- Medium-Sized Cyclophanes. 43. First Evidence for anti-syn-Ring Inversion under the Nitration of 5,13-Di-tert-butyl-8,16-dimethoxy[2.2]metacyclophane
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Nitration of 5,13-di-tert-butyl-8,16-dimethoxy[2.2]MCP (metacyclophane = MCP) (1) with various nitrating reagents led to ipso-nitration at the tert-butyl group to give 5-tert-butyl-8,16-dimethoxy-13-nitro[2.2]MCP (2), as well as the corresponding 8,16-epo
- Yamato, Takehiko,Kamimura, Hideo,Furukawa, Tsuyoshi
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- A Mild Heteroatom (O -, N -, and S -) Methylation Protocol Using Trimethyl Phosphate (TMP)-Ca(OH) 2Combination
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A mild heteroatom methylation protocol using trimethyl phosphate (TMP)-Ca(OH)2combination has been developed, which proceeds in DMF, or water, or under neat conditions, at 80 °C or at room temperature. A series of O-, N-, and S-nucleophiles, including phenols, sulfonamides, N-heterocycles, such as 9H-carbazole, indole derivatives, and 1,8-naphthalimide, and aryl/alkyl thiols, are suitable substrates for this protocol. The high efficiency, operational simplicity, scalability, cost-efficiency, and environmentally friendly nature of this protocol make it an attractive alternative to the conventional base-promoted heteroatom methylation procedures.
- Tang, Yu,Yu, Biao
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- N-Heterocyclic Carbene-Catalyzed Truce-Smiles Rearrangement of N-Arylacrylamides via the Cleavage of Unactivated C(aryl)-N Bonds
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We report on the N-heterocyclic carbene (NHC)-catalyzed Truce-Smiles rearrangement of aniline derivatives, in which an unactivated C(aryl)-N bond is cleaved, leading to the formation of a new C(aryl)-C bond. The key to the success of this reaction is the
- Yasui, Kosuke,Kamitani, Miharu,Fujimoto, Hayato,Tobisu, Mamoru
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supporting information
p. 1572 - 1576
(2021/03/03)
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- Pd-Catalyzed ipso, meta-Dimethylation of ortho-Substituted Iodoarenes via a Base-Controlled C-H Activation Cascade with Dimethyl Carbonate as the Methyl Source
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A methyl group can have a profound impact on the pharmacological properties of organic molecules. Hence, developing methylation methods and methylating reagents is essential in medicinal chemistry. We report a palladium-catalyzed dimethylation reaction of ortho-substituted iodoarenes using dimethyl carbonate as a methyl source. In the presence of K2CO3 as a base, iodoarenes are dimethylated at the ipso- and meta-positions of the iodo group, which represents a novel strategy for meta-C-H methylation. With KOAc as the base, subsequent oxidative C(sp3)-H/C(sp3)-H coupling occurs; in this case, the overall transformation achieves triple C-H activation to form three new C-C bonds. These reactions allow expedient access to 2,6-dimethylated phenols, 2,3-dihydrobenzofurans, and indanes, which are ubiquitous structural motifs and essential synthetic intermediates of biologically and pharmacologically active compounds.
- Wu, Zhuo,Wei, Feng,Wan, Bin,Zhang, Yanghui
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supporting information
p. 4524 - 4530
(2021/05/04)
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- Synthesis of a poly-heterocyclic tetra-substituted alkene via a palladium-catalyzed four-fold domino reaction for the design of polymeric molecular switches
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A facile synthesis of a complex poly-heterocyclic tetrasubstituted alkene 4 with intrinsic helical chirality containing two acrylate moieties suitable for polymerization is described. Compound 4 can act as a molecular switch and was prepared via a palladi
- Khan, Taukeer A.,Tietze, Lutz F.
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p. 1183 - 1195
(2019/07/31)
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- Palladium-Catalyzed 4-Fold Domino Reaction for the Synthesis of a Polymeric Double Switch
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A palladium-catalyzed 4-fold domino reaction consisting of two carbopalladation reactions and two C-H activation reactions, followed by the introduction of an acrylate moiety, led to the tetra-substituted helical alkene A2, using the dialkyne A3 as a subs
- Khan, Taukeer A.,Fornefeld, Torsten,Hübner, Dennis,Vana, Philipp,Tietze, Lutz F.
