- Light-Driven Carbene Catalysis for the Synthesis of Aliphatic and α-Amino Ketones
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Single-electron N-heterocyclic carbene (NHC) catalysis has gained attention recently for the synthesis of C?C bonds. Guided by density functional theory and mechanistic analyses, we report the light-driven synthesis of aliphatic and α-amino ketones using single-electron NHC operators. Computational and experimental results reveal that the reactivity of the key radical intermediate is substrate-dependent and can be modulated through steric and electronic parameters of the NHC. Catalyst potential is harnessed in the visible-light driven generation of an acyl azolium radical species that undergoes selective coupling with various radical partners to afford diverse ketone products. This methodology is showcased in the direct late-stage functionalization of amino acids and pharmaceutical compounds, highlighting the utility of single-electron NHC operators.
- Bay, Anna V.,Cheong, Paul Ha-Yeon,Farah, Abdikani Omar,Fitzpatrick, Keegan P.,González-Montiel, Gisela A.,Scheidt, Karl A.
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supporting information
p. 17925 - 17931
(2021/07/17)
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- Nickel-Mediated Photoreductive Cross Coupling of Carboxylic Acid Derivatives for Ketone Synthesis**
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A simple visible light photochemical, nickel-catalyzed synthesis of ketones from carboxylic acid-derived precursors is presented. Hantzsch ester (HE) functions as a cheap, green and strong photoreductant to facilitate radical generation and also engages in the Ni-catalytic cycle to restore the reactive species. With this dual role, HE allows for the coupling of a large variety of radicals (1°,2°, benzylic, α-oxy & α-amino) with aroyl and alkanoyl moieties, a new feature in reactions of this type. With both precursors deriving from abundant carboxylic acids, this protocol is a welcome addition to the organic chemistry toolbox. The reaction proceeds under mild conditions without the need for toxic metal reagents or bases and shows a wide scope, including pharmaceuticals and complex molecular architectures.
- Brauer, Jan,Quraishi, Elisabeth,Kammer, Lisa Marie,Opatz, Till
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supporting information
p. 18168 - 18174
(2021/11/30)
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- Rapid and Direct Photocatalytic C(sp3)?H Acylation and Arylation in Flow
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Herein, we report a photocatalytic procedure that enables the acylation/arylation of unfunctionalized alkyl derivatives in flow. The method exploits the ability of the decatungstate anion to act as a hydrogen atom abstractor and produce nucleophilic carbon-centered radicals that are intercepted by a nickel catalyst to ultimately forge C(sp3)?C(sp2) bonds. Owing to the intensified conditions in flow, the reaction time can be reduced from 12–48 hours to only 5–15 minutes. Finally, kinetic measurements highlight how the intensified conditions do not change the reaction mechanism but reliably speed up the overall process.
- Bovy, Lo?c,Broersma, Rémy,Mazzarella, Daniele,No?l, Timothy,Pulcinella, Antonio
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supporting information
p. 21277 - 21282
(2021/08/23)
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- Visible-Light Decatungstate/Disulfide Dual Catalysis for the Hydro-Functionalization of Styrenes
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We describe an efficient photoredox system, relying on decatungstate/disulfide catalysts, for the hydrofunctionalization of styrenes. In this methodology the use of disulfide as a cocatalyst was shown to be crucial for the reaction efficiency. This photoredox system was employed for the hydro-carbamoylation, -acylation, -alkylation, and -silylation of styrenes, giving access to a large variety of useful building blocks and high-value molecules such as amides and unsymmetrical ketones from simple starting materials.
