- Diastereoselective olefin amidoacylationviaphotoredox PCET/nickel-dual catalysis: reaction scope and mechanistic insights
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The selective 1,2-aminoacylation of olefins provides opportunities for the rapid construction of nitrogen-containing molecules. However, the lack of CO-free acylation reactions has limited their application. By using photoredox proton-coupled electron transfer (PCET)/Ni dual-catalysis, a highly regio- and diastereoselective amidoacylation of unactivated olefins has been developed. Various acyl electrophiles are compatible, including alkyl- and aryl acyl chlorides and anhydrides, as well asin situactivated carboxylic acids. Hammett studies and other mechanistic experiments to elucidate features of the diastereoselectivity, a transient absorption study of the PCET step, as well as computational evidence, provide an in-depth understanding of the disclosed transformation.
- Anna, Jessica M.,Hong, Xin,Molander, Gary A.,Saeednia, Borna,Zhang, Shuo-Qing,Zheng, Shuai,Zhou, Jiawang
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p. 4131 - 4137
(2020/05/13)
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- Decarboxylative Borylation of mCPBA-Activated Aliphatic Acids
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A decarboxylative borylation of aliphatic acids for the synthesis of a variety of alkylboronates has been developed by mixing m-chloroperoxybenzoic acid (mCPBA)-activated fatty acids with bis(catecholato)diboron in N,N-dimethylformamide (DMF) at room temperature. A radical chain process is involved in the reaction which initiates from the B-B bond homolysis followed by the radical transfer from the boron atom to the carbon atom with subsequent decarboxylation and borylation.
- Wei, Dian,Liu, Tu-Ming,Zhou, Bo,Han, Bing
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supporting information
p. 234 - 238
(2020/01/02)
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- Modular Tuning of Electrophilic Reactivity of Iridium Nitrenoids for the Intermolecular Selective α-Amidation of β-Keto Esters
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We report herein an Ir-catalyzed intermolecular amino group transfer to β-keto esters (amides) to access α-aminocarbonyl products with excellent chemoselectivity. The key strategy was to engineer electrophilicity of the putative Ir-nitrenoids by tuning electronic property of the κ2-N,O chelating ligands, thus facilitating nucleophilic addition of enol π-bonds of 1,3-dicarbonyl substrates.
- Lee, Minhan,Jung, Hoimin,Kim, Dongwook,Park, Jung-Woo,Chang, Sukbok
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supporting information
p. 11999 - 12004
(2020/08/06)
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- Iron-Catalyzed Intramolecular C-H Amination of α-Azidyl Amides
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Iron-catalyzed intramolecular C-H amination of aliphatic azides has recently emerged as a powerful tool for the preparation of nitrogen heterocycles. This paper reports that α-azidyl amides can be converted in high efficacy to imidazolinone compounds via intramolecular C(sp3)-H amination by the action of a simple catalytic system composed of FeCl2 and a β-diketiminate ligand. The reactions provide a simple and atom-economical approach toward polysubstituted imidazolinones.
- Zhao, Xiaopeng,Liang, Siyu,Fan, Xing,Yang, Tonghao,Yu, Wei
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supporting information
p. 1559 - 1563
(2019/03/20)
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- Visible Light-Mediated Decarboxylative Alkylation of Pharmaceutically Relevant Heterocycles
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A net redox-neutral method for the decarboxylative alkylation of heteroarenes using photoredox catalysis is reported. Additionally, this method features the use of simple, commercially available carboxylic acid derivatives as alkylating agents, enabling the facile alkylation of a variety of biologically relevant heterocyclic scaffolds under mild conditions.
- Sun, Alexandra C.,McClain, Edward J.,Beatty, Joel W.,Stephenson, Corey R. J.
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supporting information
p. 3487 - 3490
(2018/06/26)
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- Novel non-trimethoxylphenyl piperlongumine derivatives selectively kill cancer cells
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Piperlongumine (PL) is a natural alkaloid with broad biological activities. Twelve analogues have been designed and synthesized with non-substituted benzyl rings or heterocycles in this work. Most of the compounds showed better anticancer activities than the parent PL without apparent toxicity in normal cells. Elevation of cellular ROS levels was one of the main anticancer mechanisms of these compounds. Cell apoptosis and cell cycle arrest for the best compound ZM90 were evaluated and similar mechanism of action with PL was demonstrated. The SAR was also characterized, providing worthy directions for further optimization of PL compounds.
