- Mechanochemical Syntheses of N-Containing Heterocycles with TosMIC
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A mechanochemical van Leusen pyrrole synthesis with a base leads to 3,4-disubstitued pyrroles in moderate to excellent yields. The developed protocol is compatible with a range of electron-withdrawing groups and can also be applied to the synthesis of oxazoles. Attempts to mechanochemically convert the resulting pyrroles into porphyrins proved to be difficult.
- Bolm, Carsten,Molitor, Claude,Rissanen, Kari,Schumacher, Christian,Smid, Sabrina,Truong, Khai-Nghi
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p. 14213 - 14222
(2021/09/07)
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- Borane-Catalyzed, Chemoselective Reduction and Hydrofunctionalization of Enones Enabled by B-O Transborylation
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The use of stoichiometric organoborane reductants in organic synthesis is well established. Here these reagents have been rendered catalytic through an isodesmic B-O/B-H transborylation applied in the borane-catalyzed, chemoselective alkene reduction and formal hydrofunctionalization of enones. The reaction was found to proceed by a 1,4-hydroboration of the enone and B-O/B-H transborylation with HBpin, enabling catalyst turnover. Single-turnover and isotopic labeling experiments supported the proposed mechanism of catalysis with 1,4-hydroboration and B-O/B-H transborylation as key steps.
- Nicholson, Kieran,Langer, Thomas,Thomas, Stephen P.
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supporting information
p. 2498 - 2504
(2021/04/13)
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- Chemoselective reduction of ?,¢-unsaturated carbonyl and carboxylic compounds by hydrogen iodide
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The selective reduction of ?,¢-unsaturated carbonyl compounds was achieved to produce saturated carbonyl compounds with aqueous HI solution. The introduction of an aryl group at an ? or ¢ position efficiently facilitated the reduction with good yield. The reaction was applicable to compounds bearing carboxylic acids and halogen atoms. Through the investigation of the reaction mechanism, it was found that Michael-type addition of iodide occurred to produce ¢-iodo compounds followed by the reduction of C-I bond via anionic and radical paths.
- Matsumoto, Shoji,Marumoto, Hayato,Akazome, Motohiro,Otani, Yasuhiko,Kaiho, Tatsuo
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p. 590 - 599
(2021/03/29)
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- Facile Synthesis of Polysubstituted 2-Pyrones via TfOH-Mediated Ring Expansion of 2-Acylcyclopropane-1-carboxylates
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A facile route to polysubstituted 2-pyrones from readily available 2-acylcyclopropane-1-aryl-1-carboxylates mediated by TfOH is reported. The strongly donating 1-aryl group is important for directing the C-C bond cleavage of the donor-acceptor cyclopropane ring, which then leads to the formation of the 2-pyrone ring through lactonization.
- Shao, Jiru,An, Caiyun,Wang, Sunewang R.
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p. 4030 - 4041
(2021/07/19)
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- Discovery of trisubstituted pyrazolines as a novel scaffold for the development of selective phosphodiesterase 5 inhibitors
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Celecoxib, is a selective cyclooxygenase-2 (COX2) inhibitor with a 1,5-diaryl pyrazole scaffold. Celecoxib has a better safety profile compared to other COX2 inhibitors having side effects of systemic hypertension and thromboembolic complications. This may be partly attributed to an off-target activity involving phosphodiesterase 5 (PDE5) inhibition and the potentiation of NO/cGMP signalling allowing coronary vasodilation and aortic relaxation. Inspired by the structure of celecoxib, we synthesized a chemically diverse series of compounds containing a 1,3,5-trisubstituted pyrazoline scaffold to improve PDE5 inhibitory potency, while eliminating COX2 inhibitory activity. SAR studies for PDE5 inhibition revealed an essential role for a carboxylic acid functionality at the 1-phenyl and the importance of the non-planar pyrazoline core over the planar pyrazole with the 5-phenyl moiety tolerating a range of substituents. These modifications led to new PDE5 inhibitors with approximately 20-fold improved potency to inhibit PDE5 and no COX-2 inhibitory activity compared with celecoxib. PDE isozyme profiling of compound 11 revealed a favorable selectivity profile. These results suggest that trisubstituted pyrazolines provide a promising scaffold for further chemical optimization to identify novel PDE5 inhibitors with potential for less side effects compared with available PDE5 inhibitors used for the treatment of penile erectile dysfunction and pulmonary hypertension.
- Abdel-Halim, Mohammad,Tinsley, Heather,Keeton, Adam B.,Weam, Mohammed,Atta, Noha H.,Hammam, Mennatallah A.,Hefnawy, Amr,Hartmann, Rolf W.,Engel, Matthias,Piazza, Gary A.,Abadi, Ashraf H.
-
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- Synthesis of Vicinal Quaternary All-Carbon Centers via Acid-catalyzed Cycloisomerization of Neopentylic Epoxides
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We report our studies on the development of a catalytic cycloisomerization of 2,2-disubstituted neopentylic epoxides to produce highly substituted tetralins and chromanes. Termination of the sequence occurs via Friedel-Crafts-type alkylation of the remote (hetero)arene linker. The transformation is efficiently promoted by sulfuric acid and proceeds best in 1,1,1,3,3,3-hexafluoroisopropanol (HFIP) as the solvent. Variation of the substitution pattern provided detailed insights into the migration tendencies and revealed a competing disproportionation pathway of dihydronaphthalenes.