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supporting information
p. 2007 - 2010
(2018/04/16)
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- Semi-quantitative models for identifying potent and selective transthyretin amyloidogenesis inhibitors
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Rate-limiting dissociation of the tetrameric protein transthyretin (TTR), followed by monomer misfolding and misassembly, appears to cause degenerative diseases in humans known as the transthyretin amyloidoses, based on human genetic, biochemical and pharmacologic evidence. Small molecules that bind to the generally unoccupied thyroxine binding pockets in the native TTR tetramer kinetically stabilize the tetramer, slowing subunit dissociation proportional to the extent that the molecules stabilize the native state over the dissociative transition state—thereby inhibiting amyloidogenesis. Herein, we use previously reported structure-activity relationship data to develop two semi-quantitative algorithms for identifying the structures of potent and selective transthyretin kinetic stabilizers/amyloidogenesis inhibitors. The viability of these prediction algorithms, in particular the more robust in silico docking model, is perhaps best validated by the clinical success of tafamidis, the first-in-class drug approved in Europe, Japan, South America, and elsewhere for treating transthyretin aggregation-associated familial amyloid polyneuropathy. Tafamidis is also being evaluated in a fully-enrolled placebo-controlled clinical trial for its efficacy against TTR cardiomyopathy. These prediction algorithms will be useful for identifying second generation TTR kinetic stabilizers, should these be needed to ameliorate the central nervous system or ophthalmologic pathology caused by TTR aggregation in organs not accessed by oral tafamidis administration.
- Connelly, Stephen,Mortenson, David E.,Choi, Sungwook,Wilson, Ian A.,Powers, Evan T.,Kelly, Jeffery W.,Johnson, Steven M.
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supporting information
p. 3441 - 3449
(2017/07/07)
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- A new tactic for tocopherol synthesis using intramolecular benzyne trapping by an alcohol
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A formal total synthesis of (S)-α-Tocopherol, the major component of natural Vitamin E has been achieved using intramolecular benzyne trapping as a key step to form the chroman ring. The synthesis also features an efficient new method for benzotriazole N-Amination using an oxaziridine; chiral, nonracemic intermediates are generated using asymmetric dihydroxylation.
- Knight, David W.,Xu, Qing
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p. 647 - 672
(2017/04/10)
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- Synthesis of a new mutagenic benzoazepinoquinolinone derivative
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A novel mutagenic compound 1, isolated as a Maillard product from tryptophan and glucose, was synthesized using Larock's quinoline formation, where addition of iodonium cation to an acetylene moiety of N-propargylaniline triggers subsequent intramolecular
- Ozeki, Minoru,Muroyama, Atsushi,Kajimoto, Tetsuya,Watanabe, Tetsushi,Wakabayashi, Keiji,Node, Manabu
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scheme or table
p. 1781 - 1784
(2009/12/09)
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- A synthesis of α-tocopherol featuring benzyne trapping by an alcohol
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A formal total synthesis of α-tocopherol, the main component of Vitamin E, has been achieved in which a central step is the intramolecular trapping of a highly substituted benzyne by an alcohol group to establish the pyran ring.
- Knight, David W.,Qing, Xu
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scheme or table
p. 3534 - 3537
(2009/12/01)
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- Spiro derivatives as lipoxygenase inhibitors
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The present invention is concerned with certain novel spiro substituted heterocylic ring derivatives. These compounds may be useful in the manufacture of pharmaceutical compositions for treating disorders mediated by lipoxygenases. They may also be useful
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Page/Page column 97
(2008/06/13)
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- ρ-heteroatom-substituted phenols and uses thereof
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The present invention provides an antiproliferative p-heteroatom-substituted phenol compound having the structure formula STR1 wherein m is 0 to 3, n is 0 to 4 when Het is nitrogen, wherein R is selected from the group consisting of hydrogen, alkyl, arylmethyl and acyl; R1 is alkyl; R2 is selected from the group consisting of hydrogen and alkyl; R3 is selected from the group consisting of alkyl and acyl when Het is nitrogen, R4 is selected from the group consisting of hydrogen and alkyl; R5 is selected from the group consisting of hydrogen and alkyl; and R6 and R7 are selected from the group consisting of hydrogen, alkyl and R6 and R7 together may represent oxygen. Also provided are various methods for the treatment of a pathological cell proliferative disease comprising administering to an animal) a pharmacologically and therapeutically effective dose of a pharmaceutical composition comprising a p-heteroatom-substituted phenols or an analog thereof.