- Zhang, Youjun,Ma, Hao,Wu, Yuelin,Wu, Zhongli,Yao, Zhengguang,Zhang, Wannian,Zhuang, Chunlin,Miao, Zhenyuan
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supporting information
p. 2308 - 2312
(2017/05/10)
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- Compounds with cardiac myosin activating function and pharmaceutical composition containing the same for treating or preventing heart failure
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The present invention relates to a compound having a cardiotonic activating function and a pharmaceutical composition containing the same. The composition comprising the compound according to the present invention is effective in preventing or treating heart failure. In addition, the compound is represented by chemical formula 2 or is pharmaceutically acceptable salt thereof.COPYRIGHT KIPO 2016
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Paragraph 1268-1271
(2017/02/02)
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- The synergistic effect of copper chromite spinel nanoparticles (CuCr2O4) and basic ionic liquid on the synthesis of cyclopropanecarboxylic acids
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Abstract: An efficient synthesis of cyclopropanecarboxylic acids using copper chromite spinel nanoparticles and basic ionic liquid is described. In this study, a relatively simple method starting with trans-cinnamic acid for the synthesis of (±)-trans-2-phenylcyclopropanecarboxylic acid, a key intermediate in the synthesis of tranylcypromine sulfate as an active pharmaceutical ingredient, was employed. Using a combination of basic ionic liquid [Bmim]OH and copper chromite spinel nanoparticles as a catalytic system, the best results were obtained in THF as a polar solvent. This method is a useful alternative to other approaches described in the literature. The use of commercially available chemicals, decreased environmental hazards, with no need for the separation of stereoisomers, and consequently a reduced number of overall steps, are the advantages of this approach that make it an appropriate choice at an increased scale. Graphical Abstract: [Figure not available: see fulltext.]
- Ghasemi, Mohammad Hadi,Kowsari, Elaheh
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p. 7963 - 7975
(2016/11/25)
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- Compounds with cardiac myosin activating function and pharmaceutical composition containing the same for treating or preventing heart failure
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Disclosed are a compound having cardiotonic activity and a pharmaceutical composition containing the same, and the composition containing the compound, according to the present invention, is useful for preventing and treating heart failure.COPYRIGHT KIPO 2016
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Paragraph 1266-1271
(2016/10/07)
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- α7 NICOTINIC ACETYLCHOLINE RECEPTOR MODULATORS AND USES THEREOF-I
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The present invention relates to chemical compounds of formula (I), with the substituents as described in the specification, useful in the positive modulation of the alpha 7 nicotinic acetylcholine receptor (α7 nAChR). The invention also relates to the use of these compounds in the treatment or prevention of a broad range of diseases in which the positive modulation of α7 nAChR is advantageous, including neurodegenerative and neuropsychiatric diseases and also neuropathic pain and inflammatory diseases.
- -
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Page/Page column 53, 55, 56
(2014/02/16)
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- Synthesis of 2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazoles via the cyclopropyliminium rearrangement of substituted 2-cyclopropylbenzimidazoles
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2-Cyclopropylbenzimidazole derivatives with various substituents in the small ring undergo cyclopropyliminium rearrangement into 2,3- dihydropyrrolobenzimidazoles substituted at positions 1, 2 or 3. The substrates containing a functional group in position 1 of the cyclopropane ring form products substituted at position 3. Substituents at position 2 in most cases lead to the formation of a mixture of isomers. The reaction can be directed to yield one of the isomers predominantly by varying the solvent polarity.
- Salikov, Rinat F.,Platonov, Dmitry N.,Frumkin, Aleksandr E.,Lipilin, Dmitry L.,Tomilov, Yury V.
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p. 3495 - 3505
(2013/04/23)
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- CANNABINOID-2-RECEPTOR AGONISTS
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The present invention relates to cannabinnoid-2-receptor (CB2R) agonist compounds. The present invention also relates to processes for the preparation of these compounds, to pharmaceutical compositions comprising them and to their use as therapeutic agents for the treatment and/or prevention of diseases or conditions in which CB2R stimulation is beneficial (especially inflammatory conditions).
- -
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Paragraph 00319
(2013/04/10)
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- Auxiliary-enabled Pd-catalyzed direct arylation of methylene C(sp 3)-H bond of cyclopropanes: Highly diastereoselective assembling of Di- and trisubstituted cyclopropanecarboxamides
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An auxiliary-enabled and Pd(OAc)2-catalyzed direct arylation of C(sp3)-H bonds of cyclopropanes and production of di- and trisubstituted cyclopropanecarboxamides having contiguous stereocenters are reported. The installation of aryl groups on cyclopropanecarboxamides led to the assembling of novel mono- and di- aryl-N-(quinolin-8-yl)cyclopropanecarboxamide scaffolds and mono- and di- aryl-N-(2-(methylthio)phenyl) cyclopropanecarboxamides. The stereochemistry of products was unequivocally assigned from the X-ray structures of key compounds.