- Schmid, Matthias,Sokol, Kevin R.,Wein, Lukas A.,Torres Venegas, Sofia,Meisenbichler, Christina,Wurst, Klaus,Podewitz, Maren,Magauer, Thomas
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supporting information
p. 6526 - 6531
(2020/09/02)
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- Diversified Transformations of Tetrahydroindolizines to Construct Chiral 3-Arylindolizines and Dicarbofunctionalized 1,5-Diketones
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Enantioselective diverse synthesis of a small-molecule collection with structural and functional similarities or differences in an efficient manner is an appealing but formidable challenge. Asymmetric preparation and branching transformations of tetrahydroindolizines in succession present a useful approach to the construction of N-heterocycle-containing scaffolds with functional group, and stereochemical diversity. Herein, we report a breakthrough toward this end via an initial diastereo- A nd enantioselective [3 + 2] cycloaddition between pyridinium ylides and enones, following diversified sequential transformations. Chiral N,N′-dioxide-earth metal complexes enable the generation of optically active tetrahydroindolizines in situ, across the strong background reaction for racemate-formation. In connection with deliberate sequential transformations, involving convenient rearomatic oxidation, and light-active aza-Norrish II rearrangement, the tetrahydroindolizine intermediates were converted into the final library including 3-arylindolizine derivatives and dicarbofunctionalized 1,5-dicarbonyl compounds. More importantly, the stereochemistry of four-stereogenic centered tetrahydroindolizine intermediates could be efficiently transferred into axial chirality in 3-arylindolizines and vicinal pyridyl and aryl substituted 1,5-diketones. In addition, densely functionalized cyclopropanes and bridged cyclic compounds were also discovered depending on the nature of the pyridinium ylides. Mechanism studies were involved to explain the stereochemistry during the reaction processes.
- Feng, Xiaoming,He, Qianwen,Liu, Xiaohua,Pan, Chenjing,Su, Zhishan,Wu, Zhikun,Zhang, Dong,Zhou, Yuqiao
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supporting information
p. 15975 - 15985
(2020/10/18)
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- Allyl-Nickel Catalysis Enables Carbonyl Dehydrogenation and Oxidative Cycloalkenylation of Ketones
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We herein disclose the first report of a first-row transition metal-catalyzed α,β-dehydrogenation of carbonyl compounds using allyl-nickel catalysis. This development overcomes several limitations of previously reported allyl-palladium-catalyzed oxidation, and is further leveraged for the development of an oxidative cycloalkenylation reaction that provides access to bicycloalkenones with fused, bridged, and spirocyclic ring systems using unactivated ketone and alkene precursors.
- Huang, David,Szewczyk, Suzanne M.,Zhang, Pengpeng,Newhouse, Timothy R.
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supporting information
p. 5669 - 5674
(2019/04/26)
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- Asymmetric transfer hydrogenation of cycloalkyl vinyl ketones to allylic alcohols catalyzed by ruthenium amido complexes
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A chemoselective 1,2-reduction of cycloalkyl vinyl ketones via asymmetric transfer hydrogenation is described. The reduction proceeded smoothly with a chiral diamine ruthenium complex as a catalyst and a HCOOH-NEt3 azeotrope as both a hydrogen source and solvent under mild conditions. A wide range of 1-cycloalkyl chiral allylic alcohols were obtained in good yields and up to 87% ee. It was found that the alkyl group plays an important role in the enantioselectivity.
- Liu, Sensheng,Cui, Peng,Wang, Juan,Zhou, Haifeng,Liu, Qixing,Lv, Jinliang
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supporting information
p. 264 - 267
(2019/01/10)
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- Silver(i)-catalysed carboxylative cyclisation of primary propargylic amines in neat water using potassium bicarbonate as a carboxyl source: An environment-friendly synthesis of: Z -5-alkylidene-1,3-oxazolidin-2-ones
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Herein, we report a mild and environment-friendly synthesis of Z-5-alkylidene-2-oxazolidinones in neat water, using a low loading (2 mol%) of silver carbonate as a catalyst. Instead of pressurised gaseous carbon dioxide, potassium bicarbonate was used as the source of carboxyl. An interesting solvent effect and a C-N cleavage side reaction with a 6-endo-dig mechanism are also discussed.
- Qin, Jian-Feng,Wang, Bing,Lin, Guo-Qiang
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supporting information
p. 4656 - 4661
(2019/09/09)
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- Enantioselective Copper-Catalyzed 1,5-Cyanotrifluoromethylation of Vinylcyclopropanes
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A copper-catalyzed enantioselective 1,5-cyanotrifluoromethylation of vinylcyclopropanes has been developed using a radical relay strategy. This asymmetric reaction has demonstrated high enantioselective control, broad substrate scope, and mild conditions. Initiated by the in situ generated CF3 radical from Togni's reagent, this method offers a new solution for remote enantioselective bifunctionalization of alkenes and thus provides a straightforward way for the synthesis of chiral CF3-containing internal alkenylnitriles.
- Zhang, Zi-Qi,Meng, Xiang-Yu,Sheng, Jie,Lan, Quan,Wang, Xi-Sheng
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supporting information
p. 8256 - 8260
(2019/10/16)
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- Visible Light-Induced Aerobic Epoxidation of α,β-Unsaturated Ketones Mediated by Amidines
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An aerobic photoepoxidation of α,β-unsaturated ketones driven by visible light in the presence of tetramethylguanidine (3b), tetraphenylporphine (H2TPP), and molecular oxygen under mild conditions was revealed. The corresponding α,β-epoxy ketones were obtained in yields of up to 94% in 96 h. The reaction time was shortened to 4.6 h by flow synthesis. The mechanism related to singlet oxygen was supported by experiments and density functional theory (DFT) calculations.
- Wu, Yufeng,Zhou, Guangli,Meng, Qingwei,Tang, Xiaofei,Liu, Guangzhi,Yin, Hang,Zhao, Jingnan,Yang, Fan,Yu, Zongyi,Luo, Yi
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p. 13051 - 13062
(2018/10/25)
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- Chalcone and cinnamate synthesis via one-pot enol silane formation-Mukaiyama aldol reactions of ketones and acetate esters
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Aryl alkyl ketones, acetate esters, and acetamides undergo facile one-pot enol silane formation, Mukaiyama aldol addition, and dehydrosilyloxylation in the presence of an amine base and excess trimethylsilyl trifluoromethanesulfonate. The chalcone and cinnamate products are generally recovered in high yield. The relative stoichiometry of the trimethylsilyl trifluoromethanesulfonate and amine base reagents determines whether the reaction yields the β-silyloxy carbonyl product or the α,β-unsaturated carbonyl.
