- Mechanical metal activation for Ni-catalyzed, Mn-mediated cross-electrophile coupling between aryl and alkyl bromides
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Liquid-assisted grinding has been successfully applied to eliminate the requirements of chemical activators and anhydrous solvents in nickel-catalyzed, manganese-mediated cross-electrophile coupling between aryl and alkyl bromides. In addition to the traditional reaction parameters, mechanical ones,e.g.the rotational speed of mill, the filling degree of jar and ball size, have been found to affect the catalytic efficiency remarkably, implying the involvement of the regeneration of nickel(0) species in the rate-determining steps. A combined evaluation of the reaction and mechanical parameters led to an optimal condition under which a variety ofn-alky aromatics with various functional groups could be readily obtained in good yields with a 1 mol% catalyst loading. The practical application of liquid-assisted grinding-enabled aryl/alkyl cross-electrophile coupling has been demonstrated in the gram-scale synthesis of 6-methoxytetralone.
- Wu, Sisi,Shi, Weijia,Zou, Gang
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supporting information
p. 11269 - 11274
(2021/07/02)
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- Visible-light induced metal-free cascade Wittig/hydroalkylation reactions
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Cascade reactions are green and powerful transformations for building multiple carbon-carbon bonds in one step. Through a relay olefination and radical addition process, we were able to develop the cascade Wittig/hydroalkylation reactions induced by visible light. This metal-free radical approach features mild conditions, robustness, and excellent functionality compatibility. It allows access to saturated C3 homologation products directly from aldehydes or ketones. The synthetic utility of this method is demonstrated by a two-step synthesis ofindolizidine 209D.
- Miao, Pannan,Li, Ruining,Lin, Xianfeng,Rao, Liangming,Sun, Zhankui
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supporting information
p. 1638 - 1641
(2021/03/09)
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- Structure activity relationship exploration of 5-hydroxy-2-(3-phenylpropyl)chromones as a unique 5-HT2B receptor antagonist scaffold
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Antagonists for the serotonin receptor 2B (5-HT2B) have clinical applications towards migraine, anxiety, irritable bowl syndrome, and MDMA abuse; however, few selective 5-HT2B antagonists have been identified. Previous studies from these labs identified a natural product, 5-hydroxy-2-(2-phenylethyl)chromone (5-HPEC, 2) as the first non-nitrogenous ligand for the 5-HT2B receptor. Studies on 5-HPEC optimization led to the identification of 5-hydroxy-2-(3-phenylpropyl)chromone (5-HPPC, 3), which showed a tenfold improvement in binding affinity over 2 at 5-HT2B. This study aimed to further improve receptor pharmacology of this unique scaffold. Guided by molecular modeling studies modifications at the C-3′ and C-4′ positions of 3 were made to probe their effects on ligand binding affinity and efficacy. Among the derivatives synthesized 5-hydroxy-2-(3-(3-cyanophenyl)propyl)chromone (5-HCPC, 3d) showed the most promise with a multifold improvement in binding affinity (pKi = 7.1 ± 0.07) over 3 with retained antagonism.
- Kim, Minsoo,Truss, Myles,Pagare, Piyusha P.,Essandoh, Martha A.,Zhang, Yan,Williams, Dwight A.
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- Preparation method of substituted butyrate derivatives
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The invention discloses a preparation method of substituted butyrate derivatives. The method specifically comprises the following steps: by taking compounds shown in a formula 1, a formula 2 and a formula 3 as raw materials, carrying out an illumination reaction process in the presence of a photocatalyst and a hydrogen transfer catalyst to obtain a target compound shown in a formula I through one-step reaction. The invention discloses a free radical-mediated olefin bifunctional reaction without a cyclopropanation intermediate. The reaction can realize a product which can be obtained through cyclopropanation and cyclopropane ring opening processes traditionally in one step. Meanwhile, the preparation method of the compound is simple, uses cheap and easily available compounds as raw materials, and has the beneficial effects of one-step synthesis, mild reaction conditions, fast reaction, low cost, less generated waste, simple and safe operation, high atom economy, high selectivity, extremely wide substrate applicability, high yield and the like.
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Paragraph 0081-0084
(2020/07/15)
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- Radical-Mediated Strategies for the Functionalization of Alkenes with Diazo Compounds
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One of the most common reactions of diazo compounds with alkenes is cyclopropanation, which occurs through metal carbene or free carbene intermediates. Alternative functionalization of alkenes with diazo compounds is limited, and a methodology for the addition of the elements of Z-CHR2 (with Z = H or heteroatom, and CHR2 originates from N2 CR2) across a carbon-carbon double bond has not been reported. Here we report a novel reaction of diazo compounds utilizing a radical-mediated addition strategy to achieve difunctionalization of diverse alkenes. Diazo compounds are transformed to carbon radicals with a photocatalyst or an iron catalyst through PCET processes. The carbon radical selectively adds to diverse alkenes, delivering new carbon radical species, and then forms products through hydroalkylation by thiol-assisted hydrogen atom transfer (HAT), or forms azidoalkylation products through an iron catalytic cycle. These two processes are highly complementary, proceed under mild reaction conditions, and show high functional group tolerance. Furthermore, both transformations are successfully performed on a gram-scale, and diverse γ-amino esters, γ-amino alcohols, and complex spirolactams are easily prepared with commercially available reagents. Mechanistic studies reveal the plausible pathways that link the two processes and explain the unique advantages of each.