- Prieto, Alexis,Taillefer, Marc
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supporting information
p. 1484 - 1488
(2021/03/08)
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- Hydrogen borrowing catalysis using 1° and 2° alcohols: Investigation and scope leading to α and β branched products
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The alkylation of a variety of ketones using 1° or 2° alcohols under hydrogen borrowing catalysis is described. Initial research focused on the α-alkylation of cyclopropyl ketones with higher 1° alcohols (i.e. larger than MeOH), leading to the formation of α-branched products. Our search for additional substrates with which to explore this chemistry led us to discover that di-ortho-substituted aryl ketones were also privileged scaffolds, with Ph? (C6Me5) ketones being the optimal choice. Further investigations revealed that this motif was crucial for alkylation with 2° alcohols forming β-branched products, which also provided an opportunity to study diastereoselective and intramolecular hydrogen borrowing processes.
- Frost, James R.,Cheong, Choon Boon,Akhtar, Wasim M.,Caputo, Dimitri F.J.,Christensen, Kirsten E.,Stevenson, Neil G.,Donohoe, Timothy J.
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supporting information
(2021/04/07)
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- Synergistic Activation of Amides and Hydrocarbons for Direct C(sp3)–H Acylation Enabled by Metallaphotoredox Catalysis
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The utilizations of omnipresent, thermodynamically stable amides and aliphatic C(sp3)?H bonds for various functionalizations are ongoing challenges in catalysis. In particular, the direct coupling between the two functional groups has not been realized. Here, we report the synergistic activation of the two challenging bonds, the amide C?N and unactivated aliphatic C(sp3)?H, via metallaphotoredox catalysis to directly acylate aliphatic C?H bonds utilizing amides as stable and readily accessible acyl surrogates. N-acylsuccinimides served as efficient acyl reagents for the streamlined synthesis of synthetically useful ketones from simple C(sp3)?H substrates. Detailed mechanistic investigations using both computational and experimental mechanistic studies were performed to construct a detailed and complete catalytic cycle. The origin of the superior reactivity of the N-acylsuccinimides over other more reactive acyl sources such as acyl chlorides was found to be an uncommon reaction pathway which commences with C?H activation prior to oxidative addition of the acyl substrate.
- Baik, Mu-Hyun,Choi, Seulhui,Hong, Soon Hyeok,Lee, Geun Seok,Won, Joonghee
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supporting information
p. 16933 - 16942
(2020/08/03)
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- Visible-Light-Promoted Photocatalyst-Free Hydroacylation and Diacylation of Alkenes Tuned by NiCl2·DME
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Herein, we describe a visible light-promoted hydroacylation strategy that facilitates the preparation of ketones from alkenes and 4-acyl-1,4-dihydropyridines via an acyl radical addition and hydrogen atom transfer pathway under photocatalyst-free conditions. The efficiency was highlighted by wide substrate scope, good to high yields, successful scale-up experiments, and expedient preparation of highly functionalized ketone derivatives. In addition, this protocol allows for the synthesis of 1,4-dicarbonyl compounds through alkene diacylation in the presence of NiCl2·DME.
- Zhao, Xinxin,Li, Bing,Xia, Wujiong
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supporting information
p. 1056 - 1061
(2020/02/15)
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- Electrochemical 1,4-reduction of α,β-unsaturated ketones with methanol and ammonium chloride as hydrogen sources
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A sustainable, chemoselective 1,4-reduction of α,β-unsaturated ketones by means of an electrochemical method is presented, wherein the extremely inexpensive ammonium chloride (NH4Cl) is applied as the only additive. The reaction proceeds smoothly in the air at ambient temperature. Mechanistic studies reveal that both NH4Cl and solvent methanol work as hydrogen donors.
- Huang, Binbin,Li, Yanan,Yang, Chao,Xia, Wujiong
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supporting information
p. 6731 - 6734
(2019/06/17)
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- In Water and under Mild Conditions: α-Alkylation of Ketones with Alcohols by Phase-Transfer-Assisted Borrowing Hydrogen Catalysis
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Borrowing hydrogen is a powerful and green technique that allows readily available alcohols to be used as alkylating agents and produces water as the only by-product. Nevertheless, harsh conditions such as high temperatures and organic solvents are usually required. Herein, we present a strategy to perform the α-alkylation of ketones in aqueous media at mild temperatures by combining borrowing hydrogen with phase-transfer catalysis. A broad scope of methyl ketones was functionalized with alkyl and benzyl alcohols in moderate to good yields at 40 °C. The protocol was also highly effective at large scale and room temperature.
