- Design and synthesis of Mannich base-type derivatives containing imidazole and benzimidazole as lead compounds for drug discovery in Chagas Disease
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The protozoan parasite Trypanosoma cruzi is the causative agent of Chagas disease, the most important parasitic infection in Latin America. The only treatments currently available are nitro-derivative drugs that are characterised by high toxicity and limited efficacy. Therefore, there is an urgent need for more effective, less toxic therapeutic agents. We have previously identified the potential for Mannich base derivatives as novel inhibitors of this parasite. To further explore this family of compounds, we synthesised a panel of 69 new analogues, based on multi-parametric structure-activity relationships, which allowed optimization of both anti-parasitic activity, physicochemical parameters and ADME properties. Additionally, we optimized our in vitro screening approaches against all three developmental forms of the parasite, allowing us to discard the least effective and trypanostatic derivatives at an early stage. We ultimately identified derivative 3c, which demonstrated excellent trypanocidal properties, and a synergistic mode of action against trypomastigotes in combination with the reference drug benznidazole. Both its druggability and low-cost production make this derivative a promising candidate for the preclinical, in vivo assays of the Chagas disease drug-discovery pipeline.
- Atherton, Richard L.,Kelly, John M.,Olmo, Francisco,Sanz-Serrano, Julen,Alcolea, Verónica,Beltran-Hortelano, Iván,Pérez-Silanes, Silvia,Rubio-Hernández, Mercedes
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- Enantio- and Diastereodivergent Synthesis of Spirocycles through Dual-Metal-Catalyzed [3+2] Annulation of 2-Vinyloxiranes with Nucleophilic Dipoles
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The development of efficient and straightforward methods for obtaining all optically active isomers of structurally rigid spirocycles from readily available starting materials is of great value in drug discovery and chiral ligand development. However, the
- Huo, Xiaohong,Luo, Yicong,Peng, Youbin,Wu, Liang,Zhang, Wanbin
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supporting information
p. 24941 - 24949
(2021/10/25)
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- PROCESS FOR THE DIRECT ALPHA-METHYLENATION OF KETONES
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The invention relates to a process for preparing an α-methylene ketone comprising the step of reacting a ketone with formaldehyde in the presence of a catalyst which is an organic compound comprising at least one acid function or the corresponding salt, ester or amide thereof and at least one amine function or the corresponding ammonium salt, or a zwitterion thereof.
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Page/Page column 16; 17
(2020/06/10)
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- Alkylation of Indoles with α,β-Unsaturated Ketones using Alumina in Hexanes
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We evaluated the influence of solvent on the alumina-promoted C3-alkylation of indoles with α,β-unsaturated ketones. We found that lipophilic solvents were generally superior to hydrophilic ones with hexanes offering the 3-alkyl indole products in high yields. Thus, we demonstrate an inexpensive and procedurally simple new process that pairs acidic alumina with hexanes to achieve this important Michael alkylation. The substrate scope includes twenty-four examples with reaction yields ranging from 61 to 96%. (Figure presented.).
- Zhang, Xiong,Jones-Mensah, Ebenezer,Deobald, Jackson,Magolan, Jakob
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supporting information
p. 5548 - 5551
(2019/11/19)
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- Method for synthesizing alpha,beta-unsaturated aryl ketone compound from dimethyl sulfoxide and arylethanone
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The invention discloses a method for synthesizing an alpha,beta-unsaturated aryl ketone compound from dimethyl sulfoxide and arylethanone. According to the method, dimethyl sulfoxide and arylethanoneare subjected to a one-pot reaction in the presence of carboxylate and persulfate so as to produce the alpha,beta-unsaturated aryl ketone compound. The method uses dimethyl sulfoxide as a methylenation reagent and employs a one-pot process for high-selectivity high-yield synthesis of the alpha,beta-unsaturated aryl ketone compound from arylethanone; and the method is simple to operate, low in cost, friendly to environment and beneficial for industrial production.
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Paragraph 0044; 0045-0050; 0075-0090
(2018/03/24)
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- Method for synthesizing alpha,beta-unsaturated ketone compounds from dimethyl sulfoxide and ketone compounds
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The invention discloses a method for synthesizing alpha,beta-unsaturated ketone compounds from dimethyl sulfoxide and ketone compounds. According to the method, dimethyl sulfoxide and ketone compoundsare subjected to a one-pot reaction in the presence of carboxylate and persulfate so as to produce the alpha,beta-unsaturated ketone compounds. The method uses dimethyl sulfoxide as a methylenation reagent and employs a one-pot process for high-selectivity high-yield synthesis of the alpha,beta-unsaturated ketone compounds from the ketone compounds; and the method is simple to operate, low in cost, friendly to environment and beneficial for industrial production.