- Downey, C. Wade,Glist, Hadleigh M.,Takashima, Anna,Bottum, Samuel R.,Dixon, Grant J.
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supporting information
p. 3080 - 3083
(2018/07/06)
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- 3,5-site non-aryl substituted R-azaBODIPY fluorescent dye and preparation method thereof
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The invention provides a 3,5-site non-aryl substituted R-azaBODIPY fluorescent dye and a preparation method thereof. A novel 3,5-site non-aryl substituted dye R-azaBODIPY is developed from classical and traditional 3,5-site aryl substituted azaBODIPY. The R-azaBODIPY dye is further applied to the development of biological and materials science studies, a novel dye is provided, and the varieties ofdye families are enriched. As the novel dye, the R-azaBODIPY fluorescent dye has the advantages of spectral property and the like of the classical and the traditional azaBODIPY dye and further has the significant characteristics that the fluorescence quantum yield is high, the pi-pi accumulation is inhibited, and the stability is good. The R-azaBODIPY fluorescent dye is represented by a general formula I (shown in the description). The R-azaBODIPY fluorescent dye comprises a 3,5-site non-aryl substituted structure, is a breakthrough of a traditional and classical azaBODIPY structure, has theadvantages of spectral property and the like of the classical and traditional azaBODIPY dye and further has the characteristics of relatively high fluorescence quantum yield, relatively good stabilityand relatively strong hydrophilcity.
- -
-
Paragraph 0026; 0027
(2019/01/05)
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- The Chemistry of a Non-Interacting Vicinal Frustrated Phosphane/Borane Lewis Pair
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The dimesitylphosphinocyclopentene/HB(C6F5)2-derived vicinal trans-1,2-P/B frustrated Lewis pair (FLP) 4 shows no direct phosphane–borane interaction. Toward some reagents it behaves similar to an intermolecular FLP; it cleaves dihydrogen, deprotonates terminal alkynes, and adds to organic carbonyl compounds including CO2. It shows typical intramolecular FLP reaction modes (cooperative 1,1-additions) to mesityl azide, to carbon monoxide, and to NO. The latter reaction yields a persistent P/B FLPNO nitroxide radical, which undergoes H-atom abstraction reactions. The FLP 4 serves as a template for the CO reduction by [HB(C6F5)2] to generate a FLP-η2-formylborane. The formylborane moiety is removed from the FLP template by reaction with pyridine to yield a genuine pyridine stabilized formylborane that undergoes characteristic borane carbaldehyde reactions (Wittig olefination, imine formation). Most new products were characterized by X-ray diffraction.
- Elmer, Lisa-Maria,Kehr, Gerald,Daniliuc, Constantin G.,Siedow, Melanie,Eckert, Hellmut,Tesch, Matthias,Studer, Armido,Williams, Kamille,Warren, Timothy H.,Erker, Gerhard
-
supporting information
p. 6056 - 6068
(2017/05/05)
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- Stereospecific Decarboxylative Nazarov Cyclization Mediated by Carbon Dioxide for the Preparation of Highly Substituted 2-Cyclopentenones
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Highly substituted 2-cyclopentenones were stereospecifically and regioselectively constructed with high catalytic efficiency through Lewis-acid catalyzed decarboxylative Nazarov cyclization of the cyclic carbonate derivative, which is prepared by reacting the propargyl alcohol with carbon dioxide in the presence of a silver catalyst. The stereochemistry of the 2-cyclopentenone is strictly controlled by the geometry of the alkene in the starting material. This method is applicable for various substrates.
- Komatsuki, Keiichi,Sadamitsu, Yuta,Sekine, Kohei,Saito, Kodai,Yamada, Tohru
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supporting information
p. 11594 - 11598
(2017/09/11)
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- AgII-Mediated Synthesis of β-Fluoroketones by Oxidative Cyclopropanol Opening
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A regioselective synthesis of β-fluorinated ketones by silver(II)-mediated ring opening is described. Commercially available AgF2 serves as both an oxidant and fluorine-atom source. A variety of β-fluorinated ketones are efficiently prepared from tertiary cyclopropanol precursors, offering a straightforward approach for the introduction of a fluorine atom at a remote site. Selectivity is observed in the site of bond cleavage, which leads to fluorination at the more substituted site. A radical mediated sequential homolytic C–C bond cleavage and C–F bond formation is suggested.
- Deng, Yuanlin,Kauser, Nabeelah I.,Islam, Shahidul M.,Mohr, Justin T.
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p. 5872 - 5879
(2017/10/31)
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- 13C NMR spectroscopy of heterocycles: 1-phenyl-3-aryl/t-butyl-5-arylpyrazoles
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A series of chalcones 1-12 were converted to pyrazolines (1Pi-12Pi) by reaction with phenylhydrazine followed by DDQ oxidation to produce the corresponding pyrazoles (1Pz-12Pz). Three 1-phenyl-3-t-butyl-5-arylpyrazoles (13Pz-15Pz) were synthesized using an analogous approach. Molecular modeling studies predicted the 5-aryl group of the pyrazoles for both series to have a torsion angle of 52°-54° whereas the 1-phenyl group was predicted to have 35°-37° torsion angles. The 3-aryl group was predicted to be essentially coplanar (-3°) with the pyrazole system in the first series. 13C NMR data for both series, 1Pz-12Pz and 13Pz-15Pz, were collected in DMSO-d6 at 50°C. A plot of the C4 chemical shifts for 1Pz-12Pz versus Hammet constants for 5-aryl substituents yielded a very good linear correlation (R2=0.96) with a slope of 1.5. The chemical shift data for C4 showed little or no dependence on 3-aryl substituents. The result for 13Pz-15Pz, despite only three points, was consistent with the first series results and yielded a ρ value of 2.0. Distal transmission of substituent effects (5-aryl groups) to C4 of the pyrazole system was reduced by roughly 50-60% of that of the analogous planar isoxazole system, but are not consistent with results for the similarly twisted 4-bromoisoxazoles.