- Rakers, Lena,Sch?fers, Felix,Glorius, Frank
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supporting information
p. 15529 - 15532
(2018/10/09)
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- Radical-Based C?C Bond-Forming Processes Enabled by the Photoexcitation of 4-Alkyl-1,4-dihydropyridines
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We report herein that 4-alkyl-1,4-dihydropyridines (alkyl-DHPs) can directly reach an electronically excited state upon light absorption and trigger the generation of C(sp3)-centered radicals without the need for an external photocatalyst. Selective excitation with a violet-light-emitting diode turns alkyl-DHPs into strong reducing agents that can activate reagents through single-electron transfer manifolds while undergoing homolytic cleavage to generate radicals. We used this photochemical dual-reactivity profile to trigger radical-based carbon–carbon bond-forming processes, including nickel-catalyzed cross-coupling reactions.
- Buzzetti, Luca,Prieto, Alexis,Roy, Sudipta Raha,Melchiorre, Paolo
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supporting information
p. 15039 - 15043
(2017/11/20)
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- Synergistic Visible-Light Photoredox/Nickel-Catalyzed Synthesis of Aliphatic Ketones via N-C Cleavage of Imides
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An electrophilic, imide-based, visible-light-promoted photoredox/Ni-catalyzed cross-coupling reaction for the synthesis of aliphatic ketones has been developed. This protocol proceeds through N-C(O) bond activation, made possible through the lower activation energy for metal insertion into this bond due to delocalization of the lone pair of electrons on the nitrogen by electron-withdrawing groups. The operationally simple and mild cross-coupling reaction is performed at ambient temperature and exhibits tolerance for a variety of functional groups.
- Amani, Javad,Alam, Rauful,Badir, Shorouk,Molander, Gary A.
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p. 2426 - 2429
(2017/05/12)
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- Synergistic Photoredox/Nickel Coupling of Acyl Chlorides with Secondary Alkyltrifluoroborates: Dialkyl Ketone Synthesis
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Visible light photoredox/nickel dual catalysis has been employed in the cross-coupling of acyl chlorides with potassium alkyltrifluoroborates. This protocol, based on single-electron-mediated alkyl transfer, circumvents the restriction of using reactive alkylmetallic nucleophiles in transition-metal-catalyzed acylation and achieves a mild and efficient method for the synthesis of unsymmetrical alkyl ketones. In this approach, a variety of acyl chlorides have been successfully coupled with structurally diverse potassium alkyltrifluoroborates, generating the corresponding ketones with good yields.
- Amani, Javad,Molander, Gary A.
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p. 1856 - 1863
(2017/02/10)
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- Direct Conversion of Carboxylic Acids to Alkyl Ketones
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An efficient and mild method for acyl-Csp3 bond formation based on the direct conversion of carboxylic acids has been established. This protocol is enabled by the synergistic, Ir-photoredox/nickel catalytic cross-coupling of in situ activated c
- Amani, Javad,Molander, Gary A.
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p. 3612 - 3615
(2017/07/15)
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- Efficient alkylation of ketones with primary alcohols catalyzed by ruthenium(II)/P,N ligand complexes
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An efficient catalytic system containing [RuCl2(η6-p-cymene)]2 and one P,N ligand, N-diphenylphosphino-2-aminopyridine (L1) was loaded in catalyzing the alkylation of ketones with primary alcohols for a diverse array of substrates. Other five P,N ligands based on pyridin-2-amine and pyrimidin-2-amine were also examined in this reaction to explore the influence of steric hindrance and electronic effects. Monitoring by 1H NMR and ESI-MS reveals a stable cationic L1-coordinated ruthenium hydride intermediate, identified as [Ru(η6-p-cymene)(κ2-L1)H]+. Organic intermediates consistent with a three-step dehydrogenation, alkylation and hydrogenation pathway were also observed. The final step in this reaction, the ruthenium-catalysed transfer hydrogenation reduction of α,β-unsaturated ketone with benzyl alcohol was performed separately.
