- Benzylic Aroylation of Toluenes Mediated by a LiN(SiMe3)2/Cs+System
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Chemoselective deprotonative functionalization of benzylic C-H bonds is challenging, because the arene ring contains multiple aromatic C(sp2)-H bonds, which can be competitively deprotonated and lead to selectivity issues. Recently it was found that bimetallic [MN(SiMe3)2 M = Li, Na]/Cs+ combinations exhibit excellent benzylic selectivity. Herein, is reported the first deprotonative addition of toluenes to Weinreb amides mediated by LiN(SiMe3)2/CsF for the synthesis of a diverse array of 2-arylacetophenones. Surprisingly, simple methyl benzoates also react with toluenes under similar conditions to form 2-arylacetophenones without double addition to give tertiary alcohol products. This finding greatly increases the practicality and impact of this chemistry. Some challenging substrates with respect to benzylic deprotonations, such as fluoro and methoxy substituted toluenes, are selectively transformed to 2-aryl acetophenones. The value of benzylic deprotonation of 3-fluorotoluene is demonstrated by the synthesis of a key intermediate in the preparation of Polmacoxib.
- Gu, Yuanyun,Zhang, Zhen,Wang, Yan-En,Dai, Ziteng,Yuan, Yaqi,Xiong, Dan,Li, Jie,Walsh, Patrick J.,Mao, Jianyou
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supporting information
p. 406 - 418
(2022/01/14)
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- Asymmetric transfer hydrogenation of heterocycle-containing acetophenone derivatives using N-functionalised [(benzene)Ru(II)(TsDPEN)] complexes
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The application of enantiomerically-pure ruthenium(II) catalysts containing N - functionalised TsDPEN ligand to the asymmetric transfer hydrogenation of 15 examples of α-heterocyclic acetophenone derivatives is reported. Products of up to 99% ee were formed.
- Barrios-Rivera, Jonathan,Xu, Yingjian,Clarkson, Guy J.,Wills, Martin
-
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- Highly efficient asymmetric bioreduction of 1-aryl-2-(azaaryl)ethanones. Chemoenzymatic synthesis of lanicemine
-
Different ketoreductases (KREDs) have been used to promote a highly selective reduction of several 1-aryl-2-(azaaryl)ethanones (azaaryl = pyridinyl, quinolin-2-yl), the corresponding secondary alcohols being obtained with very high yields and enantiomeric excesses (ee > 99%). The absolute configuration of each optically active alcohol has been assigned by means of modified Mosher and Kelly methods, two shielding effects being evaluated: (1) the Mosher phenyl ring effect on the azaaryl protons and (2) the one of the azaaryl ring on the Mosher methoxy group. In addition, the biologically active amine lanicemine has been synthesized from (R)-1-phenyl-2-(pyridin-2-yl)ethanol, thus proving the utility of the secondary alcohols here prepared.
- Liz, Ramón,Liardo, Elisa,Rebolledo, Francisca
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supporting information
p. 8214 - 8220
(2019/09/19)
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- Small molecule that reverses dexamethasone resistance in t-cell acute lymphoblastic leukemia (T-ALL)
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Glucocorticoids are one of the most utilized and effective therapies in treating T-cell acute lymphoblastic leukemia. However, patients often develop resistance to glucocorticoids, rendering these therapies ineffective. We screened 9517 compounds, selected for their lead-like properties, chosen from among 3372615 compounds, against a dexamethasone-resistant T-ALL cell line to identify small molecules that reverse glucocorticoid resistance. We synthesized analogues of the most effective compound, termed J9, from the screen in order to define the scaffolds structure-activity relationship. Active compounds restored sensitivity to glucocorticoids through upregulation of the glucocorticoid receptor. This compound and mechanism may provide a strategy for overcoming glucocorticoid resistance in patients with T-ALL.
- Cantley, Alexandra M.,Welsch, Matthew,Ambesi-Impiombato, Alberto,Sanchez-Martin, Marta,Kim, Mi-Yeon,Bauer, Andras,Ferrando, Adolfo,Stockwell, Brent R.
