- Site-Selective Pd-Catalyzed C(sp3)?H Arylation of Heteroaromatic Ketones
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A ligand-controlled site-selective C(sp3)?H arylation of heteroaromatic ketones has been developed using Pd catalysis. The reaction occurred selectively at the α- or β-position of the ketone side-chain. The switch from α- to β-arylation was realized by addition of a pyridone ligand. The α-arylation process showed broad scope and high site- and chemoselectivity, whereas the β-arylation was more limited. Mechanistic investigations suggested that α-arylation occurs through C?H activation/oxidative addition/reductive elimination whereas β-arylation involves desaturation and aryl insertion.
- Kudashev, Anton,Baudoin, Olivier
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supporting information
p. 17688 - 17694
(2021/11/16)
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- Light-Driven Enantioselective Synthesis of Pyrroline Derivatives by a Radical/Polar Cascade Reaction
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Herein, a light-driven, atom-economical process that provides access to enantiomerically enriched substituted chiral 1-pyrroline derivatives is introduced. The strategy involves the distal functionalization of acyl heterocycles through a hydrogen-atom transfer (HAT) process and the use of tailor-made ketimines as reliable electrophilic partners. This transformation is translated into an enantiomerically controlled radical/polar cascade reaction in which water is produced as the sole by-product and stereoselectivity is dictated by coordination to a chiral-at-rhodium catalyst.
- Rodríguez, Ricardo I.,Mollari, Leonardo,Alemán, José
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p. 4555 - 4560
(2021/01/18)
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- Selective Acylation of Aryl- A nd Heteroarylmagnesium Reagents with Esters in Continuous Flow
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A selective acylation of readily accessible organomagnesium reagents with commercially available esters proceeds at convenient temperatures and short residence times in continuous flow. Flow conditions allow us to prevent premature collapse of the hemiacetal intermediates despite noncryogenic conditions, thus furnishing ketones in good yields. Throughout, the coordinating ability of the ester and/or Grignard was crucial for the reaction outcome. This was leveraged by the obtention of several bisaryl ketones using 2-hydroxy ester derivatives as substrates.
- Heinz, Benjamin,Djukanovic, Dimitrije,Ganiek, Maximilian A.,Martin, Benjamin,Schenkel, Berthold,Knochel, Paul
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supporting information
p. 493 - 496
(2020/01/31)
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- Photoenzymatic Hydrogenation of Heteroaromatic Olefins Using ‘Ene’-Reductases with Photoredox Catalysts
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Flavin-dependent ‘ene’-reductases (EREDs) are highly selective catalysts for the asymmetric reduction of activated alkenes. This function is, however, limited to enones, enoates, and nitroalkenes using the native hydride transfer mechanism. Here we demonstrate that EREDs can reduce vinyl pyridines when irradiated with visible light in the presence of a photoredox catalyst. Experimental evidence suggests the reaction proceeds via a radical mechanism where the vinyl pyridine is reduced to the corresponding neutral benzylic radical in solution. DFT calculations reveal this radical to be “dynamically stable”, suggesting it is sufficiently long-lived to diffuse into the enzyme active site for stereoselective hydrogen atom transfer. This reduction mechanism is distinct from the native one, highlighting the opportunity to expand the synthetic capabilities of existing enzyme platforms by exploiting new mechanistic models.
- Biegasiewicz, Kyle F.,Black, Michael J.,Chung, Megan M.,Hyster, Todd K.,Meichan, Andrew J.,Nakano, Yuji,Sandoval, Braddock A.,Zhu, Tianyu
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p. 10484 - 10488
(2020/04/29)
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- Site-selective c-h acylation of pyridinium derivatives by photoredox catalysis
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A strategy for visible-light-induced site-selective C-H acylation of pyridinium salts was developed by employing N-methoxy-or N-aminopyridinium salts, offering a powerful synthetic tool for accessing highly valuable C2- A nd C4-acylated pyridines. The met
- Jung, Sungwoo,Lee, Hyeonyeong,Moon, Yonghoon,Jung, Hoi-Yun,Hong, Sungwoo
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p. 9891 - 9896
(2019/10/14)
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- Manganese-Catalyzed α-Alkylation of Ketones, Esters, and Amides Using Alcohols
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Herein we report the manganese-catalyzed C-C bond-forming reactions via α-alkylation of ketones, amides, and esters, using primary alcohols. β-Alkylation of secondary alcohols by primary alcohols to obtain α-alkylated ketones is also reported. The reactions are catalyzed by a (iPr-PNP)Mn(H)(CO)2 pincer complex under mild conditions in the presence of (catalytic) base liberating water (and H2 in the case of secondary alcohol alkylation) as the sole byproduct.
- Chakraborty, Subrata,Daw, Prosenjit,Ben David, Yehoshoa,Milstein, David
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p. 10300 - 10305
(2018/10/20)
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- Direct oxidation of the Csp3–H bonds of N-heterocyclic compounds to give the corresponding ketones using a reusable heterogeneous MnOx-N@C catalyst
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Novel reusable MnOx-N@C catalyst has been developed for the direct oxidation of N-heterocycles under solvent-free conditions using TBHP as benign oxidant to give the corresponding N-heterocyclic ketones. The catalytic system exhibited a broad substrate scope and excellent regioselectivity, as well as being amenable to gram-scale synthesis. This MnOx-N@C catalyst also showed good reusability and was successfully recycled six times without any significant loss of activity.