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Paragraph 0047-0049; 0080-0083
(2018/03/24)
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- Cyanomethyl anion transfer reagents for diastereoselective Corey-Chaykovsky cyclopropanation reactions
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A readily available and bench-stable cyanomethyl sulfonium salt was used in highly diastereoselective Corey-Chaykovsky cyclopropanation reactions of electron-poor olefins. This efficient method provides a rapid route to access densely functionalized cyclopropyl nitriles.
- Hommelsheim, Renè,Hock, Katharina J.,Schumacher, Christian,Hussein, Mohanad A.,Nguyen, Thanh V.,Koenigs, Rene M.
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supporting information
p. 11439 - 11442
(2018/10/20)
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- Transition Metal-Free α-Csp3-H Methylenation of Ketones to Form C=C Bond Using Dimethyl Sulfoxide as Carbon Source
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A direct α-Csp3-H methylenation of arylketones to form C=C bond using dimethyl sulfoxide as one-carbon source is achieved under transition metal-free reaction condition. Various aryl ketone derivatives react readily with DMSO, producing the α,β-unsaturated carbonyl compounds in yields of 42 to 90%. This method features a transition metal-free reaction condition, wide substrate scope and using DMSO as novel one-carbon source to form C=C bond, thus providing an efficient and expeditious approach to an important class of α,β-unsaturated carbonyl compounds. Based on the preliminary experiments, a plausible mechanism of this transformation is disclosed.
- Liu, Yu-Feng,Ji, Peng-Yi,Xu, Jing-Wen,Hu, Yu-Qun,Liu, Qiang,Luo, Wei-Ping,Guo, Can-Cheng
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p. 7159 - 7164
(2017/07/26)
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- Catalytic Asymmetric Synthesis of Quaternary Barbituric Acids
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The catalytic asymmetric α-functionalization of prochiral barbituric acids, a subtype of pseudosymmetric 1,3-diamides, to yield the corresponding 5,5-disubstituted (quaternary) derivatives remains essentially unsolved. In this study 2-alkylthio-4,6-dioxopirimidines are designed as key 1,3-diamide surrogates that perform exceedingly in amine-squaramide catalyzed C-C bond forming reactions with vinyl ketones or Morita-Baylis-Hillmann-type allyl bromides as electrophiles. Mild acid hydrolysis of adducts affords barbituric acid derivatives with an in-ring quaternary carbon in unprecedented enantioselectivity, offering valuable materials for biological evaluations.
- Del Pozo, Sandra,Vera, Silvia,Oiarbide, Mikel,Palomo, Claudio
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supporting information
p. 15308 - 15311
(2017/11/06)
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- Morita-Baylis-Hillman Reaction of α,β-Unsaturated Ketones with Allylic Acetates by the Combination of Transition-Metal Catalysis and Organomediation
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An intermolecular Morita-Baylis-Hillman (MBH) reaction of α,β-unsaturated ketones with allylic acetates under the catalysis of 10 mol % of tetrakis(triphenylphosphine)palladium(0) and mediation of tributylphosphine has been developed in the presence of acetic acid, affording the desired α-coupling products. The MBH reaction has the advantages of good tolerance to many functional groups, excellent regioselectivity and E-stereoselectivity, and moderate to good yields.
- Li, Ya-Qiong,Wang, Hai-Jun,Huang, Zhi-Zhen
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p. 4429 - 4433
(2016/07/06)
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- Iron-catalyzed α-methylenation of ketones with N,N-Dimethylacetamide: An approach for α,β-unsaturated carbonyl compounds
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In this study, we developed a general iron-catalyzed α-methylenation of ketones by using N,N-dimethylacetamide as the one-carbon source. Various ketones, including aryl and alkyl ketones, enones, and dicarbonyl compounds were well tolerated to yield the corresponding α,β-unsaturated carbonyl compounds in the presence of an iron catalyst, peroxides, and N,N-dimethylacetamide under aerobic conditions. A general and facile iron-catalyzed α-methylenation of carbonyl compounds by using N-methyl amides as the one-carbon source was developed. Various carbonyl compounds (aryl- or alkyl-substituted, enones, 1,3-dicarbonyl compounds) were well tolerated to furnish the corresponding α,β-unsaturated carbonyl compounds in the presence of an iron catalyst, peroxides, and N-methyl amides under aerobic conditions.
