- 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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- 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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- Dumbbell-Shaped 2,2’-Bipyridines: Controlled Metal Monochelation and Application to Ni-Catalyzed Cross-Couplings
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2,2’-Bipyridine ligands (dsbpys) with dumbbell-like shapes and differently substituted triarylmethyl groups at the C5 and C5’ positions showed high ligand performance in the Ni-catalyzed cross-electrophile coupling and the Ni/photoredox-synergistically catalyzed decarboxylative coupling reactions. The superior ligand effects of dsbpys compared to the conventional bpy ligands were attributed to the monochelating nature of dsbpys.
- Kim, Yongjoon,Iwai, Tomohiro,Fujii, Sho,Ueno, Kosei,Sawamura, Masaya
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supporting information
p. 2289 - 2293
(2020/12/07)
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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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- 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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- 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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- Combined Photoredox/Enzymatic C?H Benzylic Hydroxylations
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Chemical transformations that install heteroatoms into C?H bonds are of significant interest because they streamline the construction of value-added small molecules. Direct C?H oxyfunctionalization, or the one step conversion of a C?H bond to a C?O bond, could be a highly enabling transformation due to the prevalence of the resulting enantioenriched alcohols in pharmaceuticals and natural products,. Here we report a single-flask photoredox/enzymatic process for direct C?H hydroxylation that proceeds with broad reactivity, chemoselectivity and enantioselectivity. This unified strategy advances general photoredox and enzymatic catalysis synergy and enables chemoenzymatic processes for powerful and selective oxidative transformations.
- Betori, Rick C.,May, Catherine M.,Scheidt, Karl A.
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p. 16490 - 16494
(2019/11/03)
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- Metal-free visible light photoredox enables generation of carbyne equivalents via phosphonium ylide C-H activation
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Carbyne, an interesting synthetic intermediate, has recently been generated from hypervalent iodine precursors via photoredox catalysis. Given the underexplored chemistry of carbyne, due to the paucity of carbyne sources, we are intrigued to discover a new source for this reactive species from classical reagents-phosphonium ylides. Our novel strategy employing phosphonium ylides in an olefin hydrocarbonation reaction features a facile approach for constructing carbon-carbon bonds through metal-free and benign reaction conditions. Moreover, the hydrocarbonation products were delivered in a highly regioselective manner.
- Das, Mrinmoy,Vu, Minh Duy,Zhang, Qi,Liu, Xue-Wei
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p. 1687 - 1691
(2019/02/14)
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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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- Cobalt(i)-catalysed CH-alkylation of terminal olefins, and beyond
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Cobalester, a natural nontoxic vitamin B12 derivative, was found to catalyse unusual olefinic sp2 C-H alkylation with diazo reagents as a carbene source instead of the expected cyclopropanation.
- Giedyk, Maciej,Goliszewska, Katarzyna,ó Proinsias, Keith,Gryko, Dorota
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p. 1389 - 1392
(2016/01/25)
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- Borontribromide-mediated C-C bond formation in cyclic ketones: A transition metal free approach
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Borontribromide (BBr3) is a well-known demethylating agent. The current investigation was focused on a new application of borontribromide as a C-C bond forming agent in cyclic ketones. In this study, borontribromide mediated C-C bond formation reactions of tetralones, chromenone, thiochromenone and indanones were explored. A methoxy group containing ketones showed selective C-C bond formation reaction instead of demethylation of the methoxy group. MM2 steric energy calculations for the final products showed that the reaction favored the formation of exo- or endo-cyclic double bond containing products, depending upon their low MM2 steric energy in a specific frame structure, as observed in X-ray crystallography. A comprehensive crystallographic and pi-stacking analysis of product 10a demonstrated the formation of 10a as an enantiomeric mixture, and its centre of inversion was stabilized by a set of three unique pi-pi interactions.
- Ahmad, Imran,Pathak, Vinay,Vasudev, Prema G.,Maurya, Hardesh K.,Gupta, Atul
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p. 24619 - 24634
(2014/07/07)
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- Discovery of synthetic methoxy-substituted 4-phenylbutyric acid derivatives as chemical chaperones
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In this study, we evaluated the chemical chaperone activity of synthetic 4-phenylbutyric acid (4-PBA) derivatives. These derivatives have a methoxy group at the benzene ring and/or longer or shorter fatty acid portions. Several 4-PBA derivatives demonstrated higher antiaggregation activity than 4-PBA. Moreover, 4-(4-methoxyphenyl)butanoic acid (7b) showed protective effects against endoplasmic reticulum stress-induced neuronal cell death.
- Mimori, Seisuke,Okuma, Yasunobu,Kaneko, Masayuki,Kawada, Koichi,Nomura, Yasuyuki,Murakami, Yasuoki,Hamana, Hiroshi
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p. 1051 - 1052
(2013/09/24)
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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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- Cobalt(diamine)-catalyzed cross-coupling reaction of alkyl halides with arylmagnesium reagents: Stereoselective constructions of arylated asymmetric carbons and application to total synthesis of AH13205
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A cobalt-diamine complex catalyzes the cross-coupling reactions of primary and secondary alkyl halides with aryl Grignard reagents. It is confirmed that oxidative addition of alkyl halide to cobalt proceeds via a radical process. Optically pure Ueno-Stork halo acetals undergo diastereoselective cross-coupling reactions, the products of which are transformed into optically active THF derivatives. A sequential radical cyclization/arylation reaction under cobalt catalysis provides extremely short access to a synthetic prostaglandin AH13205.