- Liu, Shi-Yuan,Xu, Lin-Yan,Liu, Chun-Yu,Ren, Zhi-Gang,Young, David James,Lang, Jian-Ping
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p. 2374 - 2381
(2017/04/03)
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- Iridium(I) N-Heterocyclic Carbene (NHC)/Phosphine Catalysts for Mild and Chemoselective Hydrogenation Processes
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The directed chemoselective hydrogenation of olefins has been established by using iridium(I) catalysts, which feature a tuned NHC/phosphine ligand combination. This selective reduction process has been demonstrated in a wide array of solvents, including more environmentally acceptable media, also allowing further refinement of hydrogenation selectivity. The directed, chemoselective hydrogenation of olefins has been established by using iridium(I) catalysts, which feature a tuned NHC/phosphine ligand combination. This selective reduction process has been demonstrated in a wide array of solvents, including more environmentally acceptable media, also allowing further refinement of hydrogenation selectivity.
- Kerr, William J.,Mudd, Richard J.,Brown, Jack A.
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p. 4738 - 4742
(2016/04/05)
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- Transition-Metal-Free Self-Hydrogen-Transferring Allylic Isomerization
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Phenanthroline and tert-butoxide have been established as powerful radical initiators in reactions such as the SRN1-type coupling reactions due to the cooperation of large heteroarenes and a special feature of tert-butoxide. The first phenanthroline-tert-butoxide-catalyzed transition-metal-free allylic isomerization is described. The resulting ketones are key intermediates for indenes. The control experiments rule out the base-promoted allylic anion pathway. The radical pathway is supported by experimental evidence that includes kinetic study, kinetic isotope effect, isotope-labeling experiments, trapping experiments, and EPR experiments.
- Zheng, Hong-Xing,Xiao, Zu-Feng,Yao, Chuan-Zhi,Li, Qiang-Qiang,Ning, Xiao-Shan,Kang, Yan-Biao,Tang, Yong
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supporting information
p. 6102 - 6105
(2016/01/09)
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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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p. 14604 - 14607
(2015/03/04)
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- C-X (X=Br, I) bond-tolerant aerobic oxidative cross-coupling: A strategy to selectively construct β-aryl ketones and aldehydes
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Using moelcular oxygen as the terminal oxidant, various aryl halide-containing β-aryl ketones and aldehydes can be synthesized directly from readily available allyic alcohols and boronic acids via palladium-catalyzed oxidative cross-coupling reactions. The dual roles of copper, including electron-carrier and Lewis acid functions, are supposed to be critical for the high reactivity and selectivity of this aerobic oxidative coupling transformation. Copyright
- Chen, Mao,Wang, Jie,Chai, Ziyi,You, Cai,Lei, Aiwen
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supporting information; experimental part
p. 341 - 346
(2012/05/04)
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- Cross-coupling reaction of alcohols for carbon-carbon bond formation using pincer-type NHC/palladium catalysts
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A cross-coupling reaction of different alcohols was achieved using a pincer-type NHC/PdBr complex as the catalyst precursor, and the reaction, under either Ar or H2 gas, displayed a broad substrate scope with respect to both primary and secondary alcohol components, with high alcohol product selectivity. The Royal Society of Chemistry 2010.
- Kose, Osamu,Saito, Susumu
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supporting information; experimental part
p. 896 - 900
(2010/06/20)
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- Titanocene-catalyzed conjugate reduction of αβ-unsaturated carbonyl derivatives
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"Chemical Equation Presented" A titanocene-catalyzed conjugate reduction of αβ-unsaturated carbonyl derivatives has been developed. A series of carbonyl compounds including aldehydes, ketones, esters, and amides proved viable in the reduction process providing an efficient, chemoselective method for the catalytic reduction of unsaturated carbonyl derivatives.