- Li, Yi-Ming,Lou, Shao-Jie,Zhou, Qin-Hua,Zhu, Lian-Wen,Zhu, Long-Feng,Li, Lei
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supporting information
p. 3044 - 3047
(2015/05/13)
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- 1,4-Diazabicyclo[2.2.2]octane-Promoted Aminotrifluoromethylthiolation of α,β-Unsaturated Carbonyl Compounds: N-Trifluoromethylthio-4-nitrophthalimide Acts as Both the Nitrogen and SCF3 Sources
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A novel difunctionalization reaction is described. It uses N-trifluoromethylthio-4-nitrophthalimide as the reagent, which serves as both the nitrogen and SCF3 sources. In the presence of DABCO (1,4-diazabicyclo[2.2.2]octane), the nitrogen and SCF3 groups can be incorporated into α,β-unsaturated carbonyl compounds easily and give versatile β-amino ketones and esters in good yields. This difunctionalization reaction features mild reaction conditions, high atom-economy, and efficient access to α-SCF3 amino acids.
- Xiao, Qing,He, Qijie,Li, Juncheng,Wang, Jun
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supporting information
p. 6090 - 6093
(2016/01/09)
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- Desulfonylative Methenylation of β-Keto Sulfones
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A one-step strategy for the synthesis of α-methenyl ketones from β-keto sufones is reported. Success of the methodology is elaborated for the synthesis of chromanones and isoflavanones in one-step.
- Pandey, Ganesh,Vaitla, Janakiram
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supporting information
p. 4890 - 4893
(2015/10/12)
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- N-Heterocyclic carbene-catalyzed double acylation of enones with benzils
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Thiazolium carbene-catalyzed reaction of aromatic 1,2-diketones with enones in aprotic solvents gave double acylation products in good yields, whereas hydroacylation products formed by Stetter reaction were not detected at all. These results suggested the generation of aroyloxyenamine species from the 1,2-diketones instead of hydroxyenamines (Breslow intermediates). This journal is
- Takaki, Ken,Ohno, Akira,Hino, Makoto,Shitaoka, Takashi,Komeyama, Kimihiro,Yoshida, Hiroto
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supporting information
p. 12285 - 12288
(2014/12/11)
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- Palladium-catalysed carbonylative cross-coupling reactions of aryl iodides and vinyl boron derivatives as a straightforward route to aryl vinyl ketones
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The carbonylative cross-coupling of potassium vinyl trifluoroborate or 2,4,6-trivinyltricycloboroxane with aryl iodides under mild conditions affords aryl vinyl ketones. The optimisation of the reaction conditions leads to the targeted enones in good yiel
- Pirez, Cyril,Dheur, Julien,Sauthier, Mathieu,Castanet, Yves,Mortreux, André
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experimental part
p. 1745 - 1748
(2009/12/08)
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- The preparation of substituted 3,4-dihydro-1(2H)-naphthalenones from benzocyclobutenones via sequential thermal electrocyclic reactions
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1-Alkenylbenzocyclobutenols, prepared from benzocyclobutenones via the addition of alkenyl Grignard reagents or the addition of alkynyllithium reagents followed by (E)-selective reduction, undergo successive thermal 4π and 6π electrocyclisations to give substituted 3,4-dihydro-1(2H)-naphthalenones. An analogous sequence gave 3,4-dihydro-1(2H)-anthracenone from naphtho[b]cyclobuten-1(2H)-one.
- Hickman, Derek N.,Hodgetts, Kevin J.,Mackman, Peter S.,Wallace, Timothy W.,Wardleworth, J. Michael
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p. 2235 - 2260
(2007/10/03)
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- Photochemistry of α-oxo oximes. Part 9. The γ-hydrogen abstraction in α-oxo oxime ethers
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The photochemistry (λ 300 nm) of the α-oxo oxime ethers 1a and 2a has been studied with the objective of detecting any γ-H abstraction.Direct irradiation of (Z)-1a results only in (E)-(Z) isomerization, whereas direct irradiation of the isomeric α-oxo oxi
- Buys, Theo S. V.,Cerfontain, Hans,Geenevasen, Jan A. J.,Stunnenberg, Frank
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p. 188 - 194
(2007/10/02)
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- Palladium-Catalyzed Acylation of Unsaturated Halides by Anions of Enol Ethers
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Zinc salts of enol ether anions are coupled to aryl and alkenyl halides by using palladium catalysts, effecting a direct acetylation of aryl and alkenyl halides.Zinc salts of allenic ethers are coupled with aryl and alkenyl halides under similar conditions to give α,β-unsaturated ketones, the allenic ether serving as a source of the acryloyl group.Allenic ethers were γ arylated in a palladium-catalyzed coupling with aryl halides to give β,β-diaryl-α,β-unsaturated aldehydes.
- Russell, Charles E.,Hegedus, Louis S.
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p. 943 - 949
(2007/10/02)
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