- Parella, Ramarao,Gopalakrishnan, Bojan,Babu, Srinivasarao Arulananda
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supporting information
p. 3238 - 3241
(2013/07/26)
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- Enantioselective functionalization of radical intermediates in redox catalysis: Copper-catalyzed asymmetric oxytrifluoromethylation of alkenes
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Something radical: An efficient enantioselective oxytrifluoromethylation of alkenes has been developed using a copper catalyst system. Mechanistic studies are consistent with a metal-catalyzed redox radical addition mechanism in which a C-O bond is formed by the copper-mediated enantioselective trapping of a prochiral alkyl radical intermediate derived from the initial trifluoromethyl radical addition. Copyright
- Zhu, Rong,Buchwald, Stephen L.
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supporting information
p. 12655 - 12658
(2013/12/04)
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- Controlled and chemoselective reduction of secondary amides
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This communication describes a metal-free methodology involving an efficient and controlled reduction of secondary amides to imines, aldehydes, and amines in good to excellent yields under ambient pressure and temperature. The process includes a chemoselective activation of a secondary amide with triflic anhydride in the presence of 2-fluoropyridine. The electrophilic activated amide can then be reduced to the corresponding iminium using triethylsilane, a cheap, rather inert, and commercially available reagent. Imines can be isolated after a basic workup or readily transformed to the aldehydes following an acidic workup. The amine moiety can be accessed via a sequential reductive amination by the addition of silane and Hantzsch ester hydride in a one-pot reaction. Moreover, this reduction tolerates various functional groups that are usually reactive under reductive conditions and is very selective to secondary amides.
- Pelletier, Guillaume,Bechara, William S.,Charette, Andre B.
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supporting information; experimental part
p. 12817 - 12819
(2010/11/05)
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- Selective 5-hydroxytryptamine 2c receptor agonists derived from the lead compound tranylcypromine: Identification of drugs with antidepressant-like action
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We report here the design, synthesis, and pharmacological properties of a series of compounds related to tranylcypromine (9), which itself was discovered as a lead compound in a high-throughput screening campaign. Starting from 9, which shows modest activity as a 5-HT2C agonist, a series of 1-aminomethyl-2- phenylcyclopropanes was investigated as 5-HT2C agonists through iterative structural modifications. Key pharmacophore feature of this new class of ligands is a 2-aminomethyl-trans-cyclopropyl side chain attached to a substituted be zene ring. Among the tested compounds, several were potent and efficacious 5-HT2C receptor agonists with selectivity over both 5-HT2A and 5-HT2B receptors in functional assays. The most promising compound is 37, with 120- and 14-fold selectivity over 5-HT 2A and 5-HT2B, respectively (EC50) 585, 65, and 4.8 nM at the 2A, 2B, and 2C subtypes, respectively). In animal studies, compound 37 (10-60 mg/kg) decreased immobility time in the mouse forced swim test.
- Sung, Jin Cho,Jensen, Niels H.,Kurome, Toru,Kadari, Sudhakar,Manzano, Michael L.,Malberg, Jessica E.,Caldarone, Barbara,Roth, Bryan L.,Kozikowski, Alan P.
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experimental part
p. 1885 - 1902
(2009/12/07)
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- 5-HT2C RECEPTOR AGONISTS AS ANORECTIC AGENTS
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This invention relates to compounds which modulate receptors of the 5-HT2 family of receptors, and particularly to compounds which modulate 5-HT2C receptors. Compounds of the invention include agonists and selective agonists for the 5-HT2C receptor. Compounds of the invention include selective agonists for the 5-HT2C receptor which exhibit significantly less or no agonist activity on the 5-HT2A receptor and/or the 5-HT2B receptor. Compounds of this invention are those of Formula I and pharmaceutically acceptable salts, esters and solvates (including hydrates) wherein variables are defined in the specification hereof.