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supporting information
p. 754 - 759
(2014/08/05)
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- MAP KINASE MODULATORS AND USES THEREOF
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The invention provides for novel MAP kinase inhibitors and compositions comprising the same. In some embodiments, the MAP kinase inhibitors are p38a MAP kinase inhibitors. The invention further provides for methods for treatment of diseases comprising adm
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Paragraph 00218
(2014/09/29)
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- NOVEL DIHYDROPYRIMIDIN-2(1H)-ONE COMPOUNDS AS S-NITROSOGLUTATHIONE REDUCTASE INHIBITORS
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The present invention is directed to novel dihydropyrimidin-2(1H)-one compounds useful as S-nitrosoglutathione reductase (GSNOR) inhibitors, pharmaceutical compositions comprising such compounds, and methods of making and using the same.
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Page/Page column 147
(2011/04/24)
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- SELECTIVE SUBTYPE ALPHA 2 ADRENERGIC AGENTS AND METHODS FOR USE THEREOF
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The invention provides well-defined heterocyclic compounds that are useful as subtype selective alpha 2 adrenergic agonists. As such, the compounds described herein are useful in treating a wide variety of disorders associated with selective subtype modulation of alpha 2 adrenergic receptors.
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Page/Page column 44
(2009/08/16)
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- OXAZOLIDINE AND THIAZOLIDINE SELECTIVE SUBTYPE ALPHA 2 ADRENERGIC AGENTS AND METHODS FOR USE THEREOF
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The invention provides oxazolidine and thiazolidine derivatives that are useful as subtype selective alpha 2 adrenergic agonists. As such, the compounds described herein are useful in treating a wide variety of disorders associated with selective subtype
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Page/Page column 37
(2009/08/16)
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- Protein Kinase Targeted Therapeutics
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The present invention relates to compositions and methods useful in treating diseases and disorders related to protein kinases. In particular, the present invention relates to compositions and methods useful for targeting protein kinases related to mitoge
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Page/Page column 14; sheet 1
(2010/11/30)
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- HETEROCYCLIC COMPOUNDS
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New compounds of formula (I), wherein the meanings for the various substituents are as disclosed in the description. These compounds are useful as p38 kinase inhibitors.
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Page/Page column 43
(2008/06/13)
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- Synthesis and SAR of 2,3-diarylpyrrole inhibitors of parasite cGMP-dependent protein kinase as novel anticoccidial agents
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Several analogs of 2,3-diaryl pyrroles were synthesized and evaluated as inhibitors of Eimeria tenella cGMP-dependent protein kinase and in in vivo anticoccidial assays. A 4-fluorophenyl group enhances both in vitro and in vivo activities. The most potent
- Biftu, Tesfaye,Feng, Dennis,Ponpipom, Mitree,Girotra, Narindar,Liang, Gui-Bai,Qian, Xiaoxia,Bugianesi, Robert,Simeone, Joseph,Chang, Linda,Gurnett, Anne,Liberator, Paul,Dulski, Paula,Leavitt, Penny Sue,Crumley, Tami,Misura, Andrew,Murphy, Terence,Rattray, Sandra,Samaras, Samantha,Tamas, Tamas,Mathew, John,Brown, Christine,Thompson, Don,Schmatz, Dennis,Fisher, Michael,Wyvratt, Matthew
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p. 3296 - 3301
(2007/10/03)
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- PYRAZOLOPYRIDINE DERIVATES
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New compounds of formula (I) and the salts, solvates and prodrugs thereof, wherein the meanings for the various substituents are as disclosed in the description. These compounds are useful as p38 kinase inhibitors.
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- Substituted 2-aryl-3-(heteroaryl)-imidazo[1,2-a]pyrimidines, and related pharmaceutical compositions and methods
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This invention relates to a series of imidazopyrimidines of Formula I, and pharmaceutical compositions containing them. The compounds of the invention inhibit the production of a number of inflammatory cytokines and are useful in the treatment and prevention of diseases associated with the overproduction thereof.
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- Adenosine A3 receptor antagonists
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A pharmaceutical composition for antagonizing adenosine at adenosine A3receptors which comprises a 1,3-azole compound substituted on the 4- or 5-position, or both, by a pyridyl which may be substituted is provided and can be used as a prophylactic and therapeutic agent for asthma, allergosis, inflammation, and so on.
