- Migratory Hydrogenation of Terminal Alkynes by Base/Cobalt Relay Catalysis
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Migratory functionalization of alkenes has emerged as a powerful strategy to achieve functionalization at a distal position to the original reactive site on a hydrocarbon chain. However, an analogous protocol for alkyne substrates is yet to be developed. Herein, a base and cobalt relay catalytic process for the selective synthesis of (Z)-2-alkenes and conjugated E alkenes by migratory hydrogenation of terminal alkynes is disclosed. Mechanistic studies support a relay catalytic process involving a sequential base-catalyzed isomerization of terminal alkynes and cobalt-catalyzed hydrogenation of either 2-alkynes or conjugated diene intermediates. Notably, this practical non-noble metal catalytic system enables efficient control of the chemo-, regio-, and stereoselectivity of this transformation.
- Liu, Bingxue,Liu, Qiang,Liu, Xufang
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supporting information
p. 6750 - 6755
(2020/03/13)
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- Direct Access to Isotopically Labeled Aliphatic Ketones Mediated by Nickel(I) Activation
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An extensive range of functionalized aliphatic ketones with good functional-group tolerance has been prepared by a NiI-promoted coupling of either primary or secondary alkyl iodides with NN2 pincer NiII-acyl complexes. The latter were easily accessed from the corresponding NiII-alkyl complexes with stoichiometric CO. This Ni-mediated carbonylative coupling is adaptable to late-stage carbon isotope labeling, as illustrated by the preparation of isotopically labelled pharmaceuticals. Preliminary investigations suggest the intermediacy of carbon-centered radicals.
- Donslund, Aske S.,Pedersen, Simon S.,Gaardbo, Cecilie,Neumann, Karoline T.,Kingston, Lee,Elmore, Charles S.,Skrydstrup, Troels
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supporting information
p. 8099 - 8103
(2020/03/16)
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- Allyl 4-Chlorophenyl Sulfone as a Versatile 1,1-Synthon for Sequential α-Alkylation/Cobalt-Catalyzed Allylic Substitution
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Despite their unique potential as rare 1,1-dipole synthons, allyl sulfones are rarely used in target-oriented syntheses, likely due to the lack of a general catalytic method for their branch-selective allylic substitution. Herein, we identified allyl 4-chlorophenyl sulfone as a versatile linchpin for both base-mediated α-derivatization and subsequent cobalt-catalyzed allylic substitution. The sequential transformations allow for highly regioselective access to branched allylic substitution products with a variety of aliphatic side chains. The photoredox-enabled cobalt catalysis is indispensable for achieving high yields and regioselectivity for the desulfonylative substitution in contrast to traditional metal-catalyzed protocols, which lead to inferior outcomes in the corresponding transformations.
- Kojima, Masahiro,Matsunaga, Shigeki
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p. 1934 - 1946
(2020/07/03)
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- Electrophilic Cyanative Alkenylation of Arenes
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A variety of appropriately substituted internal alkynes were transformed into the corresponding cyano-substituted phenanthrenes, dihydronaphthalenes, and cyclohepta-1,3,5-trienes in moderate to excellent yields by treatment with imidazolium thiocyanate 1, which serves as an easy to handle [CN]+ precursor, in the presence of BCl3. The synthetic value of the method is additionally demonstrated by the transformation of the primarily obtained products into heavily substituted quinolines. Additionally, the dynamic properties of the prepared dibenzocyclohepta-1,3,5-trienes have been investigated.
- Zhao, Mingyue,Barrado, Alejandro G.,Sprenger, Kristin,Golz, Christopher,Mata, Ricardo A.,Alcarazo, Manuel
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supporting information
p. 4932 - 4937
(2020/06/08)
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- Transition-Metal-Free Borylation of Alkyl Iodides via a Radical Mechanism
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We describe an operationally simple transition-metal-free borylation of alkyl iodides. This method uses commercially available diboron reagents as the boron source and exhibits excellent functional group compatibility. Furthermore, a diverse range of prim
- Liu, Qianyi,Hong, Junting,Sun, Beiqi,Bai, Guangcan,Li, Feng,Liu, Guoquan,Yang, Yang,Mo, Fanyang
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supporting information
(2019/07/08)
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- Discovery, synthesis, and structure-activity relations of 3,4-dihydro-1H-spiro(naphthalene-2,2′-piperidin)-1-ones as potassium-competitive acid blockers
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With the aim to discover a gastric antisecretory agent more potent than the existing proton pump inhibitors, novel 3,4-dihydro-1H-spiro(naphthalene-2,2′-piperidin)-1-one derivatives, which could occupy two important lipophilic pockets (described as LP-1 and LP-2) of H+,K+-ATPase and can strongly bind to the K+-binding site, were designed based on a docking model. Among the compounds synthesized, compound 4d showed a strong H+,K+-ATPase-inhibitory activity and a high stomach concentration in rats, resulting in potent inhibitory action on histamine-stimulated gastric acid secretion in rats. Furthermore, 4d exerted significant inhibitory action on histamine-stimulated gastric-acid secretion in rats with a rapid onset and moderate duration of action after the administration. These findings may lead to a new insight into the drug design of potassium-competitive acid blockers.