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Page/Page column 35; 72-73
(2008/06/13)
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- 3-(4-Aroyl-1-methyl-1H-2-pyrrolyl)-N-hydroxy-2-propenamides as a New Class of Synthetic Histone Deacetylase Inhibitors. 2. Effect of Pyrrole-C2 and/or -C4 Substitutions on Biological Activity
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Previous SAR studies (Part 1: Mai, A.; et al. J. Med. Chem. 2003, 46, 512-524) performed on some portions (pyrrole-C4, pyrrole-N 1, and hydroxamate group) of 3-(4-benzoyl-1-methyl-1H-pyrrol-2-yl)-N-hydroxy-2-propenamide (1a) highlighted its 4-phenylacetyl (1b) and 4-cynnamoyl (1c) analogues as more potent compounds in inhibiting maize HD2 activity in vitro. In the present paper, we investigated the effect on anti-HD2 activity of chemical substitutions performed on the pyrrole-C2 ethene chains of 1a-c, which were replaced with methylene, ethylene, substituted ethene, and 1,3-butadiene chains (compounds 2). Biological results clearly indicated the unsubstituted ethene chain as the best structural motif to get the highest HDAC inhibitory activity, the sole exception to this rule being the introduction of the 1,3-butadienyl moiety into the 1a chemical structure (IC50(2f) = 0.77 μM; IC 50(1a) = 3.8 μM). IC50 values of compounds 3, prepared as 1b homologues, revealed that between benzene and carbonyl groups at the pyrrole-C4 position a hydrocarbon spacer length ranging from two to five methylenes is well accepted by the APHA template, being that 3a (two methylenes) and 3d (five methylenes) are more potent (2.3- and 1.4-fold, respectively) than 1b, while the introduction of a higher number of methylene units (see 3e,f) decreased the inhibitory activities of the derivatives. Particularly, 3a (IC50 = 0.043 μM) showed the same potency as SAHA in inhibiting HD2 in vitro, and it was 3000- and 2.6-fold more potent than sodium valproate and HC-toxin and was 4.3- and 6-fold less potent than trapoxin and TSA, respectively. Finally, conformationally constrained forms of 1b,c (compounds 4), prepared with the aim to obtain some information potentially useful for a future 3D-QSAR study, showed the same (4a,b) or higher (4c,d) HD2 inhibiting activities in comparison with those of the reference drugs. Molecular modeling and docking calculations on the designed compounds performed in parallel with the chemistry work fully supported the synthetic effort and gave insights into the binding mode of the more flexible APHA derivatives (i.e., 3a). Despite the difference of potency between 1b and 3a in the enzyme assay, the two APHA derivatives showed similar antiproliferative and cytodifferentiating activities in vivo on Friends MEL cells, being that 3a is more potent than 1b in the differentiation assay only at the highest tested dose (48 μM).
- Mai, Antonello,Massa, Silvio,Cerbara, Ilaria,Valente, Sergio,Ragno, Rino,Bottoni, Patrizia,Scatena, Roberto,Loidl, Peter,Brosch, Gerald
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p. 1098 - 1109
(2007/10/03)
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- Novel non-peptidic neuropeptide Y Y2 receptor antagonists
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Through SAR studies of a piperidinylindoline cinnamide HTS lead, the first potent, non-peptide, low molecular weight selective Neuropeptide Y Y 2 (NPY Y2) antagonists have been synthesized. The SAR studies around the piperidinyl, the indolinyl, and the cinnamyl moieties are discussed.
- Jablonowski, Jill A.,Chai, Wenying,Li, Xiaobing,Rudolph, Dale A.,Murray, William V.,Youngman, Mark A.,Dax, Scott L.,Nepomuceno, Diane,Bonaventure, Pascal,Lovenberg, Timothy W.,Carruthers, Nicholas I.
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p. 1239 - 1242
(2007/10/03)
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- Hypersensitive mechanistic probe studies of cytochrome P450-catalyzed hydroxylation reactions. Implications for the cationic pathway
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Details of the mechanism of cytochrome P450-catalyzed hydroxylation reactions were investigated by oxidation of trans-2-phenyl-1- alkylcyclopropanes (alkyl = methyl (1), ethyl (2), 1-propyl (3), 1- methylethyl (4)) and trans-2-(4-(trifluoromethyl)phenyl)-1-alkylcyclopropanes (alkyl = methyl (5), ethyl (6)). The syntheses of 3 and 6 and their possible oxidation products are reported. Oxidation of the probes with the cytochrome P450 isozyme CYP2B1 gave unrearranged cyclopropylcarbinols as major products and small amounts of ring-opened alcohol products in all cases except for 4. Phenolic products also were produced from substrates 1-4. The maximum lifetimes of putative radical intermediates were less than 1 ps, and the results with substrate 4 require that no intermediate was formed. The results were analyzed in the context of recent mechanistic proposals for cytochrome P450-catalyzed hydroxylations. Oxidation of a 'radical' component in the transition state of an insertion reaction to produce a cation is inconsistent with the results. The results also provide little support for a new alternative mechanism for hydroxylation, the agostic complex model (Collman, J.P.; Chien, A. S.; Eberspacher, T. A.; Brauman, J. I. J. Am. Chem. Soc. 1998, 120, 425). Formation of 'cationic' rearrangement products via solvolysis of first-formed protonated alcohol products produced by insertion of the 'OH+' moiety from iron-complexed hydrogen peroxide also is not supported by the results. The most consistent mechanistic description is the recently reported multistate reactivity paradigm (Shaik, S.; Filatov, M.; Schroder, D.; Schwarz, H. Chem. Eur. J. 1998, 4, 193).