- Su, Yong-Liang,Liu, Geng-Xin,Liu, Jun-Wen,Tram, Linh,Qiu, Huang,Doyle, Michael P.
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supporting information
p. 13846 - 13855
(2020/09/21)
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- Nickel-Catalyzed Cross-Electrophile Coupling of Aryl Chlorides with Primary Alkyl Chlorides
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Alkyl chlorides and aryl chlorides are among the most abundant and stable carbon electrophiles. Although their coupling with carbon nucleophiles is well developed, the cross-electrophile coupling of aryl chlorides with alkyl chlorides has remained a chall
- Gilbert, Michael M.,Goldfogel, Matthew J.,Kim, Seoyoung,Weix, Daniel J.
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supporting information
p. 9902 - 9907
(2020/06/27)
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- Electrochemical Nickel Catalysis for Sp2-Sp3 Cross-Electrophile Coupling Reactions of Unactivated Alkyl Halides
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A constant-current electrochemical method for reducing catalytic nickel complexes in sp2-sp3 cross-electrophile coupling reactions has been developed. The electrochemical reduction provides reliable nickel catalyst activation and turnover and offers a tunable parameter for reaction optimization, in contrast to more standard activated metal powder reductants. The electrochemical reactions give yields (i.e., 51-86%) and selectivities as high or superior to those using metal powder reductants and provide access to a wider substrate scope.
- Perkins, Robert J.,Pedro, Dylan J.,Hansen, Eric C.
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supporting information
p. 3755 - 3758
(2017/07/26)
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- α-Diazo-β-ketonitriles: Uniquely reactive substrates for arene and alkene cyclopropanation
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An investigation of the intramolecular cyclopropanation reactions of α-diazo-β-ketonitriles is reported. These studies reveal that α-diazo-β-ketonitriles exhibit unique reactivity in their ability to undergo arene cyclopropanation reactions; other similar acceptor-acceptor- substituted diazo substrates instead produce mixtures of C-H insertion and dimerization products. α-Diazo-β-ketonitriles also undergo highly efficient intramolecular cyclopropanation of tri- and tetrasubstituted alkenes. In addition, the α-cyano-α-ketocyclopropane products are demonstrated to serve as substrates for SN2, SN2′, and aldehyde cycloaddition reactions.
- Nani, Roger R.,Reisman, Sarah E.
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supporting information
p. 7304 - 7311
(2013/06/27)
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- Replacing conventional carbon nucleophiles with electrophiles: Nickel-catalyzed reductive alkylation of aryl bromides and chlorides
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A general method is presented for the synthesis of alkylated arenes by the chemoselective combination of two electrophilic carbons. Under the optimized conditions, a variety of aryl and vinyl bromides are reductively coupled with alkyl bromides in high yields. Under similar conditions, activated aryl chlorides can also be coupled with bromoalkanes. The protocols are highly functional-group tolerant (-OH, -NHTs, -OAc, -OTs, -OTf, -COMe, -NHBoc, -NHCbz, -CN, -SO2Me), and the reactions are assembled on the benchtop with no special precautions to exclude air or moisture. The reaction displays different chemoselectivity than conventional cross-coupling reactions, such as the Suzuki-Miyaura, Stille, and Hiyama-Denmark reactions. Substrates bearing both an electrophilic and nucleophilic carbon result in selective coupling at the electrophilic carbon (R-X) and no reaction at the nucleophilic carbon (R-[M]) for organoboron (-Bpin), organotin (-SnMe3), and organosilicon (-SiMe2OH) containing organic halides (X-R-[M]). A Hammett study showed a linear correlation of σ and σ(-) parameters with the relative rate of reaction of substituted aryl bromides with bromoalkanes. The small ρ values for these correlations (1.2-1.7) indicate that oxidative addition of the bromoarene is not the turnover-frequency determining step. The rate of reaction has a positive dependence on the concentration of alkyl bromide and catalyst, no dependence upon the amount of zinc (reducing agent), and an inverse dependence upon aryl halide concentration. These results and studies with an organic reductant (TDAE) argue against the intermediacy of organozinc reagents.
- Everson, Daniel A.,Jones, Brittany A.,Weix, Daniel J.
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supporting information; experimental part
p. 6146 - 6159
(2012/05/07)
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- Direct method for carbon-carbon bond formation: The functional group tolerant cobalt-catalyzed alkylation of aryl halides
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(Figure Presented). A new protocol for the direct cobaltcatalyzed alkylation of aryl halides has been developed that proceeds smoothly in the presence of phosphanes or bipyridines as ligands with a variety of alkyl halides, including challenging alkyl electrophiles bearing β hydrogen atoms (see scheme). Sensitive functional groups are tolerated on both coupling partners, thus, significantly extending the general scope of transition-metal-catalyzed alkylation of aryl halides.
- Amatore, Muriel,Gosmini, Corinne
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supporting information; experimental part
p. 5848 - 5852
(2010/09/03)
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