 plays the role of an initiator in the oxidation
of intermediate 7 to 2. Metabolite 2 was subjected to a ruthenium tetroxide-mediated C–H
oxidation to form metabolites 3 and 4 as
a mixture that were purified to isolate pure standards of these metabolites.
Metabolite 5 was synthesized from readily available advanced
intermediate 9
via a House–Meinwald-type
rearrangement in one step using a base
This report describes the development of a photochemical method for C(sp 2 )À H pyridination that leverages the photoexcitation of electron donor-acceptor (EDA) complexes. Experimental and DFT studies show that black light (λ max � 350 nm) irradiation of solutions of protonated pyridines (acceptors) and aromatic CÀ H substrates (donors) results in single electron transfer to form aryl radical cation intermediates that can be trapped with pyridine nucleophiles under aerobic conditions. With some modification of the reaction conditions, this EDA activation mode is also effective for promoting the oxidatively triggered S N Ar pyridination of aryl halides. Overall, this report represents an inexpensive and atom-economical approach to photochemical pyridination reactions that eliminates the requirement of an exogenous photocatalyst.
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