- Ren, Lanhui,Wang, Lianyue,Lü, Ying,Li, Guosong,Gao, Shuang
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p. 1216 - 1221
(2016/09/07)
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- A Nitrogen-Assisted One-Pot Heteroaryl Ketone Synthesis from Carboxylic Acids and Heteroaryl Halides
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A practical and highly effective one-pot synthesis of versatile heteroaryl ketones directly from carboxylic acids and heteroaryl halides under mild conditions is reported. This method does not require derivatization of carboxylic acids (preparation of acid chlorides, Weinreb amides, etc.) or the use of any additives/catalysts. A wide substrate scope of carboxylic acids with high functional group tolerance has also been demonstrated. The results reveal that the presence of an α-nitrogen on the halide substrate greatly improves the desired ketone formation.
- Demkiw, Krystyna,Araki, Hirofumi,Elliott, Eric L.,Franklin, Christopher L.,Fukuzumi, Yoonjoo,Hicks, Frederick,Hosoi, Kazushi,Hukui, Tadashi,Ishimaru, Yoichiro,O'Brien, Erin,Omori, Yoshimasa,Mineno, Masahiro,Mizufune, Hideya,Sawada, Naotaka,Sawai, Yasuhiro,Zhu, Lei
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p. 3447 - 3456
(2016/05/19)
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- N-heterocyclic carbene-catalyzed α-alkylation of ketones with primary alcohols
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Several N-heterocyclic carbene precursors are synthesized and used in the α-alkylations of ketones with primary alcohols. With the assistance of a base, these N-heterocyclic carbenes can catalyze the reaction smoothly to furnish dialkylated ketones in good-to-excellent yields.
- Zhu, Yanfang,Cai, Chun,Lu, Guoping
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p. 1666 - 1671
(2015/01/09)
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- Cyclodehydrations leading to indene products having n-heterocyclic substituents
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In this Note, we describe superacid-promoted cyclodehydrations leading to functionalized indenes. The product indenes are synthesized having N-heterocyclic substituents, including pyridyl, imidazolyl, pyrimdyl, and other groups. A mechanism is proposed in
- Boblak, Kenneth N.,Klumpp, Douglas A.
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p. 5852 - 5857
(2014/07/08)
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- Tuning reactivity of diphenylpropynone derivatives with metal-associated amyloid-β species via structural modifications
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A diphenylpropynone derivative, DPP2, has been recently demonstrated to target metal-associated amyloid-β (metal-Aβ) species implicated in Alzheimer's disease (AD). DPP2 was shown to interact with metal-Aβ species and subsequently control Aβ aggregation (reactivity) in vitro; however, its cytotoxicity has limited further biological applications. In order to improve reactivity toward Aβ species and lower cytotoxicity, along with gaining an understanding of a structure-reactivity-cytotoxicity relationship, we designed, prepared, and characterized a series of small molecules (C1/C2, P1/P2, and PA1/PA2) as structurally modified DPP2 analogues. A similar metal binding site to that of DPP2 was contained in these compounds while their structures were varied to afford different interactions and reactivities with metal ions, Aβ species, and metal-Aβ species. Distinct reactivities of our chemical family toward in vitro Aβ aggregation in the absence and presence of metal ions were observed. Among our chemical series, the compound (C2) with a relatively rigid backbone and a dimethylamino group was observed to noticeably regulate both metal-free and metal-mediated Aβ aggregation to different extents. Using our compounds, cell viability was significantly improved, compared to that with DPP2. Lastly, modifications on the DPP framework maintained the structural properties for potential blood-brain barrier (BBB) permeability. Overall, our studies demonstrated that structural variations adjacent to the metal binding site of DPP2 could govern different metal binding properties, interactions with Aβ and metal-Aβ species, reactivity toward metal-free and metal-induced Aβ aggregation, and cytotoxicity of the compounds, establishing a structure-reactivity-cytotoxicity relationship. This information could help gain insight into structural optimization for developing nontoxic chemical reagents toward targeting metal-Aβ species and modulating their reactivity in biological systems.
- Liu, Yuzhong,Kochi, Akiko,Pithadia, Amit S.,Lee, Sanghyun,Nam, Younwoo,Beck, Michael W.,He, Xiaoming,Lee, Dongkuk,Lim, Mi Hee
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p. 8121 - 8130
(2013/08/23)
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- Aerobic oxidation of secondary benzylic alcohols and direct oxidative amidation of aryl aldehydes promoted by sodium hydride
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We reported herein new reactivities and possible mechanistic implications of a simplest oxidant (NaH/air) uncovered on a broad range of useful transformations, including aerobic alcohol oxidations, allylic alcohol isomerizations and oxidations, cyclopropyl alcohol fragmentations, and direct aryl aldehyde oxidative amidations. These readily implementable transition-metal-free processes feature exceptional material accessibility, operational simplicity, and environmental compatibility, and add new dimensions to its synthetic utilities that are fairly robust yet had not previously been fully realized and systematically explored.
