- Magnesium oxide as a heterogeneous and recyclable base for the N-methylation of indole and O-methylation of phenol using dimethyl carbonate as a green methylating agent
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This work reports a mild efficient and sustainable protocol for N-methylation of indole and O-methylation of phenol using dimethylcarbonate as an environmentally safe, non-toxic, biodegradable and green methylating agent under microwave conditions. Magnesium oxide (MgO) has been employed as a heterogeneous and recyclable base for clean N-methylation of indole and O-methylation of phenol with dimethylcarbonate. Basic properties of the fresh and recycled MgO were measured by temperature programmed desorption (CO2-TPD) analysis. The CO2-TPD runs suggested that both strong and moderately basic sites are present on the oxide, while only the moderately basic sites are responsible for the N-and O-methylation of indole and phenol, respectively, using DMC as a methylating agent. The CO2-TPD analysis showed that the basic sites on fresh and recycled MgO were comparable. The MgO was isolated by simple filtration and recycled efficiently without loss in activity and selectivity.
- Gadge, Sandip T.,Mishra, Ashish,Gajengi, Aravind L.,Shahi, Nileshkumar V.,Bhanage, Bhalchandra M.
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p. 50271 - 50276
(2014/12/10)
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- GFAT INHIBITORS
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Compounds of formula (I) are provided as well as pharmaceutically acceptable salts and esters thereof, wherein the substituents are as disclosed in the specification. The compounds have utility for the treatment of type 2 diabetes mellitus.
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- First application of ionic liquids in electrophilic fluorination of arenes; Selectfluor (F-TEDA-BF4) for "green" fluorination
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The NF fluorinating agent F-TEDA-BF4 dication salt (Selectfluor) 1 dissolves in imidazolium-based ionic liquids [emim][OTf] 7, [emim][BF4] 8, [bmim][PF6] 9 and [bmim][BF4] 10 (assisted by sonication), providing a convenient medium for fluorination of arenes under essentially acid-free conditions in a simple set-up (no volatile solvent; simple extraction of the aromatics without aqueous work-up), from which the ionic liquid can be easily recycled and reused. Comparative studies in [emim][OTf] 7 with anisole as substrate show that 1 is superior to NFTh-BF4 (Accufluor) 2 and that the N-fluoropyridinium salt NFPy-B2F7 4 is least effective. The scope of the reaction has been surveyed. Substrate selectivity (k mesitylene: k durene = 10) measured in competitive experiments in 7 is clearly indicative of a conventional polar mechanism. Substrate selectivity measured without the ionic liquid in MeCN solvent is also indicative of a polar mechanism but exhibits lower magnitude (k mesitylene: kdurene = 6). Addition of dicyclohexano-24-crown-8 to the fluorination reaction mixture (1 and anisole) in 7 reduced the conversion but did not change the isomer distribution. AM1 minimization was used to model the complexation of 1 with this crown. With reactive aromatics optimal fluorination yields in ionic liquids (using 1 equivalent of the NF reagent) are around 50% (higher for naphthalene). A key control experiment suggests that the free base (produced upon transfer-fluorination) could complex to unreacted 1 (generating a bulky dimer complex which may be ineffective for fluorine transfer) in competition to N-protonation.
- Laali, Kenneth K.,Borodkin, Gennady I.
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p. 953 - 957
(2007/10/03)
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- Synthesis, Properties, and Reactivity of N,N'-Difluorobipyridinium and Related Salts and Their Applications as Reactive and Easy-To-Handle Electrophilic Fluorinating Agents with High Effective Fluorine Content
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N,N′-Difluoro-2,2′-, -2,4′-, -3,3′-, -4,4′-bipyridinium and substituted N,N′-difluoro-2,2′-bipyridinmm bis(triflates), bis(tetrafluoroborates), bis(hexafluorophosphates), and bis(hexafluoroantimonates) 1-9 were synthesized in high yields by the direct fluorination of a mixture of a bipyridyl and a Lewis acid, a Br?nsted acid, or the alkali metal salt of an acid. The higher homologues, trimer 10 and polymer 11, were also synthesized. Unsubstituted or electron-donating group-substituted N,N′- difluorobipyridinium salts are stable nonhygroscopic crystals, while the electron-withdrawing group- substituted N,N′-diflurobipyridinium salts 3, 5, and 6 are moisture-sensitive crystals. Hydrolysis of 1b in boiling water gave 3,3′-dihydroxy-2,2′-bipyridyl. The reactivity determination indicated that the fluorinating capability decreased in the order 2,2′- ? 2,4' > 3,3′- ≈ 4,4′-isomer ? N-fluoropyridinium salt and that the two N-F moieties in a molecule were effective for fluorination. This fluorination occurred in a step-by-step manner, and the reactivity difference between the first and second fluorinations was very small. N,N′-Difluoro-2,2′-bipyridinium bis(tetrafluoroborate) (1b) is thus shown to be a highly reactive and easy-to-handle electrophilic fluorinating agent with the high effective fluorine content (103.3 g/kg) for preparing many fluoro organic compounds.
