- Photoredox-catalysed regioselective synthesis of C-4-alkylated pyridines with N -(acyloxy)phthalimides
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A method of direct C-4 selective alkylation of pyridines under visible light irradiation at room temperature has been reported, using simple maleate-derived pyridinium salts as pyridine precursors and the readily available carboxylic acid-derived N-(acyloxy)phthalimides as alkyl radical precursors, affording good to excellent yields without using stoichiometric oxidants and acids. A broad range of primary, secondary, and tertiary carboxylates can be used as alkylation reagents. Oxidant and acid-sensitive functional groups can be tolerated well. This journal is
- He, Qian,Yang, Chunhao,Zhang, Xiaofei,Zhang, Zhucheng
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supporting information
p. 1969 - 1973
(2022/03/15)
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- Practical and Regioselective Synthesis of C-4-Alkylated Pyridines
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The direct position-selective C-4 alkylation of pyridines has been a long-standing challenge in heterocyclic chemistry, particularly from pyridine itself. Historically this has been addressed using prefunctionalized materials to avoid overalkylation and mixtures of regioisomers. This study reports the invention of a simple maleate-derived blocking group for pyridines that enables exquisite control for Minisci-type decarboxylative alkylation at C-4 that allows for inexpensive access to these valuable building blocks. The method is employed on a variety of different pyridines and carboxylic acid alkyl donors, is operationally simple and scalable, and is applied to access known structures in a rapid and inexpensive fashion. Finally, this work points to an interesting strategic departure for the use of Minisci chemistry at the earliest possible stage (native pyridine) rather than current dogma that almost exclusively employs Minisci chemistry as a late-stage functionalization technique.
- Baran, Phil S.,Choi, Jin,Godineau, Edouard,Laudadio, Gabriele
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p. 11927 - 11933
(2021/08/20)
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- Mechanochemical Magnesium-Mediated Minisci C-H Alkylation of Pyrimidines with Alkyl Bromides and Chlorides
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A novel method to synthesize 4-alkylpyrimidines by the mechanochemical magnesium-mediated Minisci reaction of pyrimidine derivatives and alkyl halides has been reported. The reaction process operates with a broad substrate scope and excellent regioselectivity under mild conditions with no requirement of transition-metal catalysts, solvents, and inert gas protection. The practicality of this protocol has been demonstrated by the up-scale synthesis, mechanochemical product derivatization, and antimalarial drug pyrimethamine preparation.
- Wu, Chongyang,Ying, Tao,Yang, Xinjie,Su, Weike,Dushkin, Alexandr V.,Yu, Jingbo
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supporting information
p. 6423 - 6428
(2021/08/30)
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- Heterogeneously palladium-catalyzed acceptorless dehydrogenative aromatization of cyclic amines
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In this manuscript, we report an efficient heterogeneously catalyzed acceptorless dehydrogenative aromatization of cyclic amines under relatively mild conditions. In the presence of a supported catalyst Pd/LDH (LDH = layered double hydroxide), various kinds of structurally diverse cyclic amines including piperidines, tetrahydro(iso)quinolines, and indolines could be converted into the corresponding heteroarenes. Pd/LDH could be reused several times though its catalytic activity gradually declined due to the increase in the palladium particle size.
- Oyama, Takashi,Yatabe, Takafumi,Jin, Xiongjie,Mizuno, Noritaka,Yamaguchi, Kazuya
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supporting information
p. 517 - 520
(2019/06/11)
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- Synthesis of a Series of Structurally Diverse MB327 Derivatives and Their Affinity Characterization at the Nicotinic Acetylcholine Receptor
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A novel series of 30 symmetric bispyridinium and related N-heteroaromatic bisquaternary salts with a propane-1,3-diyl linker was synthesized and characterized for their binding affinity at the MB327 binding site of nicotinic acetylcholine receptor (nAChR) from Torpedo californica. Compounds targeting this binding site are of particular interest for research into new antidotes against organophosphate poisoning, as therapeutically active 4-tert-butyl-substituted bispyridinium salt MB327 was previously identified as a nAChR re-sensitizer. Efficient access to the target compounds was provided by newly developed methods enabling N-alkylation of sterically hindered or electronically deactivated heterocycles exhibiting a wide variety of functional groups. Determination of binding affinities toward the MB327 binding site at the nAChR, using a recently developed mass spectrometry (MS)-based Binding Assay, revealed that several compounds reached affinities similar to that of MB327 (pKi=4.73±0.03). Notably, the newly prepared lipophilic 4-tert-butyl-3-phenyl-substituted bispyridinium salt PTM0022 (3 h) was found to have significantly higher binding affinity, with a pKi value of 5.16±0.07, thus representing considerable progress toward the development of more potent nAChR re-sensitizers.
- Rappenglück, Sebastian,Sichler, Sonja,H?fner, Georg,Wein, Thomas,Niessen, Karin V.,Seeger, Thomas,Paintner, Franz F.,Worek, Franz,Thiermann, Horst,Wanner, Klaus T.