- Hockstedler, Amy N.,Edjah, Beatrice A.,Azhar, Saajid Z.,Mendoza, Hadrian,Brown, Nicole A.,Arrowood, Hayley B.,Clay, Andrew C.,Shah, Anand B.,Duffek, Glenda M.,Cui, Jianmei,Baumstark, Alfons L.
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p. 125 - 131
(2017/04/14)
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- α,α-Alkylation-Halogenation and Dihalogenation of Sulfoxonium Ylides. A Direct Preparation of Geminal Difunctionalized Ketones
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A one-pot alkylation–halogenation of ketosulfoxonium ylides in the presence of alkyl halides is described. The method furnishes several gem-difunctionalized haloketones (an alkyl and F, Cl, Br, or I) in good yields. Replacing alkyl halides with a mixture of electrophilic halogen species and various halide anions led to gem-dihalogenated ketones containing a combination of the same or two different halogens. Kinetic isotopic effects as well as reaction kinetic experiments give insight to the mechanism of these reactions.
- Gallo, Rafael D. C.,Ahmad, Anees,Metzker, Gustavo,Burtoloso, Antonio C. B.
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supporting information
p. 16980 - 16984
(2017/11/27)
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- Metal- and Acid-Free Methyl Triflate Catalyzed Meyer-Schuster Rearrangement
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A novel metal- and acid-free preparation of synthetically useful α,β-unsaturated carbonyl compounds from propargyl alcohols has been realized. This Meyer-Schuster rearrangement process is effectively catalyzed by methyl triflate (20 mol%) to prepare a broad scope of conjugated E -enals and E -enones generally in good to excellent yields (up to 90%). This reaction procedure operates under mild conditions (70 °C), in air, with short reaction times (1 h). Moreover, a carbocation intermediate trapped by the solvent 2,2,2-trifluoroethanol was isolated during this transformation.
- Yang, Lu,Zeng, Qingle
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p. 3149 - 3156
(2017/07/12)
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- Chemoselective Claisen-Schmidt bis-substitutional condensation catalyzed by an alkoxy-bridged dinuclear Ti(IV) cluster
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The highly efficient and chemoselective α,α′-bis-substitution of alkanones is important in organic synthesis. Herein, a dimeric titanium cluster, Ti2Cl2(OPri)6·2HOPri (Ti2), is used in the Claisen-Schmidt condensation reaction, for the selectively activation of symmetrical ketones containing α,α′-methylene groups and production of α,α′-bis-substituted alkanones in high efficiency and chemoselectivity. The high efficiency and chemoselectivity can be extended to a variety of typical alkanones and aromatic aldehydes. Both of the oxo-bridged dimeric motif of Ti2 and the ionic Ti-Cl bond are responsible for the high efficiency and chemoselectivity.
- Wu, Yufei,Hou, Jie,Liu, Yuliang,Zhang, Mingfu,Tung, Chen-Ho,Wang, Yifeng
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p. 1511 - 1516
(2016/03/01)
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- Tertiary Amine Promoted Aziridination: Preparation of NH-Aziridines from Aliphatic α,β-Unsaturated Ketones
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trans-NH-Aziridines were prepared from aliphatic α,β-unsaturated ketones using a tertiary amine promoted reaction via in situ generated N,N-ylides. Through use of modified conditions the reaction proved to be applicable for the diastereoselective aziridination of a range of enolisable aliphatic α,β-unsaturated ketones of varying substitution patterns.
- Armstrong, Alan,Pullin, Robert D. C.,Scutt, James N.
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supporting information
p. 151 - 155
(2015/12/26)
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- Organoselenium-catalyzed baeyer-villiger oxidation of α,β-unsaturated ketones by hydrogen peroxide to access vinyl esters
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By carefully screening the organoselenium pre-catalysts and optimizing the reaction conditions, simple dibenzyl diselenide was found to be the best pre-catalyst for Baeyer-Villiger oxidation of (E)-α,β-unsaturated ketones with the green oxidant hydrogen peroxide at room temperature. The organoselenium catalyst used in this reaction could be recycled and reused several times. This new method was suitable not only for methyl unsaturated ketones, but also for alkyl and aryl unsaturated ketones. Therefore, it provided a direct, mild, practical, highly functional group-tolerant process for the chemoselective preparation of the versatile (E)-vinyl esters from the readily available (E)-α,β-unsaturated ketones. A possible mechanism was also proposed to rationalize the activity of the organoselenium catalyst in the presence of hydrogen peroxide in this Baeyer-Villiger oxidation reaction.
- Zhang, Xu,Ye, Jianqing,Yu, Lei,Shi, Xinkang,Zhang, Ming,Xu, Qing,Lautens, Mark
-
supporting information
p. 955 - 960
(2015/03/30)
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- Copper-catalyzed oxidative olefination of thiols using sulfones and phosphorous ylides
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Copper-catalyzed one-pot conversion of thiols to olefins was conducted under aerobic conditions. Thiols were oxidized to generate thioaldehydes, which reacted with sulfones or phosphorous ylides to form the corresponding olefins. The formation of thiosulfonates and phosphorous sulfides confirms that these olefination protocols proceed via thioaldehyde-sulfone and thioaldehyde-ylide adducts.