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-
- Study of radical merostabilization of electrospray FTICR/MS
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The threshold fragmentation energies (E(o)) of three different 4-(1'-substituted-2'-phenethyl)-1-methylpyridinium salts containing a neutral, an electron-donor, or an electron-acceptor group as α-substituent, respectively, were measured by Fourier Transfo
- Katritzky, Alan R.,Shipkova, Petia A.,Qi, Ming,Nichols, Daniel A.,Burton, Richard D.,Watson, Clifford H.,Eyler, John R.,Tamm, Toomas,Karelson, Mati,Zerner, Michael C.
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p. 11905 - 11911
(2007/10/03)
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- Substituted (1,2-Diarylethyl)amide Acyl-CoA:Cholesterol Acyltransferase Inhibitors: Effect of Polar Groups on in Vitro and in Vivo Activity
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Substituted (1,2-diarylethyl)amides have been prepared and evaluated for their ability to inhibit microsomal acyl-CoA:cholesterol acyltransferase activity in vitro and to lower hepatic cholesteryl ester content in vivo in a cholesterol-fed hamster.Simple unsubstituted (diarylethyl)amides were potent inhibitors in vitro but showed poor activity in vivo.Introduction of polar groups at specific locations on the diarylethylamine moiety decreased in vitro activity but increased in vivo activity.Both effects were highly structure dependent, suggesting specific interactions which were mediating activity in each model.Optimization of these opposing effects led to compounds which were potent in both models.
- Clader, John W.,Berger, Joel G.,Burrier, Robert E.,Davis, Harry R.,Domalski, Martin,et al.
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p. 1600 - 1607
(2007/10/02)
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- Keto-Enol and Imine-Enamine Tautomerism of 2-, 3- and 4-Phenacylpyridines
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Equilibrium constants for keto-enol tautomerisation and migration of hydrogen from carbon to nitrogen to form enamine or zwitterion tautomers have been measured for 2-, 3- and 4-phenacylpyridines (PyCH2COPh) in aqueous solution at 25 deg C.Relative tautomeric stabilities fall in the order ketoimine > enamine > enol and (for the 3-isomer) enol >zwitterion.Values of pKT, (-log KT) where KT=/ or /, are 1.05, 5.87 and 2.42 for the enamine or zwitterion tautomerism and 2.0, 4.86 and 4.4 for keto-enol tautomerism of the 2-, 3- and 4-isomers respectively.For the enamines KT was determined kinetically by quenching the enolate anion at a pH below its pKa and monitoring its relaxation to the ketoimine spectrophotometrically: combining rate constants for this process and the reverse reaction measured by halogen trapping of the enol or enamine gave KT.Values are compared with results of earlier indirect measurements by Katritzky.For the 3-isomer, the N-methyl-3-phenacylpyridinium ion was taken as a model for the zwitterion tautomer and a ratio of enol to zwitterion concentrations of 10:1 was derived from kinetic and equilibrium ionisation measurements corrected for a methyl substituent effect.The unusually large enol content of 2-phenacylpyridine in non-polar solvents was measured spectrophotometrically and extrapolated to water.For the 4-isomer the enol content could be obtained from a correlation of pKas of phenacylpyridine enols and vinylogously related phenols.Acidic and basic pKas of all tautomers are reported including kinetically determined values for O-protonation of the enaminones.Proton activating factors for ionisation and tautomerisation have been calculated andare compared with values for the vinylogous hydroxypyridines.The influence of charge delocalisation and electrostatic interactions on the stability of enolate and carboxylate anions is discussed.
- Carey, A. R. Edwin,Eustace, Stephen,O'Ferall, Rory A. More,Murray, Brian A.
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p. 2285 - 2296
(2007/10/02)
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- Rate-equilibrium relationships for the deprotonation of 4-phenacylpyridines and 4-phenacylpyridinium cations
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Substituent effects upon the equilibria and kinetics of enolate ion formation from eight 4-(X-phenacyl)pyridines (5), eight 1-methyl-4-(X-phenacyl)pyridinium cations (6), five 1-benzyl-4-(X-phenacyl)pyridinium cations (7), and eight 1-(X-benzyl)-4-phenacy
- Stefanidis, Dimitrios,Bunting, John W.
