- C-O Bond Activation as a Strategy in Palladium-Catalyzed Cross-Coupling
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The activation of strong C-O bonds in cross-coupling catalysis can open up new oxygenate-based feedstocks and building blocks for complex-molecule synthesis. Although Ni catalysis has been the major focus for cross-coupling of carboxylate-based electrophiles, we recently demonstrated that palladium catalyzes not only difficult C-O oxidative additions but also Suzuki-Type cross-couplings of alkenyl carboxylates under mild conditions. We propose that, depending on the reaction conditions, either a typical Pd(0)/(II) mechanism or a redox-neutral Pd(II)-only mechanism can operate. In the latter pathway, C-C bond formation occurs through carbopalladation of the alkene, and C-O cleavage by β-carboxyl elimination. 1 Introduction 2 A Mechanistic Challenge: Activating Strong C-O Bonds 3 Exploiting Vinylogy for C-Cl and C-O Oxidative Additions 4 An Alternative Mechanism for Efficient Cross-Coupling Catalysis 5 Conclusions and Outlook.
- Becica, Joseph,Leitch, David C.
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p. 641 - 646
(2020/12/14)
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- Discovery of a Pyrimidinedione Derivative as a Potent and Orally Bioavailable Axl Inhibitor
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The receptor tyrosine kinase Axl plays important roles in promoting cancer progression, metastasis, and drug resistance and has been identified as a promising target for anticancer therapeutics. We used molecular modeling-assisted structural optimization starting with the low micromolar potency compound 9 to discover compound 13c, a highly potent and orally bioavailable Axl inhibitor. Selectivity profiling showed that 13c could inhibit the well-known oncogenic kinase Met with equal potency to its inhibition of Axl superfamily kinases. Compound 13c significantly inhibited cellular Axl and Met signaling, suppressed Axl- and Met-driven cell proliferation, and restrained Gas6/Axl-mediated cancer cell migration or invasion. Furthermore, 13c exhibited significant antitumor efficacy in Axl-driven and Met-driven tumor xenograft models, causing tumor stasis or regression at well-tolerated doses. All these favorable data make 13c a promising therapeutic candidate for cancer treatment.
- Zhang, Hefeng,Peng, Xia,Dai, Yang,Shao, Jingwei,Ji, Yinchun,Sun, Yiming,Liu, Bo,Cheng, Xu,Ai, Jing,Duan, Wenhu
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supporting information
p. 3956 - 3975
(2021/04/12)
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- PYRIDONE COMPOUNDS AND METHODS OF USE IN THE MODULATION OF A PROTEIN KINASE
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The present disclosure relates generally to compounds and pharmaceutical compositions suitable as modulators of protein kinases, and methods for their use in treating disorders mediated, at least in part by, protein kinases.
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Paragraph 01117
(2021/04/02)
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- QUINOLINE DERIVATIVE
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This compound represented by general formula (I) and having a quinoline skeleton has a strong Axl inhibitory activity. Consequently, this compound can be a therapeutic agent for Axl-related diseases, for example, cancers such as acute myeloid leukemia, chronic myeloid leukemia, melanoma, breast cancer, pancreatic cancer and glioma, kidney diseases, immune system diseases and cardiovascular diseases.
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Paragraph 0178
(2017/11/17)
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- Copper-Catalyzed Double Additions and Radical Cyclization Cascades in the Re-Engineering of the Antibacterial Pleuromutilin
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A general synthetic sequence involving simply prepared starting materials provides rapid access to diverse, novel tricyclic architectures inspired by pleuromutilin. SmII-mediated radical cyclization cascades of dialdehydes, prepared using a new
- Ruscoe, Rebecca E.,Fazakerley, Neal J.,Huang, Huanming,Flitsch, Sabine,Procter, David J.
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supporting information
p. 116 - 119
(2016/01/26)
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- Experimental studies on the selective β-c-h halogenation of enones
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Here we describe the realization of a one-pot protocol for the β-C-H halogenation of cyclic enones via umpolung of the β-carbon. The developed method includes hydrazone formation and selective β-halogenation (bromination, chlorination) with N-bromosuccini
- Huber, Tatjana,Kaiser, Daniel,Rickmeier, Jens,Magauer, Thomas
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p. 2281 - 2294
(2015/03/18)
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- Cyclization of cyanoethylated ketones as a route to 6-substituted indole derivatives
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δ-Cyanoketones are quickly cyclized with KOtBu to 3-aminocyclohex-2-enone derivatives, which in turn will give substituted indoles when treated with oxalyl chloride. Thus, 3-amino-6,6-dimethylcyclohex-2-enone gave 3-chloro-6,6-dimethyl-2,5,6,7-tetrahydroindole-2,5-dione, whose structure was corroborated by X-ray crystallography, whereas the corresponding molecule without the blocking gem-dimethyl groups, 3-aminocyclohex-2-enone, gave via hydrogen shifts 6-chloro-3-hydroxyoxindole.