- Ashfeld, Brandon L.,Kosal, Andrew D.
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scheme or table
p. 44 - 47
(2010/03/03)
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- Empirical method for predicting enantioselectivity in catalytic reactions: demonstration with lipase and oxazaborolidine
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We derived a novel equation capable of predicting the degree of enantioselectivity in a catalytic reaction without any knowledge of the reaction mechanism and/or the transition-state structure, and tested the validity of this equation by changing substrates systematically in the lipase or oxazaborolidine-catalyzed reactions. A good correlation was observed between the predicted and observed E values, and the stereochemistry of the products could be predicted correctly in most cases (28 out of 30).
- Ema, Tadashi,Ura, Norichika,Yoshii, Masataka,Korenaga, Toshinobu,Sakai, Takashi
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experimental part
p. 9583 - 9591
(2010/01/06)
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- Development of a convoluted polymeric nanopalladium catalyst: α-alkylation of ketones and ring-opening alkylation of cyclic 1,3-diketones with primary alcohols
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A novel solid-phase catalyst of palladium nanoparticles, nano-Pd-V, was prepared from PdCl2 with main-chain viologen polymers via complexation and reduction. This insoluble nanocatalyst nano-Pd-V efficiently promoted α-alkylation of ketones with primary alcohols in the presence of Ba(OH)2·H2O under atmospheric conditions without organic solvents. The nano-Pd-V catalyst was reused without loss of catalytic activity. Ring-opening alkylation of cyclic 1,3-diketones with primary alcohols was also catalyzed by the nano-Pd-V catalyst.
- Yamada, Yoichi M.A.,Uozumi, Yasuhiro
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p. 8492 - 8498
(2008/02/09)
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- A solid-phase self-organized catalyst of nanopalladium with main-chain viologen polymers: α-alkylation of ketones with primary alcohols
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A novel solid-phase self-organized catalyst of palladium nanoparticles was prepared from PdCl2 with main-chain viologen polymers via complexation and reduction. This insoluble nanocatalyst nano-Pd-V efficiently promoted α-alkylation of ketones with primary alcohols in the presence of Ba(OH)2·H2O under atmospheric conditions without organic solvents. The nano-Pd-V catalyst was reused without loss of catalytic activity.
- Yamada, Yoichi M. A.,Uozumi, Yasuhiro
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p. 1375 - 1378
(2007/10/03)
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- Ruthenium-catalyzed isomerization of alkenol into alkanone in water under irradiation of microwaves
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Ruthenium catalyzed isomerization of alkenol into alkanone through a migration of C-C double bond was performed in water under irradiation of microwaves. When the reaction was performed in deuterium oxide instead of water, the trail of the migration was shown by H-D exchange reaction. Copyright
- Ishibashi, Kenichi,Takahashi, Masaaki,Yokota, Yutaka,Oshima, Koichiro,Matsubara, Seijiro
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p. 664 - 665
(2007/10/03)
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- Novel Routes to Enol Ethers, Unsymmetrical Ketones, α-Bromoalkyl Ketones, 1,4-Diketones, 2-Ethoxy-2-cyclopenetenones, and α-Keto Enamines
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Highly regioselectve SN2' reactions of adducts 6 (readily prepared by reactions of halides with the allyl anion 12 of 11) with Grignard reagents gave enol ethers 13, which were converted (in one-pot reactions from 11) into ketones 14 and α-bromoalkyl ketones 15 in good yields.The monoprotected 1,4-diketone derivative 16 (prepared by Michael addition of the allyl anion 12 with methyl vinyl ketone) was converted both into 1,4-diketones 18 and into protected γ-hydroxyalkyl ketone 20 by propenoyl, or to both functionalities.The allyl anion 12 with α-substituted acetic esters gave α-acylated adducts 24, which underwent in situ unfavored endo-trig cyclization upon treatment with NaH and secondary amines, to give 2-ethoxy-2-cyclopenetenones 27 and 28 and α-keto enamines 25 in good yield.The mechanism for the cyclization is discussed.