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p. 3163 - 3168
(2007/10/02)
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- Preparation of N-Silyl-enamines from α-Silyl Carbanions and Aromatic Nitriles
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The preparations of seven N-silyl-enamines (1a) - (1g) and their chemical behaviour are reported.Lithiated 4-(trimethylsilylmethyl)pyridine (2b) easily reacted with benzonitrile (4a) in tetrahydrofuran to give only (E)-1-phenyl-2-(4-pyridyl)-1-(trimethylsilylamino)ethene (1b) in 90percent yield.On the other hand, lithiated t-butyl trimethylsilylacetate (2c) did not react with (4a) at all, but reacted readily with 2- or 4-cyanopyridines, (4b) or (4c), and scarcely at all reacted with 3-cyanopyridine (4d) to give the corresponding t-butyl (Z)-3-trimethylsilylamino-3-pyridylpropenoates (1c), (1d), and (1e) in 68, 75, and 4percent yields, respectively.The reaction of 3-methyl-5-(trimethylsilylmethyl)isoxazole (2d) with the nitriles (4a) or (4b) gave the corresponding N-silyl-enamine (1g) or the desilylated enamines (5b,c), which were unstable and were readily hydrolyzed to the corresponding ketones (6a) or (6b).
- Konakahara, Takeo,Kurosaki, Yoshihiro
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p. 1068 - 1086
(2007/10/02)
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- Enol Content of α-Pyridyl- and Pyridinio-acetophenones
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A comparison of the effects of phenyl, pyridyl, and pyridinio substituents upon keto-enol tautomerisation and enol ionisation equilibria of acetophenone shows that polar effects upon bond hybridisation and resonance interaction with 'neutral' double bonds are important influences upon enol stability.
- Carey, A. R. Edwin,Al-Quatami, Shaikha,O'Ferrall, Rory A. More,Murray, Brian A.
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p. 1097 - 1098
(2007/10/02)
-
- Synthesis and Antifungal Activity of a Series of Novel 1,2-Disubstituted Propenones
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To find an antifungal agent other than those of the imidazole and triazole series, a new class of 1,2-disubstituted propenones I and II was prepared and tested for antifungal activity.Comparison of the structure-activity relationships showed that the conjugated structure of carbonyl and exomethylene groups in I and II plays an important role in potent antifungal acivity.However, it is noteworthy that compounds 53, 54, and 56, which have a hydroxymethyl or methoxymethyl group instead of an exo-methylene group in I, also showed potent activity.Although many compounds exhibited strong antifungal activity in vitro, none showed activity in vivo of oral efficacy against subacute systemic candidiasis in mice. '
- Ogata, Masaru,Matsumoto, Hiroshi,Kida, Shiro,Shimizu, Sumio,Tawara, Katsuya,Kawamura, Yoshimi
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p. 1497 - 1502
(2007/10/02)
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- Process for preparing certain 1-lower alkanoyl or benzoyl-4-(lower alkanoyl or benzoyl-methylidene)-1,4-dihydropyridines or acid addition salts thereof
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There is described a novel process for preparing 4-pyridinylmethyl ketones of formula (I) STR1 wherein R is alkyl, aryl or aralkyl. The process involves hydrolysis of a compound STR2 generated by reaction of an acylating agent with 4-methylpyridine. The acylating agent may be selected from compounds of formula R-CO-X and R-CO-O-CO-R where R is as defined above and X represents halogen. Compounds of formula I have utility in the preparation of a variety of products, including pharmaceutically active 1,2-dihydro-6-R-2-oxo-5 pyridinyl compounds.
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- 5-pyridyl-1,3-thiazole derivatives
-
Novel compounds of the formula: STR1 wherein R1 stands for an optionally substituted alkyl group, alkenyl group, aryl group, aralkyl group, cycloalkyl group, heterocyclic group having carbon as the bonding hand or amino group, R2 stands for a pyridyl group which may be substituted with alkyl group, and R3 stands for an optionally substituted aryl group or salts thereof, have analgesic, anti-piretic, anti-inflammatory and anti-ulcer actions, and can be administered to mammals for the therapy of pain, inflammatory diseases, rheumatic chronic diseases.