- Bergman, Jan,Stensland, Birgitta
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- NOVEL CYP17 INHIBITORS/ANTIANDROGENS
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Compounds of formula (I), wherein R1 to R8 A, B, Z1 and Z2 are as defined in the claims and pharmaceutically acceptable salts and esters thereof are disclosed. The compounds of formula (I) possess utility as androgen receptor antagonists (inhibitors) and/or cytochrome P450 monooxygenase 17a-hydroxylase/17,20-lyase (CYP17) inhibitors. The compounds are useful as medicaments in the treatment of cancer, particularly prostate cancer, and other androgen dependent conditions and diseases where androgen antagonism is desired.
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Page/Page column 35; 36
(2015/01/07)
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- Cyclization of 5-hexynoic acid to 3-alkoxy-2-cyclohexenones
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The one-pot cyclization of 5-hexynoic acid to produce 3-alkoxy-2- cyclohexenones proceeds in good yields (58-90%). 3-Hexynoic acid was converted to its acyl chloride with the aid of oxalyl chloride and was cyclized to 3-chloro-2-cyclohexenone upon addition of indium(III) chloride. Subsequent addition of alcohol nucleophiles led to the desired 3-alkoxy-2-cyclohexenones.
- Hylden, Anne T.,Uzelac, Eric J.,Ostojic, Zeljko,Wu, Ting-Ting,Sacry, Keely L.,Sacry, Krista L.,Xi, Lin,Jones, T. Nicholas
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scheme or table
p. 1323 - 1326
(2011/11/06)
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- PLATELET-ACTIVATING FACTOR RECEPTOR ANTAGONISTS
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Cyclohexyl sulfonamide compounds which are platelet-activating factor (PAF) receptor antagonists. Said compounds may be useful, for example, for the treatment of atherosclerosis or other PAF-mediated disorders, including inflammatory, cardiovascular, and immune disorders.
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Page/Page column 72-73
(2011/02/24)
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- PROCESS FOR THE PRODUCTION OF CYCLIC DIKETONES
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The present invention relates to a process for the preparation of compounds of formula (I), wherein the substituents are as defined in claim 1, by reacting a compound of formula (II), either with a chlorination or bromination agent or with a compound of formula (III) CI-SO2R9, R9 being C1-C4alkyl, C1-C4haloalkyl, phenyl or C1-C4alkyl-substituted phenyl, to form the compound of formula (IV), reacting the compound of formula (IV) with a compound of formula (V) M+-O--C(O)-Y, wherein Y is as defined above and M+ is the hydrogen cation or an alkali metal ion, alkaline earth metal ion or ammonium ion, to form the compound of formula (VI) and treating that compound with a cyanide source in the presence of a base.
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Page/Page column 19-20
(2008/06/13)
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- ANTIPRURITICS
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It is intended to provide antipruritics (drugs to control itching, antiitch agents and drugs to stop itching). It is found out that a compound having an agonistic activity to the cannabinoid receptor shows an antipruritics effect.
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Page/Page column 44
(2008/06/13)
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- PYRIDONE DERIVATIVE HAVING AFFINITY FOR CANNABINOID 2-TYPE RECEPTOR
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It was found that the compound having a binding activity to the cannabinoid type 2 receptor represented by the formula (I): wherein R' is a group represented by the formula: -Y1-Y2-Y3Ra wherein Y1 is single bond or the like; Y2 is -C(=O)-NH- or the like; Y3 is optionally substituted aryl or the like; R2 is hydrogen or the like; R3 is alkyl or the like; R4 is alkyl or the like; R5 is optionally substituted alkyl or the like; or R3 and R4 taken together with the adjacent atom form cyclic group or the like.