- Shyam, Pranab K.,Lee, Chan,Jang, Hye-Young
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supporting information
p. 1824 - 1827
(2015/07/15)
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- Oxidative kinetic resolution of racemic alkyl aryl carbinols by an electronically tuned chiral nitroxyl radical
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A method for oxidative kinetic resolution of racemic alcohols catalyzed by chiral nitroxyl radical (R,R)-1 has been developed. This method is especially effective for the kinetic resolution of tert-butyl aryl carbinols (s = up to 23).
- Hamada, Shohei,Wada, Yoshiyuki,Sasamori, Takahiro,Tokitoh, Norihiro,Furura, Takumi,Kawabata, Takeo
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supporting information
p. 1943 - 1945
(2014/03/21)
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- Iridium(I)-catalyzed regioselective C-H activation and hydrogen-isotope exchange of non-aromatic unsaturated functionality
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Isotopic labelling is a key technology of increasing importance for the investigation of new C-H activation and functionalization techniques, as well as in the construction of labelled molecules for use within both organic synthesis and drug discovery. Herein, we report for the first time selective iridium-catalyzed C-H activation and hydrogen-isotope exchange at the β-position of unsaturated organic compounds. The use of our highly active [Ir(cod)(IMes)(PPh3)][PF6] (cod = 1, 5-cyclooctadiene) catalyst, under mild reaction conditions, allows the regioselective β-activation and labelling of a range of α, β-unsaturated compounds with differing steric and electronic properties. This new process delivers high levels of isotope incorporation over short reaction times by using low levels of catalyst loading.
- Kerr, William J.,Mudd, Richard J.,Paterson, Laura C.,Brown, Jack A.
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supporting information
p. 14604 - 14607
(2015/03/04)
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- Controlling the molecular topology of vinylogous iminium ions by logical substrate design: Highly regio- and stereoselective aminocatalytic 1,6-addition to linear 2,4-dienals
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All about topology control: The title reaction yields valuable tetrahydrofuran spirooxindoles (see scheme; TMS=trimethylsilyl), and exemplifies a rare asymmetric 1,6-addition to linear 2,4-dienals proceeding with high δ-site- and stereoselectivity. A steering group at the β-dienal position ensured molecular preorganization of the catalytically active vinylogous iminium ion intermediate for highly predictable reaction outcomes. Copyright
- Silvi, Mattia,Chatterjee, Indranil,Liu, Yiankai,Melchiorre, Paolo
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supporting information
p. 10780 - 10783
(2013/10/22)
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- Part I: The development of the catalytic wittig reaction
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We have developed the first catalytic (in phosphane) Wittig reaction (CWR). The utilization of an organosilane was pivotal for success as it allowed for the chemoselective reduction of a phosphane oxide. Protocol optimization evaluated the phosphane oxide precatalyst structure, loading, organosilane, temperature, solvent, and base. These studies demonstrated that to maintain viable catalytic performance it was necessary to employ cyclic phosphane oxide precatalysts of type 1. Initial substrate studies utilized sodium carbonate as a base, and further experimentation identified N,N-diisopropylethylamine (DIPEA) as a soluble alternative. The use of DIPEA improved the ease of use, broadened the substrate scope, and decreased the precatalyst loading. The optimized protocols were compatible with alkyl, aryl, and heterocyclic (furyl, indolyl, pyridyl, pyrrolyl, and thienyl) aldehydes to produce both di- and trisubstituted olefins in moderate-to-high yields (60-96 %) by using a precatalyst loading of 4-10 mol %. Kinetic E/Z selectivity was generally 66:34; complete E selectivity for disubstituted α,β-unsaturated products was achieved through a phosphane-mediated isomerization event. The CWR was applied to the synthesis of 54, a known precursor to the anti-Alzheimer drug donepezil hydrochloride, on a multigram scale (12.2 g, 74 % yield). In addition, to our knowledge, the described CWR is the only transition-/heavy-metal-free catalytic olefination process, excluding proton-catalyzed elimination reactions. A point of difference: By utilizing an organosilane to chemoselectively reduce a phosphane oxide precatalyst to a phosphane (see scheme), the first catalytic (in phosphane) Wittig reaction has been developed. The methodology has been applied to the synthesis of 22 disubstituted and 24 trisubstituted olefins, including a multigram synthesis of a precursor to the anti-Alzheimer drug donepezil hydrochloride.
- O'Brien, Christopher J.,Nixon, Zachary S.,Holohan, Andrew J.,Kunkel, Stephen R.,Tellez, Jennifer L.,Doonan, Bryan J.,Coyle, Emma E.,Lavigne, Florie,Kang, Lauren J.,Przeworski, Katherine C.
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supporting information
p. 15281 - 15289
(2013/11/06)
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- InCl3/Me3SiCl-catalyzed direct michael addition of enol acetates to α,β-unsaturated ketones
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The direct Michael addition of enol acetates to α,β-unsaturated ketones was achieved using a combination of Lewis acid catalysts, InCl 3 and Me3SiCl, which furnished stable enol-form products that could be further transformed into functionalized 1,5-diketones by reactions with various electrophiles.
- Onishi, Yoshiharu,Yoneda, Yuki,Nishimoto, Yoshihiro,Yasuda, Makoto,Baba, Akio
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supporting information
p. 5788 - 5791
(2013/01/15)
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- On the reaction of sterically hindered α,β-unsaturated ketones with hydroxylamine: Preparation of 5-hydroxy derivatives of isoxazolidine and 4,5-dihydroisoxazole
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A reaction of hydroxylamine with α,β-unsaturated ketones containing a tertiary carbon atom α to the keto group leads to 5-hydroxyisoxazolidine and 5-hydroxy-Δ2-isoxazoline derivatives.
