Pyridine Elaboration through Organometallic Intermediates: Regiochemical Control and Completeness

International audiencePyridines carrying heterosubstituents (such as carboxy, amido, amino, alkoxy or trifluoromethyl groups or solely individual halogen atoms) can be readily and site selectively metalated. Subsequent reaction with a suitable electrophile opens rational access to a wealth of new building blocks for the synthesis of biologically active compounds. This approach relies on organometallic methods, which are both efficacious and extremely flexible as far as the substitution site and the product structure are concerned

Effects of methylphenidate: the cellular point of view

The psychostimulant methylphenidate (MPH) is the first choice of treatment in attention-deficit hyperactivity disorder and is based mainly on inhibition of dopamine transporter (DAT). Nonetheless, the complete cellular effects of MPH are still unknown. We attempted to determine whether MPH influences neurotransmitter levels, synaptic gene expression, and cell proliferation in a dose-dependent manner in rat pheochromocytoma cells (PC12) lacking DAT. PC12 were treated in a dose-dependent manner with MPH. Gene expression level of synaptotagmin (Syt) 1 and 4, syntaxin 1a (Stx1a), and synaptic vesicle glycoprotein 2C (SV2C) was measured using quantitative real-time RT-PCR. Different Neurotransmitter release was measured using high-performance liquid chromatography (HPLC). Differences in cell proliferation were evaluated via BrdU incorporation. Treatment with low-dose MPH (1-100nM) altered intra-/extracellular neurotransmitter levels, down-regulated all investigated genes as well as enhanced cell proliferation significantly. These data point to diverse effects of MPH on cell metabolism independent of inhibiting DA

The biphenyl-monitored effective size of unsaturated functional or fluorinated ortho substituents

The size of a series of typical substituents has been probed by dynamic NMR measurements of the barriers to aryl-aryl rotation of the corresponding biphenyls. The resulting B values are meaningful because only mono-ortho substituted compounds were investigated and thus the results are not compromised by the non-additivity of multiple steric effects. On the basis of the chosen model system ethynyl and cyano groups were found to be slightly smaller than a phenyl ring. In contrast, vinyl and, in particular, formyl groups proved to be larger than phenyl. The latter difference is due to the loss of conjugation forces at the planar transition state. alpha-Hydroxyhexafluoroisopropyl is slightly more bulky than tert-butyl. Pentafluorophenyl and trifluoromethoxy exhibit nearly the same effective size as phenyl and methoxy, respectively Trifluoromethyl is somewhat smaller than isopropyl

Rotational barriers of biphenyls having heavy heteroatoms as ortho-substituents: experimental and theoretical determination of steric effects

The free energies of activation for the aryl-aryl rotation of 17 biphenyl derivatives, bearing a heavy heteroatom (S, Se, Te, P, Si, Sn) as ortho substituent, have been measured by variable temperature NMR. These numbers, so called B values, represent a meaningful measure of the steric hindrance exerted by the selected substituents. DFT computations match quite satisfactorily the experimental barriers and the ground state geometries as well (determined, in two cases, by X-ray diffraction). The present values extend the available list of B values and thus provide an enlarged basis for the compilation of the space requirements of standard substituents, based solely on experimental determinations

From uncertainty to reward: BOLD characteristics differentiate signaling pathways

<p>Abstract</p> <p>Background</p> <p>Reward value and uncertainty are represented by dopamine neurons in monkeys by distinct phasic and tonic firing rates. Knowledge about the underlying differential dopaminergic pathways is crucial for a better understanding of dopamine-related processes. Using functional magnetic resonance blood-oxygen level dependent (BOLD) imaging we analyzed brain activation in 15 healthy, male subjects performing a gambling task, upon expectation of potential monetary rewards at different reward values and levels of uncertainty.</p> <p>Results</p> <p>Consistent with previous studies, ventral striatal activation was related to both reward magnitudes and values. Activation in medial and lateral orbitofrontal brain areas was best predicted by reward uncertainty. Moreover, late BOLD responses relative to trial onset were due to expectation of different reward values and likely to represent phasic dopaminergic signaling. Early BOLD responses were due to different levels of reward uncertainty and likely to represent tonic dopaminergic signals.</p> <p>Conclusions</p> <p>We conclude that differential dopaminergic signaling as revealed in animal studies is not only represented locally by involvement of distinct brain regions but also by distinct BOLD signal characteristics.</p

Reaktionen zwischen Vinylfluoriden und Lithiumorganylen

Reaction of cis- and trans-PhCH:CHF with RLi (R = Bu, Me, Ph, or PhCH2) gave stereoselectively cis- and trans-PhCH:CHR, with retention of configuration by substitution and PhC.tplbond.CH by elimination reaction. The elimination reaction follows mainly the E2cb mechanism. The substitution reaction is accomplished by an addn.-elimination sequence with extremely short-lived intermediates. These mechanisms are based on isotope effect, B-ligand effect, and F/Cl elemental effect measurements. The enhanced reactivity of vinyl fluorides towards substitution might be caused by repulsive interactions of neighboring nonbonding p-electrons. [on SciFinder (R)

Metalated 2-Alkenyl- and 1,2-Alkadienyl 2-Tetrahydropyranyl Ethers : Versatile Building Blocks for Furan Syntheses

Me3CLi metalated LiOCH2C:CCH2OTHP (THP = tetrahydro-2-pyranyl) quant. to LiOCH2CLi:C:CHOTHP which was treated with MeOH, Me(CH2)5I, or PhCH2Cl to give LiOCH2CR:C:CHOTHP [I; R = H, (CH2)5Me, CH2Ph]. Treating I with Me3CLi gave LiOCH2CR:C:CLiOTHP [R = (CH2)5Me] which was alkylated to LiOCH2CR:C:CR1OTHP [II; R = (CH2)5Me, R1 = Me, CH2CH:CHMe]. I and II were hydrolyzed by dil. acid and cyclized to 39-67% furans III [R = (CH2)5Me, R1 = H, Me, CH2CH:CHMe; R = CH2Ph, R1 = H]. In the same way, LiOCHR2C.tplbond.CCH2OTHP [R2 = Ph, CH:CMe2, Me, Pr, (Z)-CMe:CHMe] and LiOCHR3C.tplbond.CCHMeOTHP [R3 = Pr, (CH2)5Me] were converted into 53-81% furans III (R = H, R1 = CH:CMe2, Ph), IV [R = Me, R1 = (CH2)4Me; R = Pr, R1 = Et; R = CMe:CMe2, R1 = Me], and V [R = [(CH2)5Me, R1 = H, R = Pr, R1 = Et, R2 = Me]. [on SciFinder (R)