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Page/Page column 63
(2008/06/13)
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- Niobium pentachloride activation of enone derivatives: Diels-Alder and conjugate addition products
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Niobium pentachloride has proven to be a powerful activating agent for Diels-Alder or conjugate addition reactions of cycloenones. The Diels-Alder product was obtained only with an unsubstituted enone (cyclohexenone) and the highly reactive diene cyclopentadiene; substituents in the β-position of enones seem to prevent Diels-Alder reaction: oxygenated substituents favor the formation of vinyl chlorides (ethyl ether or dichloromethane as solvents) or enol ethers (ethyl acetate as solvent), while a methyl substituent prevents (any kind of transformation with NbCl5. Less reactive dienes, furan and 2-methylfuran gave the conjugate addition products of the furan ring to the enone system.
- Gomes Constantino, Mauricio,Lacerda Jr., Valdemar,Da Silva, Gil Valdo José
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p. 456 - 464
(2007/10/03)
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- 2-chloro-1,3-dimethylimidazolinium chloride. 3. Utility for chlorination, oxidation, reduction, and rearrangement reactions
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2-Chloro-1,3-dimethylimidazolinium chloride (1), which can act as a powerful dehydrating equivalent to DCC (2), is also applicable to chlorination, oxidation, reduction, and rearrangement under nearly neutral conditions. The utility of 1 for these reactions is described.
- Isobe, Toshio,Ishikawa, Tsutomu
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p. 5832 - 5835
(2007/10/03)
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- Novel Chlorotrimethylsilane Catalyzed Stereoselective Deconjugation of β-Bromo (or Iodo) Substituted α,β-Unsaturated Acyclic Ketone
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TMSCl catalyzed stereoselective isomerization (deconjugation) of β-substituted α,β-unsaturated ketones to the corresponding (Z)-β,γ-unsaturated ketones and its mechanism studies are described.
- Luo, Fen-Tair,Hsieh, Li-Chen
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p. 9585 - 9588
(2007/10/02)
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- THE REACTION OF DIALKYLTRICHLOROMETHYLPHOSPHINES WITH METHYL ISOCYANATE AND WITH SATURATED AND α,β-UNSATURATED CARBONYL COMPOUNDS
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Diethyltrichloromethylphosphine (4a) reacts with methyl isocyanate (6e) and with nonenolizable saturated aldehydes, 6b-c, to produce 1,2-λ5-oxaphosphetanes, 7b-e, whereas with enolizable saturated ketones, 6f,g, it gives mixtures of cycloaddition products, 7f,g, and vinyl chlorides, 14f,g.By treatment with 4a, 1,3-diketones 6h-j are exclusively transformed into vinyl chlorides, 14h-j. α,β-Unsaturated aldehydes, 6k,l, react with 4a to afford phosphine oxides 17k,l.The crucial role of the oxaphosphetane type intermediates, 15k,l, in the formation of 17k,l has been demonstrated. Key words: Diethyltrichloromethylphosphine; P-chlorodiethyldichloromethylenephosphorane; 1,2,λ5-oxaphosphetane; saturated and α,β-unsaturated carbonyl compounds; diethyl-(1,1-dichloroalkyl)phosphine oxides.
- Majewski, Piotr
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- VILSMEIER REAGENTS: PREPARATION OF β-HALO-α,β-UNSATURATED KETONES
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A new method for the preparation of β-chloro and β-bromo-α,β-unsaturated ketones from β-diketones is described.Utilizing Vilsmeier reagents (prepared from N,N-dimethylformamide and oxalyl chloride or oxalyl bromide) β-halo-α,β-unsaturated ketones are isolated in excellent yields.
- Mewshaw, Richard E.
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p. 3753 - 3756
(2007/10/02)
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- Synthesis of β-chloro, β-bromo, and β-iodo α,β-unsaturated ketones
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A new, efficient method for the preparation of β-chloro, β-bromo, and β-iodo α,β-unsaturated ketones is described.The method involves the reaction of β-diketones or α-hydroxymethylenecycloalkanones with triphenylphosphine dihalides in the presence of trie
- Piers, Edward,Grierson, John R.,Lau, Cheuk Kun,Nagakura, Isao
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p. 210 - 223
(2007/10/02)
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- 11β-Alkyl-2-azaestratrienes and intermediates
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11β-Alkyl-2-azaestratrienes, displaying valuable pharmacological properties, e.g. anti-viral and hypolipemic, are manufactured by a total synthesis originating with dihydroresorcinol.
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- 7-Aza-6-alkoxy-1-tetralones
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The preparation of 7-aza-6-alkoxy-1-tetralones which originates with dihydroresorcinol is disclosed herein. The subject compounds are useful intermediates in the synthesis of various compounds which possess valuable pharmacological properties.
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