- Mavrov,Firgang
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p. 606 - 615
(2013/05/09)
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- Anomalous Z-isomer content in Wittig reaction products from keto-stabilised ylides with ortho-heteroatom substituted benzaldehydes
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Wittig reaction products of keto-stabilised ylides with ortho-substituted benzaldehydes are found to show significantly higher than expected Z-alkene content (up to 50%) compared to analogous reactions of the same ylides with benzaldehyde itself. A cooperative effect is seen whereby the unusual Z-content is further augmented if the ylide bears greater steric bulk in the α′-position. These results are consistent with our previous observations on reactions of all ylide types with aldehydes bearing a β-heteroatom. Significantly, the cooperative effect, previously seen only with semi-stabilised ylides, has now been extended to stabilised ylides. Both the anomalous increase in Z-content and the cooperative effect can be rationalised within the [2+2] cycloaddition mechanism of the Wittig reaction.
- Byrne, Peter A.,Higham, Lee J.,McGovern, Pádraic,Gilheany, Declan G.
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p. 6701 - 6704
(2013/01/15)
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- Reaction of frustrated lewis pairs with conjugated ynones-selective hydrogenation of the carbon-carbon triple bond
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Frustrated, but not frustrating: Frustrated Lewis pairs (FLPs) can undergo selective 1,4-addition reactions with conjugated ynones (see scheme). Upon FLP dihydrogen activation selective hydrogenation of the carbon-carbon triple bond can be achieved, in one case even catalytically. Copyright
- Xu, Bao-Hua,Kehr, Gerald,Froehlich, Roland,Wibbeling, Birgit,Schirmer, Birgitta,Grimme, Stefan,Erker, Gerhard
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supporting information; experimental part
p. 7183 - 7186
(2011/09/30)
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- Regioselective synthesis of 3-carbo-5-phosphonylpyrazoles through a one-pot Claisen-Schmidt/1,3-dipolar cycloaddition/oxidation sequence
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A one-pot reaction involving an aldehyde, a methyl ketone, and the Bestmann-Ohira reagent has been developed for the synthesis of variously substituted 3-carbo-5-phosphonylpyrazoles. Our synthetic methodology features a domino Claisen-Schmidt/1,3-dipolar cycloaddition/oxidation sequence, which leads to the target compounds in excellent yields. We further demonstrated that this unprecedented sequence could also be combined with a copper-catalyzed azide-alkyne cycloaddition in a one-pot, four-step cascade process generating five new bonds and two heterocyclic rings. Copyright
- Martin, Anthony R.,Mohanan, Kishor,Toupet, Loic,Vasseur, Jean-Jacques,Smietana, Michael
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experimental part
p. 3184 - 3190
(2011/06/28)
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- Heteropoly compound catalyzed synthesis of both z- and e-α,β- unsaturated carbonyl compounds
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An EZ switch: The cationic species of the heteropoly compounds has a critical impact on the Z/E selectivity of the Meyer-Schuster rearrangement of propargyl alcohols (see scheme). The isolation of the thermodynamically unfavorable Z-α,β-unsaturated carbonyl compounds is notable. The high Z selectivities were obtained at a reaction temperature as high as 50°C.
- Egi, Masahiro,Umemura, Megumi,Kawai, Takuya,Akai, Shuji
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p. 12197 - 12200
(2012/01/19)
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- Triazole-gold-promoted, effective synthesis of enones from propargylic esters and alcohols: A catalyst offering chemoselectivity, acidity and ligand economy
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The air, moisture and thermally stable 1,2,3-triazole coordinated gold(I) complexes (TA-Au) were revealed as the effective catalysts in promoting propargylic ester rearrangement and sequential allene hydration, giving the enones with excellent yields (up to 97% yields, 0.2% loading). The catalysts could also catalyze the more challenging Meyer-Schuster rearrangement (0.5% loading, up to 98% yields). The reported reaction confirmed TA-Au as a chemoselective catalyst in promoting alkyne activation with high efficiency and improved ligand economy. Copyright
- Wang, Dawei,Zhang, Yanwei,Harris, Alexandria,Gautam, Lekh Nath S.,Chen, Yunfeng,Shi, Xiaodong
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supporting information; experimental part
p. 2584 - 2588
(2011/12/01)
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- Stereoselective olefination of N-sulfonyl imines with stabilized phosphonium ylides for the synthesis of electron-deficient alkenes
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An unprecedented protocol has been developed for thestereoselective synthesis of structurally diverse electron-deficient alkenes in moderate to excellent yields from readily accessible N-sulfonyl imines and stabilized phosphonium ylides. Significantly, the olefination reaction of N-sulfonylimines with nitrile-stabilized phosphonium ylides affords an array of α,β-unsaturated nitriles with high Z selectivity, and the reactions with ester-, amide-, and ketone-stabilized phosphonium ylides afford α,β-unsaturated esters, amides, and ketones with high E selectivity, respectively. Spectroscopic analysis of the reaction mixtures and trapping of the intermediates allow plausible mechanisms to be proposed. Initialimine/ylide addition leads to the formation of betaines that cyclize to form 1,2-azaphosphetanes that subsequently eliminate iminophosphoranes to yield alkenes. For the synthesis of electron-deficient 1,2-disubstituted alkenes, the presence of an electron-withdrawing group in the betaine allows rapid interconversion between its two diastereomers through proton transfer. The Z/E selectivity for alkene synthesis is determined by the different rates at which the two betaine diastereomers form the corresponding 1,2-azaphosphetane diastereomers. In contrast, the Z/E selectivity for the synthesis of electron-deficient trisubstituted alkenes originates from the diastereoselective addition of stabilized phosphonium ylides to N-sulfonyl imines.