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- Multinuclear Magnetic Resonance Spectroscopic and Semiempirical Molecular Orbital (AM1) Studies of Substituted Anisoles
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13C, 15N, and 17O NMR spectra have been recorded for 4-nitroanisole (1), its 2-methyl-, 2-chloro-, 2-bromo-, 2-iodo-, 2,6-diamethyl-, 2,6-dichloro, 2,6-dibromo-, and 2,6-diiodo-derivatives 2-9, also nitrobenzene (1a), its 3-methyl-, 3-chloro-, 3-bromo-, and 3-iodo-derivatives 2a-5a and 3,5-dichloro- and 3,5-dibromo-derivatives 7a and 8a.Analysis of the chemical shifts of carbon bearing nitro group and nitro oxygens in these compounds suggests that presence of one substituent ortho- to the methoxyl group enhances its resonance interaction with the benzene ring whereas presence of two ortho-substituents inhibits this resonance.However, in no case the resonance is completely inhibited.The extent of enhancement or inhibition is almost independent of the nature of the ortho-substituent.This conclusion has also been arrived by analyzing the reported chemical shifts of the para-carbons in anisoles 1b-9b and the corresponding carbons in benzene derivatives 1c-9c.Though evidence could not be obtained for steric enhancement of resonance using methoxyl oxygen chemical shifts, analysis of these chemical shifts in di-ortho-substituted anisoles 6-9 and 6a furnishes evidence for steric inhibition of resonance.However, 15N chemical shifts are of no use in studying these phenomena.Semiempirical molecular orbital calculations using AM1 Hamiltonian suggest that the methoxyl group is coplanar with the benzene ring in anisole, 4-nitroanisole and 2-substituted-4-nitroanisoles but is perpendicular to the benzene ring in 2,6-disubstituted-4-nitroanisoles.Moreover, in 2-substituted-4-nitroanisoles the O-methyl group is anti to the 2-substituent.
- Pandiarajan, Karuppiah,Kabilan, Senthamaraikannan,Sankar, Punnaivanam,Kolehmainen,Erkki,Nevalainen, Tapio,Kauppinen, Reijo
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p. 2639 - 2646
(2007/10/02)
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- Nitrosation and Nitrous Acid-catalysed Nitration of Anisole and 2,6-Dimethylanisole
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Rate-acidity profiles have been obtained for the nitrosation of anisole, 2,6-dimethylanisole (DMA), and 2,6-dimethylphenol (DMP) in aqueous sulphuric acid.The phenol is more reactive than the corresponding anisole, and DMA has a more shallow profile than anisole.A deuterium kinetic isotope effect (KH/kD) of 4.0 for 2H>anisole indicates that the product of nitrosation of anisole in 46.5percent sulphuric acid (p-nitrosophenol) is formed by slow proton loss from the Wheland intermediate.Intense colours were associated with the nitrosation of these compounds when nitrous acid was in excess.The kinetics of nitrous acid-catalysed nitration of anisole were studied in 43.0 and 47.0percent sulphuric acid; the product is p-nitrophenol.Nitrosation followed by oxidation by NV was the major pathway at these acidities.The other pathway has a kinetic form given by kC=k3III>V>, consistent with a process where oxidation by NV is rate-limiting.Product studies show that p-nitrophenol is formed at lower acidities and o- and p-nitroanisole at higher acidities.A mechanism is suggested involving a radical cation species, which would predominate at higher acidities and account for the kC pathway at lower acidities.The nitrous acid-catalysed nitration of DMA gives 2,6-dimethyl-4-nitroanisole in higher yield as the acidity increases.
- Dix, Leslie R.,Moodie, Roy B.
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p. 1097 - 1102
(2007/10/02)
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