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supporting information
p. 1806 - 1816
(2018/09/11)
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- Bis(phosphine)cobalt dialkyl complexes for directed catalytic alkene hydrogenation
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Planar, low-spin cobalt(II) dialkyl complexes bearing bidentate phosphine ligands, (P - P)Co-(CH2SiMe3)2, are active for the hydrogenation of geminal and 1,2-disubstituted alkenes. Hydrogenation of more hindered internal and endocyclic trisubstituted alkenes was achieved through hydroxyl group activation, an approach that also enables directed hydrogenations to yield contrasteric isomers of cyclic alkanes.
- Friedfeld, Max R.,Margulieux, Grant W.,Schaefer, Brian A.,Chirik, Paul J.
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supporting information
p. 13178 - 13181
(2015/03/30)
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- The role of ion/neutral complexes in the fragmentation of N-benzyl-(alkylpyridinium) ions
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N-Benzylpyridinium ions bearing an alkyl group at the pyridine nucleus were studied as potential precursors of gaseous ion/neutral complexes. The occurrence of I/N complexes [C6H5CH2 + ? alkylpyridine] was probed by the reactivity of the potential benzylic hydride donor sites present in the ortho-, meta- and para-alkyl groups (R = methyl, ethyl, isopropyl and benzyl). Collision-induced dissociation of the ions, carried out in an electrical ion cage mass spectrometer, revealed that hydride transfer strongly depends both on the energy requirements of the hydride transfer but also on the position of the hydride donor. Hydride transfer, giving rise to the loss of toluene, was found to occur exclusively with those N-benzylpyridinium ions which bear an isopropyl or a benzyl substituent in the ortho position of the pyridine ring, thus reflecting the intermediacy of I/N complexes. All of the putative hydride donor alkyl groups were found to be non-reactive in the meta and para positions, as were methyl and ethyl groups even in the ortho positions. Density functional calculations (B3LYP/6-311+G/3d,2p)//(B3LYP/6-31+G(d)) on the hydride-transfer and simple-cleavage channels were carried out to help rationalizing these observations. The results suggest that the intra-complex hydride abstraction from the 3- and 4-isopropyl- and from the 3- and 4-benzylpyridine neutrals, although being thermodynamically favorable, is suppressed by substantial intra-complex rotational (or reorientation) barriers.
- Kuck, Dietmar,Grützmacher, Hans-Friedrich,Barth, Dieter,Heitkamp, Sandra,Letzel, Matthias C.
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body text
p. 159 - 166
(2012/07/13)
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- (3-HYDROXY-4-AMINO-BUTAN-2-YL) -3- (2-THIAZOL-2-YL-PYRROLIDINE-1-CARBONYL) BENZAMIDE DERIVATIVES AND RELATED COMPOUNDS AS BETA-SECRETASE INHIBITORS FOR TREATING
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The present invention provides novel beta-secretase inhibitors and methods for their use, including methods of treating of Alzheimer's disease. (Formula)
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Page/Page column 67
(2009/05/29)
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- Bis(trimethylsilyl)ketene acetals as C,O-dinucleophiles: One-pot formation of polycyclic γ- and δ-lactones from pyridines and pyrazines
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Bis(trimethylsilyl)ketene acetals react with pyridines, quinoline and isoquinoline in the presence of stoichiometric amounts of methyl chloroformate to give the corresponding dihydropyridine-, dihydroquinoline- and dihydroisoquinoline-substituted carboxylic acids in satisfactory yields. The regio- and diastereoselectivities of the addition reactions, together with the presence or absence of rotamers, have been established. The isolated acids react with peracids to give β-hydroxy-δ-lactones through an intramolecular reaction. Similar lactonizations could also be brought about directly from the azaaromatic compounds in one-pot reactions with silica gel, iodine or bromine. In these cases δ-lactones or β-halo-δ-lactones were produced. The behaviour of pyrazines in these transformations is peculiar, since methyl chloroformate on its own induces the formation, through interaction with both nitrogen atoms, of polycyclic γ-lactones, a reaction formally reminiscent of the double nucleophilic addition of the same ketene acetals to (arene)tricarbonylchromium complexes. Most of the new structures were assigned through X-ray crystal structure determinations. Wiley-VCH Verlag GmbH & Co. KGaA, 2005.
- Rudler, Henri,Denise, Bernard,Xu, Yiming,Parlier, Andree,Vaissermann, Jacqueline
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p. 3724 - 3744
(2007/10/03)
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- Alkylpyridines transformations over acidic catalysts. An example of radical reactions on ionic surfaces
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4-Methyl-, 4-ethyl-, and 4-isopropylpyridine, ethyl-, and isopropylbenzene transformations were studied over the series of amorphous silica-aluminas. The main reactions of alkylpyridines were the transformations of the alkyl side chain. The crucial role of one-electron donor (radical) centres in the mentioned reactions was evidenced by the physicochemical characterization of the catalyst surfaces, the apparent correlation of activity vs. active centres concentration, and the dependence of product composition upon reaction conditions.