- Umemoto, Teruo,Nagayoshi, Masayuki,Adachi, Kenji,Tomizawa, Ginjiro
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p. 3379 - 3385
(2007/10/03)
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- N,N′-Difluoro-1,4-diazoniabicyclo[2.2.2]octane Salts, Highly Reactive and Easy-to-Handle Electrophilic Fluorinating Agents
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A series of N,N′-difluoro-1,4-diazoniabicyclo[2.2.2]octane salts were synthesized in a pure form by the fluorination of 1,4-diazabicyclo[2.2.2]octane with F2 diluted with N2 in the presence of a Bronsted acid in fluoro alcohol or acetonitrile or by fluorination followed by a treatment with a different Bronsted or Lewis acid. Their complete structural assignment was made based on spectral and elemental analyses of the isolated crystals. A great through-bond interaction between the two N-F's of the salt was observed on 19FNMR. An assessment was made of the usefulness of N,N′-difluoro-1,4-diazoniabicyclo[2.2.2]octane bis(triflate), bis(HSO2), bis(BF4), and bis(SbF6) salts for electrophilic fluorination; the bis-(BF4) salt was demonstrated to be widely applicable as a highly reactive and easy-to-handle fluorinating agent. Thus, the bis(BF4) salt readily fluorinated activated aromatics, active methylene compounds or their salts, substituted styrenes, and vinyl acetates under mild conditions. It was shown that one N-F of the salt was effective for fluorination and that the other N-F played a role to activate fluorination through the bonds. Thus, the reaction mechanism was discussed, and fluorination followed by an immediate intramolecular one-electron transfer was suggested.
- Umemoto, Teruo,Nagayoshi, Masayuki
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p. 2287 - 2295
(2007/10/03)
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- Phenethylthiazolylthiourea (PETT) compounds as a new class of HIV-1 reverse transcriptase inhibitors. 2. Synthesis and further structure-activity relationship studies of PETT analogs
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Phenylethylthiazolylthiourea (PETT) derivatives have been identified as a new series of nonnucleoside inhibitors of HIV-1 RT. Structure-activity relationship studies of this class of compounds resulted in the identification of N-[2-(2-pyridyl)ethyl]-N'-[2-(5-bromopyridyl)]-thiourea hydrochloride (trovirdine; LY300046.HCl) as a highly potent anti-HIV-1 agent. Trovirdine is currently in phase one clinical trials for potential use in the treatment of AIDS. Extension of these structure-activity relationship studies to identify additional compounds in this series with improved properties is ongoing. A part of this work is described here. Replacement of the two aromatic moleties of the PETT compounds by various substituted or unsubstituted heteroaromatic rings was investigated. In addition, the effects of multiple substitution in the phenyl ring were also studied. The antiviral activities were determined on wild-type and constructed mutants of HIV-1 RT and on wild-type HIV-1 and mutant viruses derived thereof, Ile100 and Cys181, in cell culture assays. Some selected compounds were determined on double- mutant viruses, HIV-1 (Ile100/Asn103) and HIV-1 (Ile100/Cys181). A number of highly potent analogs were synthesized. These compounds displayed IC50's against wild-type RT between 0.6 and 5 nM. In cell culture, these agents inhibited wild-type HIV-1 with ED50's between I and 5 nM in MT-4 cells. In addition, these derivatives inhibited mutant HIV-1 RT (Ile 100) with IC50's between 20 and 50 nM and mutant HIV-1 RT (Cys 181) with IC50's between 4 and 10 nM, and in cell culture they inhibited mutant HIV-1 (Ile100) with ED50's between 9 and 100 nM and mutant HIV-1 (Cys181) with ED50's between 3 and 20 nM.
- Cantrell, Amanda S.,Engelhardt, Per,H?gberg, Marita,Jaskunas, S. Richard,Johansson, Nils Gunnar,Jordan, Christopher L.,Kangasmets?, Jussi,Kinnick, Michael D.,Lind, Peter,Morin Jr., John M.,Muesing,Noreén, Rolf,?berg, Bo,Pranc, Paul,Sahlberg, Christer,Ternansky, Robert J.,Vasileff, Robert T.,Vrang, Lotta,West, Sarah J.,Zhang, Hong
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p. 4261 - 4274
(2007/10/03)
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- Syntheses of 2,5- and 2,6-Difluoronorepinephrine, 2,5-Difluoroepinephrine, and 2,6-Difluorophenylephrine: Effect of Disubstitution with Fluorine on Adrenergic Activity
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Synthetic routes to difluorinated analogs of the adrenergic agonists, norepinephrine (NE), epinephrine (E), and phenylephrine (PE) have been developed.The syntheses were based on elaboration of the ethanolamine side chains from the appropriately polyfunctionalized benzaldehydes.The benzaldehydes were prepared from precursor difluorinated benzenes by sequential regioselective lithiations and reaction with electrophiles to introduce hydroxyl and carboxaldehyde functionalities.Binding and functional assay data demonstrate that the 2,6-difluorinated analogs are relatively inactive at both α- and β-adrenergic receptors.These results are consistent with earlier observations that 2-fluoro substitution of adrenergic agonists decreases α-adrenergic activity whereas 6-fluoro substitution decreases β-adrenergic activity.
- Chen, George T.,King, Michael,Gusovsky, Fabian,Creveling, Cyrus R.,Daly, John W.,et al.
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p. 3947 - 3955
(2007/10/02)
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