- Ohmiya, Hirohisa,Yorimitsu, Hideki,Oshima, Koichiro
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p. 1886 - 1889
(2007/10/03)
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- BENZOTHIAZIN-3-ONE COMPOUND AND INTERMEDIATE THEREFOR
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A medicine which contains as an active ingredient a benzothiazin-3-one-compound represented by the formula (1): (wherein n is 3 or 4; R represents ethyl or hydrogen; and R 1 represents hologeno, alkoxy, haloalkyl, or haloalkoxy) or a pharmaceutically acceptable salt thereof. It is useful as a therapeutic or preventive agent for arthrosis deformans, chondrodegenerative discases such as chronic articular rheumatism, cancers, gingivitis, etc. Also provided are an intermediate for the compound and a process for producing the compound.
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Page/Page column 33
(2008/06/13)
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- Facile preparation of organozinc bromides using electrogenerated highly reactive zinc and its use in cross-coupling reaction
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Highly reactive zinc was readily prepared by electrolysis of a DMF solution containing pyrene as a mediator with a platinum cathode and a zinc anode. Preferential reduction of pyrene occurred to generate the corresponding radical anion, which reduced zinc ions generated from anodic dissolution to give zero valent zinc with high reactivity. The reactive zinc was successfully used for an efficient transformation of bromoalkanes into the corresponding organozinc bromides. Organozinc bromides obtained were further used successfully in Pd-catalyzed cross-coupling reaction with various aryl iodides and bromides.
- Kurono, Nobuhito,Inoue, Tomio,Tokuda, Masao
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p. 11125 - 11131
(2007/10/03)
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- One-step cross-coupling reaction of functionalized alkyl iodides with aryl halides by the use of an electrochemical method
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Organozinc compounds of functionalized alkyl iodide carrying an alkoxycarbonyl, cyano or alkenyl group were prepared in high yields under mild conditions (0°C-r.t., 10min in DMF) by the reaction of iodides with an electrogenerated reactive zinc (EGZn). Cross-coupling of the organozinc compounds with various aryl halides in the presence of 5 mol% Pd(P(o- Tol)3)2Cl2 in THF gave the corresponding cross-coupled products in moderate to high yields. These cross-coupling reactions can be also achieved in one step and in one pot by the use of an electrochemical method utilizing a Pt cathode and Zn anode.
- Kurono, Nobuhito,Sugita, Kazuya,Takasugi, Shingo,Tokuda, Masao
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p. 6097 - 6108
(2007/10/03)
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- Ring opening of cyclopropanecarboxylates using samarium(ii) diiodide (SmI2)-HMPA-THF system
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Cyclopropane ring of 2- and 2,3-substituted cyclopropanecarboxylates (1) was regioselectively cleaved using SmI2-HMPA-THF system in the presence of tert-BuOH to give 4- and 3,4-substituted butyrates (2) in moderate to good yields.
- Yamashita,Okuyama,Ohhara,Kawasaki,Ohta
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p. 708 - 710
(2007/10/02)
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- Ring opening of cyclopropanemonocarboxylates and 1,1- cyclopropanedicarboxylates using samarium(II) diiodide (SmI2)-HMPA-THF system
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The cyclopropane ring in 2-substituted 1,1-cyclopropanedicarboxylates was regioselectively opened by using samarium(II) diiodide (Sml2) in a hexamethylphosphoric triamide (HMPA)-tetrahydrofuran (THF) (1:10) system under mild and neutral conditions to give (2-substituted ethyl)malonates in moderate to good yields. The cyclopropane ring in 2-substituted cyclopropanecarboxylates or 2-substituted 3- (trimethylsilyl)cyclopropanecarboxylates was similarly cleaved regioselectively by using Sml2 in a HMPA-THF (1:1) system to give 4- arylbutyrates or 4-aryl-3-(trimethylsilyl)butyrates in 16-89% yields. The reaction mechanism of these ring-opening reactions is discussed.
- Yamashita,Okuyama,Ohhara,Kawasaki,Sakai,Nakata,Kawabe,Kusumoto,Ohta
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p. 2075 - 2081
(2007/10/03)
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- ARYLATION AND VINYLATION OF 2-CARBOETHOXYETHYLZINC IODIDE AND 3-CARBOETHOXYPROPYLZINC IODIDE CATALYZED BY PALLADIUM
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By the palladium catalysis 2-carboethoxyethylzinc iodide reacts with aryl iodides and vinyl iodides or triflates to provide the coupling products (ethyl 3-arylpropionates and ethyl 4-pentenoates, respectively) in satisfactory yields.The similar coupling reaction is observed for the reaction with 3-carboethoxypropylzinc iodide.
- Tamaru, Y.,Ochiai, H.,Nakamura, T.,Yoshida, Z.
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p. 955 - 958
(2007/10/02)
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