- Katritzky, Alan R.,Zhang, Guifen,Jiang, Jinlong
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p. 7605 - 7611
(2007/10/03)
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- Acyl Radicals: Intermolecular and Intramolecular Alkene Addition Reactions
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A full study of the use of phenyl selenoesters as precursors to acyl radicals and their subsequent participation in intermolecular and intramolecular alkene addition reactions is detailed.Primary alkyl-, vinyl-, and arylsubstituted acyl radicals generated by Bu3SnH treatment of the corresponding phenyl selenoesters participate cleanly in intermolecular addition reactions with alkenes bearing electron-withdrawing or radical-stabilizing substituents at rates that exceed those of the potentially competitive decarbonylation or reduction.Similarly, their intramolecular addition to activated or unactivated alkenes proceeds without significant competitive reduction or decarbonylation and at rates generally >/= 1 x 106 s-1 with some occuring at rates >/= 3 x 107 s-1.Consistent with their behavior in intermolecular addition reactions, the 5-exo-trig cyclizations of secondary and tertiary alkyl-substituted acyl radicals to an unactivated olefin acceptor may be accompanied by varying degrees of decarbonylation, even under low-temperature free-radical conditions.Studies are presented which suggest that the intramolecular additions of acyl radicals to alkenes under the conditions detailed herein may be regarded as irreversible, kinetically controlled processes which exhibit regioselectivity that is predictable based on well-established empirical rules set forth for the analogous free-radical cyclization reactions of alkyl radicals.
- Boger, Dale L.,Mathvink, Robert J.
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p. 1429 - 1443
(2007/10/02)
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- Double Alkylation of Carbon Monoxide via Free Radicals: Synthesis of Unsymmetrical Ketones
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A novel method for the synthesis of unsymmetrical ketones via the free radical carbonylation of alkyl halides is described.The mechanism of the reaction involves the trapping of an alkyl free radical by CO, the addition of the acyl free radical so formed to an alkene, and termination of the reaction by the abstraction of a hydrogen atom from tributyltin hydride by the product acyl-substituted free radical.
- Ryu, Ilhyong,Kusano, Kazuya,Yamazaki, Hiroshi,Sonoda, Noboru
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p. 5003 - 5005
(2007/10/02)
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- Phenyl Selenoesters as Effective Precursors of Acyl Radicals for Use in Intermolecular Alkene Addition Reactions
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The scope of the use of phenyl selenoesters as effective precursors to acyl radicals for use in intermolecular olefin addition reactions is detailed.
- Boger, Dale L.,Mathvink, Robert J.
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p. 1777 - 1779
(2007/10/02)
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- HIGHLY CHEMOSELECTIVE SYNTHESIS OF KETONES FROM CARBOXYLIC ACIDS AND GRIGNARD REAGENTS USING α-CHLOROENAMINES AS A CONDENSATION REAGENT
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α-Chloroenamines are found to be an effective condensation reagent of carboxylic acids and Grignard reagents under mild conditions to afford chemoselectively the corresponding ketones in high yields and in one-pot operation.
- Fujisawa, Tamotsu,Mori, Toshiki,Higuchi, Kazunobu,Sato, Toshio
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p. 1791 - 1794
(2007/10/02)
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- ONE-POT SYNTHESIS OF KETONES FROM CARBOXYLIC ACIDS AND GRIGNARD REAGENTS USING N,N-DIPHENYL-p-METHOXYPHENYLCHLOROMETHYLENIMINIUM CHLORIDE
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N,N-Diphenyl-p-methoxyphenylchloromethyleniminium chloride is found to be an effective condensation reagent of carboxylic acids and Grignard reagents under mild conditions to afford the corresponding ketones in high yields.
- Fujisawa, Tamotsu,Mori, Toshiki,Sato, Toshio
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p. 5059 - 5062
(2007/10/02)
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