- Toy, Patrick H.,Newcomb, Martin,Hollenberg, Paul F.
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p. 7719 - 7729
(2007/10/03)
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- Picosecond radical kinetics. Ring openings of phenyl substituted cyclopropylcarbinyl radicals
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Rate constants for ring openings of the trans-(2-phenylcyclopropyl)carbinyl radical (1a), the cis-(2-phenylcyclopropyl)carbinyl radical (1b), and the (2,2-diphenylcyclopropyl)carbinyl radical (1c) were studied by competition kinetics using PTOC esters as radical precursors and hydrogen atom transfer trapping from benzeneselenol as the basis reaction. Radical la was studied in two solvents, toluene and THF; the experimental Arrhenius function for ring opening of 1a was log (kr·s) = 13.9 - 33/2.3RT (R in kcal/mol). It is possible that the immediate precursor to 1a, acyloxy radical 3a, suffers a concomitant decarboxylation-ring opening process that competes with simple decarboxylation leading to 1a. The experimental rate constant for ring opening of la at 25°C is 3 × 1011 s-1. Preliminary kinetic studies of radicals 1b and 1c gave Arrhenius functions of log (kr·s) = 13.9 - 3.1/2.3RT and log (kr·s) = 13.1 - 2.0/2.3RT, respectively, and the respective rate constants for ring openings at 25°C are 4 and 5 × 1011 s-1. Rate constants for ring openings of substituted cyclopropylcarbinyl radicals were estimated by Marcus theory using the known rate constants and equilibrium constant for the parent system and expected ΔG° values for the substituted systems. From these results, the estimated rate constants at 25°C for ring opening of 1a and 1b were 1 × 1011 s-1 and that for le was 4 × 1011 s-1. Precursors to radicals 1, such as the corresponding hydrocarbons, represent hypersensitive radical probes that, in principle, can provide unequivocal conclusions regarding the intermediacy of a radical in a reaction.
- Newcomb, Martin,Johnson, Cathy C.,Manek, M. Beata,Varick, Thomas R.
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p. 10915 - 10921
(2007/10/02)
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- VIBRATIONAL CIRCULAR DICHROISM OF OPTICALLY ACTIVE CYCLOPROPANES. 3. TRANS-2-PHENYLCYCLOPROPANECARBOXYLIC ACID DERIVATIVES AND RELATED COMPOUNDS
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Vibrational circular dichroism (VCD) data are presented for a series of (1R,2R)-trans-2-phenyl-1-(R-substituted)cyclopropanes where R=COOCH3, COOCD3, COOH, CONH2, COCl, CN, CH2OH, CD2OD, CH3, CD3, and NH2 (1S,2R).In addition, VCD for (1S,2S)-1-phenylpropylene oxide is presented for comparison.These data can be correlated to show certain characteristic, structure-indicating transitions common to all of the molecules.This is particularly true in the cyclopropane C-H stretching bands in the near-IR and less so of CH2 deformations and ring modes in the mid-IR.To elucidate these comparisons it is necessary to interpret the frerquency shifts of the characteristic bands as the substituent is varied.The range of compounds studied permits such an analysis for certain characteristic modes.The results for monocarbonyl and-cyano substitution further explain the presence and absence, respectively, of coupled oscillator VCD in the corresponding symmetrically disubstituted cyclopropyl compounds.
- Yasui, Sritana C.,Keiderling, Timothy A.
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p. 2311 - 2320
(2007/10/02)
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- Generation and Reactions of Lithiated tert-Butyl and 2,6-Di(tert-butyl)-4-methylphenyl Cyclopropanecarboxylates
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tert-Butyl and 2,6-di(tert-butyl)-4-methylphenyl (BHT) cyclopropanecarboxylates (4, 6, 24, 25) are lithiated with LiN(i-Pr)2 and t-BuLi, respectively.Reactions with alkyl halides, aldehydes, acyl chlorides, and heteroelectrophiles give α-substituted BHT esters which can be cleaved (t-BuOK/H2O/THF) to the corresponding carboxylic acids or reduced (LiAlH4/THF) to the cyclopropanemethanols.
- Haener, Robert,Maetzke, Thomas,Seebach, Dieter
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p. 1655 - 1665
(2007/10/02)
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