- Wang, Xinbo,Wang, David Zhigang
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supporting information; experimental part
p. 3406 - 3411
(2011/06/17)
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- Pd-catalyzed cross-coupling reactions of pyridine carboxylic acid chlorides with alkylzinc reagents
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The efficient cross-coupling reaction to afford ketones from pyridine carboxylic acid chlorides and alkylzinc reagents in the presence of Pd(phen)Cl2 is reported. In the case of chloronicotinoyl chlorides, none of Negishi cross-coupling product
- Iwai, Toshiyuki,Nakai, Takeo,Mihara, Masatoshi,Ito, Takatoshi,Mizuno, Takumi,Ohno, Toshinobu
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scheme or table
p. 1091 - 1094
(2009/09/25)
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- The epoxy-Ramberg-Baecklund reaction (ERBR): A sulfone-based method for the synthesis of allylic alcohols
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The epoxy-Ramberg-Baecklund reaction (ERBR) is outlined, in which α,β-epoxy sulfones are converted into a range of mono-, di- and tri-substituted allylic alcohols, on treatment with base. Modification of this method enabled the preparation of enantio-enriched allylic alcohols following the diastereoselective epoxidation of enantio-enriched vinyl sulfones that were accessed efficiently from the chiral pool. The scope, optimisation and limitations of the ERBR as a method for the preparation of allylic alcohols are discussed. Wiley-VCH Verlag GmbH & Co. KGaA, 2006.
- Evans, Paul,Johnson, Paul,Taylor, Richard J. K.
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p. 1740 - 1754
(2007/10/03)
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- Lewis Acid-prompted Conjugate Reduction of α,β-Unsaturated Carbonyl Compounds by 2-Phenylbenzothiazoline (2-Phenyl-2,3-dihydrobenzothiazole)
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Reduction of various α,β-unsaturated ketones (3a-g) and (4a-d) in methanol by the benzothiazoline (1) in the presence of aluminium chloride gives, in all cases, the corresponding saturated ketones (5a-g) and (6a-d)without any of the unsaturated or saturated alcohol.Reduction of α,β-unsaturated esters (7a,b) similarly gives the saturated esters (9a,b), while reaction of cinnamaldehyde (8) with compound (1) does not occur at all.Among the Lewis acids examined, aluminium chloride gives the best results.Reduction of 2'-azachalcone (21) with 2-phenylbenzothiazoline reveals that, in the reduction product, the deuterium atom is located at the β-position with respect to the carbonyl group.The result obtained from the reduction of the same substrate with compound (1) in methanol shows that no incorporation of a hydrogen atom from the solvent takes place and suggests (indirectly) that the introduced hydrogen atom at the α-position of the product comes from the benzothiazoline (1).The reaction of (Z)-1,2-dibenzoyl-1,2-diphenylethylene (30) with compound (1) in the presence of aluminium chloride stereospecifically yields meso-1,2-dibenzoyl-1,2-diphenylethane (31).This shows that the transfer of two hydrogens from compound (1) to the carbon-carbon double bond of the enone proceeds via cis-addition.Experiments with ethyl phenylpropiolate (28) also support cis-reduction for the present conjugate reduction.These results are interpreted in terms of a mechanism involving synchronous transport of a pair of hydrogens from the benzothiazoline (1); i.e a cyclic addition of the two hydrogens either in exact or nearly exact concurrence.
- Chikashita, Hidenori,Miyazaki, Makoto,Itoh, Kazuyoshi
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p. 699 - 706
(2007/10/02)
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- AlCl3-Promoted Conjugate Reduction of α,β-Unsaturated Carbonyl Compounds with 1,3-Dimethyl-2-phenylbenzimidazoline
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The reduction of a variety of α,β-unsaturated carbonyl compounds, except for α,β-unsaturated aldehyde, to the corresponding saturated carbonyl compounds was effectively performed by using 1,3-dimethyl-2-phenylbenzimidazoline (DMBI) as a reducing agent with the aid of AlCl3.The reduction is discussed on the basis of the hydride-donating ability of DMBI, together with the role of AlCl3 as an electrophilic activator for the substrates.The catalytic efficiency of Lewis acids was found to be proportional to the efficiency to form a complex with a carbonyl group.The reduction of 2-cinnamoylpyridine with 2-deuterated DMBI revealed that in the reduction product, a deuterium atom was located at the β-position with respect to the carbonyl group.On the other hand, the reduction of the same substrate with DMBI followed by quenching with D2O gave a reduced product which contained a deuterium label at the α-position.These results were interpreted in terms of a mechanism involving an enolate intermediate produced by either a one-step hydride transfer or a sequential transfer of an electron (e) and a hydrogen atom (H.) from the reducing agent to the substrate.
- Chikashita, Hidenori,Itoh, Kazuyoshi
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p. 1747 - 1752
(2007/10/02)
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