- Fang, Fan,Li, Yuan,Tian, Shi-Kai
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experimental part
p. 1084 - 1091
(2011/04/15)
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- Long chain dicationic phase transfer catalysts in the condensation reactions of aromatic aldehydes in water under ultrasonic effect
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Long chain dicationic ammonium salts were used successfully as phase transfer catalyst in the condensation reactions of aromatic aldehydes in water under ultrasonic irradiation for the first time. The quaternary salt having longer distance between the cation centers was more effective than the mono- and dicationic ones having short chain.
- Esen, Ilker,Yolacan, Cigdem,Aydogan, Feray
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experimental part
p. 2289 - 2292
(2010/11/05)
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- Chemoselective conjugate reduction of α,β-unsaturated ketones catalyzed by rhodium amido complexes in aqueous media
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Although a notable feature of Noyori's Ru-TsDPEN complex is that the transfer hydrogenation reaction is highly chemoselective for the C-O functional group and tolerant of alkenes, our early report indicated that the chemoselectivity could be switched from C-O to C-C bonds in the transfer hydrogenation of activated α,β-unsaturated ketones. Now we have found that a variety of α,β-unsaturated ketones, even without other electron-withdrawing functional groups, could be reduced on the alkenic double bonds with high selectivities employing amido-rhodium hydride complex in aqueous media, and up to 100% chemoselectivity has been achieved. It is notable that the chemoselectivity was improved significantly on going from organic solvent to water. Moreover, a 1,4-addition mechanism has been proposed on the basis of the corresponding experimental details and computational analysis.
- Li, Xuefeng,Li, Liangchun,Tang, Yuanfu,Zhong, Ling,Cun, Linfeng,Zhu, Jin,Liao, Jian,Deng, Jingen
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supporting information; experimental part
p. 2981 - 2988
(2010/07/05)
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- Gold-catalyzed meyer-schuster rearrangement: Application to the synthesis of prostaglandins
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Synthetic pathway paved with gold: An improved protocol for the Meyer-Schuster rearrangement is presented using novel gold catalysts. This method is used to provide a straightforward synthetic approach to prostaglandins.
- Ramon, Ruben S.,Gaillard, Sylvain,Slawin, Alexandra M. Z.,Porta, Alessio,D'Alfonso, Alessandro,Zanoni, Giuseppe,Nolan, Steven P.
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scheme or table
p. 3665 - 3668
(2010/10/04)
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- [(NHC)AuCl]-catalyzed Meyer-Schuster rearrangement: scope and limitations
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An efficient catalytic system allowing for the synthesis of a variety of α,β-unsaturated ketones has been developed. [(NHC)AuCl] (NHC{double bond, long}N-heterocyclic carbene) in the presence of a silver(I) salt was found to catalyze the Meyer-Schuster rearrangement, leading to α,β-unsaturated ketones from easily accessible propargylic alcohols in high yields. Catalysis was performed in a 2:1 mixture of methanol and water at 60 °C and afforded good yields even for tertiary alcohols and sterically demanding substrates. Thorough evaluation of the present catalytic system uncovered that it was unsuitable for terminal alkynes and primary alcohols. In these cases low yields of the target molecules were obtained due to the formation of unexpected by-products.
- Ramón, Rubén S.,Marion, Nicolas,Nolan, Steven P.
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experimental part
p. 1767 - 1773
(2009/06/18)
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- Stereoseleetive synthesis of polysubstituted alkenes through a phosphine-mediated three-component system of aldehydes, α-halo carbonyl compounds, and terminal alkenes
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A study was conducted to demonstrate stereoselective synthesis of polysubstituted alkenes through a phosphine-mediated three-component system of aldehydes, α-halo carbonyl compounds, and terminal alkenes. Triphenylphosphine, α-halo carbonyl compounds, and methyl acrylate were added to a solution of aldehyde in chloroform or 1-propanol under nitrogen at room temperature. The resulting mixture was stirred at the specified temperature until transformation was completely observed by thin layer chromatography (TLC) analysis. The mixture was cooled to room temperature and purified by column chromatography on silica gel, eluting with petroleum ether/ethyl acetate. The study demonstrated that the first one-pot and three-component reaction of aldehydes, α-haloacetates, and terminal alkenes was developed in the presence of phenylphosphine to produce a wide range of trisubstituted alkenes with significant stereoselectivity.
- Liu, Da-Neng,Tian, Shi-Kai
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supporting information; experimental part
p. 4538 - 4542
(2009/12/25)
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- Sequential hiyaima coupling/narasaka acylation reaction of (e)-1,2-disilylethene: rapid assembly of α,β-unsaturated carbonyl motifs
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The synthesis and application of (E)-1,2-disilylethene 5 as a central functional building block in a sequential Hiyama coupling/Narasaka acylation reaction are described, Its use in the rapid and versatile construction of α,β-unsaturated carbonyl motifs found in a number of polyunsaturated natural products has been demonstrated. It was observed that due to the differential intrinsic reactivity of the two carbon-silicon bonds, this bis-metallated lynchpin-type reagent is activated selectively and sequentially by Pd and Rh catalysis, negating the need for any protecting group, A number of (E)-α,β-unsaturated ketones were efficiently synthesized with complete chemoselectively in the presence of a variety of halides and anhydride acids. Conjugated polyunsaturated ketones and diversely α'-functionalized α,β-enones, such, as chalcones, a heterocyclic dienone and the highly conjugated ethyl (2Z,4E)-6-oxo-6-(2-thienyl)hexa-2,4-dienoate, were obtained in good overall yields. Thus, this coupling sequence provides a high degree of modularity, that is, a single template is likely to produce a large number of synthetic targets.