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- Synthese von Pyridylphenyl-imidazothiazolen
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The synthesis of the isomeric 6(5)-phenyl-5(6)-pyridyl-2,3-dihydroimidazothiazoles are described.Only the synthesis of 5-phenyl-6-(2-pyridyl)-2,3-dihydroimidazothiazole failed.
- Klose, Walter,Schwarz, Katica
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p. 669 - 671
(2007/10/02)
-
- Facile Dibenzoylation of Picoline
-
In the presence of triethylamine, 2- and 4-picolines reacted with an excess of benzoyl chloride in refluxing acetonitrile to give the corresponding 1-benzoyl-phenacylidenedihydropyridines.The difference in reactivity between 2- an 4-picoline toward such a
- Suzuki, Toshinobu,Mitsuhashi, Keiryo
-
p. 1487 - 1489
(2007/10/02)
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- REGIOSELECTIVE ADDITION OF TITANIUM ENOLATES TO 1-ACYLPYRIDINIUM SALTS. A CONVENIENT SYNTHESIS OF 4-(2-OXOALKYL)PYRIDINES
-
Titanium enolates add to the 4-position of 1-phenoxycarbonylpyridinium salts to give 1,4-dihydropyridines; subsequent aromatization provides 4-(2-oxoalkyl)pyridines.
- Comins, Daniel L.,Brown, Jack D.
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p. 3297 - 3300
(2007/10/02)
-
- REGIOSELECTIVE SYNTHESIS OF 4-(2-OXOALKYL)PYRIDINES VIA 1,4-DIHYDROPYRIDINE DERIVATIVES USING SILYL ENOL ETHERS AND PYRIDINIUM SALTS
-
Trimethylsilyl enol ethers (1) reacted with 1-ethoxycarbonylpyridinium chloride (3) at 4-position with high regioselectivity to afford 1-ethoxycarbonyl-4-(2-oxoalkyl)-1,4-dihydropyridines (4) in 42-87percent yields.When 2,2,2-trichloroethyl chloroformate
- Akiba, Kin-ya,Nishihara, Yoshihiro,Wada, Makoto
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p. 5269 - 5272
(2007/10/02)
-
- 1-Acyl-4-alkylidene-1,4-dihydropyridines, 7. Activation with Boron Trifluoride: Intermolecular Acyl Group Transfer and Formation of 1-(4-Pyridyl)-2-alkanones
-
1-Acyl-4-alkylidene-1,4-dihydropyridines 5, representatives of the thermally stable enamides, can be activated by means of boron trifluoride 6, so the ketones 7 result from attack of 6 on 5 (intermolecular acyl group transfer).The mechanism of this reaction, which has not previously been observed for enamides, is strongly suggested to be as follows: 5 and 6 form first the adduct 21, which attacks 5 with formation of 27.Special examples of 5 (11 and 12) are found to be reactive enough that the ketone 7h or the sulfone 15 can be obtained from their isolable precursors (14 and 13) without Lewis-acid activation. 13 is particularly noteworthy: being the precursor of the salt 16, which is generated in situ, it serves as an extremely effective tosylating agent.Even tertiary alcohols are attackted by 16.
- Anders, Ernst,Will, Wolfgang,Stankowiak, Achim
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p. 3192 - 3204
(2007/10/02)
-
- Synthetic Applications of N-N Linked Heterocycles. Part 8. Regiospecific Synthesis of 4-(α-Acylalkyl)pyridines by Attack of Lithium Enolates of Ketones γ to N-(2,6-Dimethyl-4-oxopyridin-1-yl)pyridinium Salts
-
The addition of N-(2,6-dimethyl-4-oxopyridin-1-yl)pyridinium salts (2) - (4) to lithium enolates (1) of ketones in tetrahydrofuran at low temperatures gives regiospecifically high yields of 1,4-dihydro-adducts (5) - (7).These are readily isolated and can be decomposed under free-radical conditions, also in high yield, to 4-(α-acylalkyl)pyridines (8) - (10).Unsymmetrical dialkyl ketones give a mixture of two isomeric products, the ratio depending upon reaction conditions and steric factors. αβ-Unsaturated ketones, however, give products resulting from reaction exclusively at the position α' to the carbonyl group.
- Lee, Cheuk Man,Sammes, Michael P.,Katritzky, Alan R.
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p. 2458 - 2462
(2007/10/02)
-