- Imaeda, Toshihiro,Ono, Koji,Nakai, Kazuo,Hori, Yasunobu,Matsukawa, Jun,Takagi, Terufumi,Fujioka, Yasushi,Tarui, Naoki,Kondo, Mitsuyo,Imanishi, Akio,Inatomi, Nobuhiro,Kajino, Masahiro,Itoh, Fumio,Nishida, Haruyuki
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p. 3719 - 3735
(2017/06/13)
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- Discovery, characterization and biological evaluation of a novel (R)-4,4-difluoropiperidine scaffold as dopamine receptor 4 (D4R) antagonists
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Herein, we report the synthesis and structure–activity relationship of a novel series of (R)-4,4-difluoropiperidine core scaffold as dopamine receptor 4 (D4) antagonists. A series of compounds from this scaffold are highly potent against the D4receptor and selective against the other dopamine receptors. In addition, we were able to confirm the active isomer as the (R)-enantiomer via an X-ray crystal structure.
- Jeffries, Daniel E.,Witt, Jonathan O.,McCollum, Andrea L.,Temple, Kayla J.,Hurtado, Miguel A.,Harp, Joel M.,Blobaum, Anna L.,Lindsley, Craig W.,Hopkins, Corey R.
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p. 5757 - 5764
(2016/11/28)
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- Light-mediated deoxygenation of alcohols with a dimeric gold catalyst
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A new protocol for the reductive deoxygenation of primary alcohols was explored. This photo-mediated method combines a novel approach to bromination of alcohols merged with the powerful reducing capability of [Au2(dppm)2]Cl2 [dppm = 1,1-bis(diphenylphosphino)methane] as a photoredox catalyst. The highly efficient methods discussed are marked by the use of UVA light-emitting diodes, which have significantly reduced reaction times and lowered setup cost.
- McCallum, Terry,Slavko, Ekaterina,Morin, Mathieu,Barriault, Louis
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supporting information
p. 81 - 85
(2015/02/18)
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- PROCESS FOR THE PREPARATION OF N-IODOAMIDES
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The present invention provides new stable crystalline N-iodoamides - 1-iodo- 3,5,5-trimethylhydantoin (1-ITMH) and 3-iodo-4,4-dimethyl-2-oxazolidinone (IDMO). The present invention further provides a process for the preparation of organic iodides using N-iodoamides of this invention and recovery of the amide co-products from waste water.
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Paragraph 00209-00210
(2015/05/26)
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- The prins cascade cyclization reaction for the synthesis of angularly-fused tetrahydropyran and piperidine derivatives
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2-Arylethylbut-3-en-1-ol is found to undergo smooth Prins cascade reactions with various aldehydes in the presence of Sc(OTf)3 (10 mol-%) and a stoichiometric amount of TsOH to afford the corresponding trans-fused hexahydro-1H-benzo[f]isochrome
- Subba Reddy,Kumar, Harish,Borkar, Prashant,Yadav,Sridhar
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supporting information
p. 1993 - 1999
(2013/05/22)
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- Design and synthesis of phenethyl benzo[1,4]oxazine-3-ones as potent inhibitors of PI3Kinaseγ
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The Type 1 PI3Kinases comprise a family of enzymes, which primarily phosphorylate PIP2 to give the second messenger PIP3, a key player in many intracellular signaling processes [Science, 2002, 296, 1655; Trends Pharmacol. Sci. 2003, 24, 366]. Of the four type 1 PI3Ks, the γ-isoform, which is expressed almost exclusively in leukocytes [Curr. Biol., 1997, 7, R470], is of particular interest with respect to its role in inflammatory diseases such as rheumatoid arthritis (RA) and chronic obstructive pulmonary disease (COPD) [Mol. Med. Today, 2000, 6, 347]. Investigation of a series of 4,6-disubstituted-4H-benzo[1,4]oxazin-3-ones has led to the identification of single-digit nanomolar inhibitors of PI3Kγ, several of which had good cell based activity and were shown to be active in vivo in an aspectic peritonitis model of inflammatory cell migration.
- Lanni Jr., Thomas B.,Greene, Keri L.,Kolz, Christine N.,Para, Kimberly S.,Visnick, Melean,Mobley, James L.,Dudley, David T.,Baginski, Theodore J.,Liimatta, Marya B.