- Thiot, Carine,Mioskowski, Charles,Wagner, Alain
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experimental part
p. 3219 - 3227
(2009/12/09)
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- Sml2-promoted reformatsky-type coupling reactions in exceptionally hindered contexts
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Highly substituted, very hindered enones were synthesized using a two-step procedure that utilizes a diiodosamarium-promoted Reformatsky-type coupling and dehydration using Martin sulfurane. Both α-chloro- and α-bromoketones were coupled with a variety of carbonyl nucleophiles to form the intermediate β-hydroxyketones, occurring with excellent diastereoselectivity, favoring the syn isomer (R1 = Me). This technique complements other methods and enables the preparation of enones outside of the scope of current olefination methodology.
- Sparling, Brian A.,Moslin, Ryan M.,Jamison, Timothy F.
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supporting information; experimental part
p. 1291 - 1294
(2009/04/08)
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- Acyl palladium species in synthesis: Single-step synthesis of α,β-unsaturated ketones from acid chlorides
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Conditions are reported for the facile, one-pot synthesis of α,β-unsaturated ketones via the palladium-catalysed cross-coupling of acyl chlorides with hydrozirconated acetylenes, and its use in the 2-step synthesis of d-5-O-benzyl deoxyxylulose. The Royal Society of Chemistry.
- Cox, Russell J.,Evitt, Andrew S.
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p. 229 - 232
(2008/03/14)
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- Cationic rhodium(I)/bisphosphane complex-catalyzed isomerization of secondary propargylic alcohols to α,β-enones
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We have determined that hydrogenated cationic Rh(I)/bisphosphane complexes are highly active catalysts for the isomerization of secondary propargylic alcohols to α,β-enones. A kinetic resolution of secondary propargylic alcohols proceeded with moderate selectivity with [Rh((R)-BINA-P)]OTf as a catalyst. Mechanistic studies revealed that the isomerization proceeds through intramolecular 1,3- and 1,2-hydrogen migration pathways. The isomerization of propargylic diol derivatives was also investigated, which revealed that 1,4-diketones, furans, and α,β-enones were obtained from 2-butyn-1,4-diol, 1-methoxy-2-butyn-4-ol, and 1-acetoxy-2-butyn-4-ol derivatives, respectively. Furthermore, chemoselectivity of the isomerization of an acetylenic diol was investigated, and preferential oxidation of a propargylic hydroxy group was observed. Wiley-VCH Verlag GmbH & Co. KGaA, 2007.
- Tanaka, Ken,Shoji, Takeaki,Hirano, Masao
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p. 2687 - 2699
(2008/02/08)
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- Asymmetric transfer hydrogenation of α,β-unsaturated, α-tosyloxy and α-substituted ketones
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Asymmetric transfer hydrogenation of cyclic and acyclic α,β-unsaturated ketones catalysed by η6-p-cymene/ ruthenium(II) and η5-pentamethylcyclopentadienyl/rhodium(III) complexes have been investigated. Cyclic α,β-unsaturated ketones appeared to be more suitable substrates for the synthesis of enantiomerically pure allylic alcohols than do acyclic α,β-unsaturated ketones. A proposed mechanism for the formation of 4-phenyl-[1,3]-dioxolan-2-one from α-tosyloxy- and halo-substituted acetophenones is discussed. The results of further investigations into the reduction of a range of α- tosyloxyacetophenones and the dynamic kinetic resolution of α-substituted ketones is presented.
- Peach, Philip,Cross, David J.,Kenny, Jennifer A.,Mann, Inderjit,Houson, Ian,Campbell, Lynne,Walsgrove, Tim,Wills, Martin
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p. 1864 - 1876
(2007/10/03)
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- Cationic rhodium(I)/BINAP complex-catalyzed isomerization of secondary propargylic alcohols to α,β-enones
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(Chemical Equation Presented) We have developed a cationic rhodium(I)/BINAP complex-catalyzed isomerization of secondary propargylic alcohols to α,β-enones. The asymmetric variant of this reaction, a kinetic resolution of secondary propargylic alcohols, was also developed with good selectivity. The mechanistic study revealed that the isomerization proceeds through intramolecular 1,3- and 1,2-hydrogen migration pathways.
- Tanaka, Ken,Shoji, Takeaki
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p. 3561 - 3563
(2007/10/03)
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- Kinetic resolution of acyclic secondary allylic silyl ethers catalyzed by chiral ketones
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Kinetic resolution of acyclic secondary allylic silyl ethers by chiral dioxiranes generated in situ from chiral ketones (R)-1 and (R)-2 and Oxone was investigated. An efficient and catalytic method has been developed for kinetic resolution of those substrates with a CCl3, tert-butyl, or CF3 group at the α-position. In particular, high selectivities (S up to 100) were observed for kinetic resolutions of racemic α-trichloromethyl allylic silyl ethers 7 and 9-15 catalyzed by ketones (R)-2. Both the recovered substrates and the resulting epoxides were obtained in high enantiomeric excess. On the basis of steric and electrostatic interactions between the chiral dioxiranes and the racemic substrates, a model was proposed to rationalize the enantioselectivities and diastereoselectivities in the chiral ketone-catalyzed kinetic resolution process.
- Yang,Jiao,Yip,Lai,Wong
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p. 4619 - 4624
(2007/10/03)
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- An efficient procedure for the diastereoselective dehydration of β-hydroxy carbonyl compounds by CeCl3·7H2O/Nal system
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(Formula presented) The dehydration of β-hydroxy ketones and β-hydroxy esters is a synthetically useful method for the conversion of these compounds to the corresponding α,β-unsaturated derivatives. Cerium(III) chloride heptahydrate in combination with sodium iodide in refluxing acetonitrile acts as an efficient reagent for this conversion. The present procedure, which utilizes cheap and "friendly" reagents, offers the corresponding (E)-enones in good yields as the only isolable products.
- Bartoli, Giuseppe,Bellucci, Maria C.,Petrini, Marino,Marcantoni, Enrico,Sambri, Letizia,Torregiani, Elisabetta
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p. 1791 - 1793
(2007/10/03)
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