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p. 756 - 760
(2007/10/03)
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- Hypervalent iodine(III)-induced intramolecular cyclization of α-(aryl)alkyl-β-dicarbonyl compounds: A convenient synthesis of benzannulated and spirobenzannulated compounds
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A novel hypervalent iodine(III)-induced direct intramolecular cyclization of α-(aryl)alkyl-β-dicarbonyl compounds has been described. Both meta- and para-substituted phenol ether derivatives containing acyclic or cyclic 1,3-dicarbonyl moieties at the side chain undergo this reaction in a facile manner. The reactions afford benzannulated and spirobenzannulated compounds that are of biological importance. The reaction is found to be general, mild, and high yielding. The mechanism of the reaction has been shown to involve a cation radical intermediate.
- Arisawa,Ramesh,Nakajima,Tohma,Kita
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- 2-substituted (2SR)-2-amino-2-((1SR,2SR)-2-carboxycycloprop-1- yl)glycines as potent and selective antagonists of group II metabotropic glutamate receptors. 2. Effects of aromatic substitution, pharmacological characterization, and bioavailability
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In this paper we describe the synthesis of a series of α-substituted analogues of the potent and selective group II metabotropic glutamate receptor (mGluR) agonist (1S,1'S,2'S)-carboxycyclopropylglycine (2, L-CCG 1). Incorporation of a substituent on the amino acid carbon converted the agonist 2 into an antagonist. All of the compounds were prepared and tested as a series of four isomers, i.e., two racemic diastereomers. On the basis of the improvement in affinity realized for the α-phenylethyl analogue 3, in this paper we explored the effects of substitution on the aromatic ring as a strategy to increase the affinity of these compounds for group II mGluRs. Affinity for group II mGluRs was measured using [3H]glutamic acid (Glu) binding in rat forebrain membranes. Antagonist activity was confirmed for these compounds by measuring their ability to antagonize (1S,3R)-1- aminocyclopentane-1,3-dicarboxylic acid-induced inhibition of forskolin stimulated cyclic-AMP in RGT cells transfected with human mGluR2 and mGluR3. Meta substitution on the aromatic ring of 3 with a variety of substituents, both electron donating (e.g., methyl, hydroxy, amino, methoxy, phenyl, phenoxy) and electron withdrawing (e.g., fluorine, chlorine, bromine, carboxy, trifluoromethyl) gave from 1.5- to 4.5-fold increases in affinity. Substitution with p-fluorine, as in 97 (IC50 = 0.022 ± 0.002), was the exception. Here, a greater increase in affinity was realized than for either the ortho- or meta-substituted analogues; 97 was the most potent compound resulting from monosubstitution of the aromatic. At best, only modest increases in affinity were realized for certain compounds bearing either two chlorines or two fluorines, and two methoxy groups gave no improvement in affinity (all examined in a variety of substitution patterns). Three amino acids, 4, 5, and 104, were resolved into their four constituent isomers, and affinity and functional activity for group II mGluRs was found to reside solely in the S,S,S-isomers of each, consistent with 1. With an IC50 = 2.9 ± 0.6 nM, the resolved xanthylmethyl compound 168 was the most potent compound from this SAR. Amino acid 168 demonstrated high plasma levels following intraperitoneal (ip) administration and readily penetrated into the brain. This compound, however, had only limited (~5%) oral bioavailability. Systemic administration of 168 protected mice from limbic seizures produced by the mGluR agonist 3,5-dihydroxyphenylglycine, with an ED50 = 31 mg/kg (ip, 60 min preinjection). Thus, 168 represents a valuable tool to study the role of group II mGluRs in disease.
- Ornstein, Paul L.,Bleisch, Thomas J.,Arnold, M. Brian,Kennedy, Joseph H.,Wright, Rebecca A.,Johnson, Bryan G.,Tizzano, Joseph P.,Helton, David R.,Kallman, Mary Jeanne,Schoepp, Darryle D.,Hérin, Marc
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p. 358 - 378
(2007/10/03)
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- Covenient Halodeamination and Hydrodeamination of Primary Amines
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Treatment of p-toluenesulfonamides of primary amines with 2 equiv of chloroamine at room temperature in the presence of base leads to reductive deamination.If excess chloroamine is present, the corresponding alkyl or aryl halides are obtained instead in good yields.Both reactions presumably proceed via tosylhydrazine and diazene intermediates; the course of the reaction is often governed by steric hindrance.Treatment of the isolated tosylhydrazine intermediate with base and chloroamine, bromine, or iodine also leads to the corresponding halides in very good yields.
- Guziec, Frank S.,Wei, Dongchu
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p. 3772 - 3776
(2007/10/02)
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- Reductive Deoxygenation of Aryl Aldehydes and Ketones and Benzylic, Allylic, and Tertiary Alcohols by ZnI2-NaCNBH3
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Sodium cyanoborohydride in the presence of zinc iodide is found to exhibit unique and selective reducing properties.The reagents reduce aryl aldehydes and ketones as well as benzylic, allylic, and tertiary alcohols to the corresponding hydrocarbons.
- Lau, C. K.,Dufresne, Claude,Belanger, Patrice C.,Pietre, Sylvie,Scheigetz, John
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p. 3038 - 3043
(2007/10/02)
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