- Kijenski,Malinowski,Kowalczyk,Osawaru
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p. 719 - 736
(2007/10/03)
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- Substituent Effects on the CC Bond Strength, 18. - Stabilization of Alkyl Radicals by 4-Pyridyl, 1-Naphthyl or 2-Naphthyl Substituents in α-Position
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The formation of the α-substituted radicals 7-9 with the 4-pyridyl (7), 1-naphthyl (8), and the 2-naphthyl (9) substituent by thermolysis of their dimers 1-3 in solution was investigated.The activation parameters of the homolysis of the central CC bond were obtained from kinetic measurements of the thermal cleavage of 1-3 in the presence of radical scavengers.These data were compared with those obtained from the thermolysis of alkanes which cleave into α-alkyl branched radicals, and which lose the same amount of strain during the dissociation.The "strain-free" radical stabilization enthalpies of the α-substituted radicals were obtained in this way. - Key Words: Bond cleavage, C-C, kinetics of / Radicals, stability of
- Herberg, Clemens,Peyman, Anuschirwan,Noelke, Margot,Beckhaus, Hans-Dieter,Ruechardt, Christoph
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p. 881 - 884
(2007/10/02)
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- NUCLEOPHILIC CATALYSIS OF THE AMINOLYSIS OF ACTIVATED VINYL HALIDES BY ORGANIC BASES
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The existence of nucleophilic catalysis in the aminolysis of activated vinyl halides has been revealed.The limits and conditions of catalysis have been established from the results of a stepwise investigation of the kinetics of the processes occurring (the rate is limited by the formation or consumption of the intermediate vinylammonium salt).The nucleophilic catalysts studied form the following series in the efficiency of their action in SNVin-substitution involving amines in acetonitrile: 4-isopropylpyridine > pyridine > trimethylamine > 4-N,N-dimethylaminopyridine N-oxide > N-methylimidazole > N-methylpiperidine.
- Kravchenko, V. V.,Popov, A. F.,Kotenko, A. A.
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p. 1601 - 1605
(2007/10/02)
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- Alkylation of Pyridine in Free Radical Chain Reactions Utilizing Alkylmercurials
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Pyridines or N,N,N',N'-tetramethyl-p-phenylenediamine will undergo a photostimulated free radical chain reaction with alkylmercury halides or carboxylates, yielding ring alkylated substitution products.Alkene mercuration products (R1CH(Y)CH(R2)HgX with Y=HO, RO, CH3CONH; X=Cl, CH3CO2, CF3CO2) can be used without isolation for the alkylation reaction
- Russell, Glen A.,Guo, Deliang,Khanna, Rajive K.
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p. 3423 - 3425
(2007/10/02)
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- NMR Studies of Picolyl-type Carbanions. VIII. Anions Produced by Reactions of Alkyl-substituted Pyridines with Butyllithium
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The 1H and 13C NMR spectra have been observed for the anions, produced from methyl-, ethyl-, and isopropylpyridines, in tetrahydrofuran (THF).Two kinds of anions are formed concomitantly by lithium-proton exchange and addition of butyllithium from 2-ethyl, 2-isopropyl, 4-methyl, and 4-ethylpyridines.The former reaction tends to occur at the substituent bonded to the position adjacent to nitrogen, and the latter one occurs at the position adjacent to nitrogen without substituent.In the anions formed by the exchange from 2- and 4-ethylpyridines, a specific ring protonis coupled to the α-carbon, and, further, the ortho- or meta-protons (or -carbons) in the latter anion are nonequivalent respectively at room temperature.The α-carbons in these anions are virtually sp2-hybridized.
- Konishi, Kazuyori,Matsumoto, Hiroshi,Saito, Katsuhiro,Takahashi, Kensuke
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p. 2294 - 2297
(2007/10/02)
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- A Convenient Method for the Regioselective Synthesis of 4-Alkyl(aryl)pyridines Using Pyridinium Salts
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RCu.BF3 reacted with 1-ethocycarbonylpyridinium chloride at the 4-position with almost complete regioselectivity (>99percent) to afford the corresponding 1,4-dihydropyridine derivatives in high yields (81-94percent).The dihydropyridines were oxidized by oxygen to give 4-alkyl(aryl)pyridines (38-68percent).Grignard reagents also reacted with 1-t-butyldimethylsilylpyridinium triflate with almost complete regioselectivity (>99percent) to afford the corresponding 1,4-dihydropyridines, which were easily oxidized to give 4-substituted pyridines in higher yields than above (58-70percent).
- Akiba, Kin-ya,Iseki, Yuji,Wada, Makoto
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p. 1994 - 1999
(2007/10/02)
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- Process for recovering oxygenated organic compounds from dilute aqueous solutions employing liquid extraction media
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A thermally efficient process for recovering an oxygenated organic material, such as ethanol, present in dilute aqueous solution is disclosed which comprises contacting said dilute aqueous solution with at least one inert extractant which is liquid at ambient temperature and pressure, said extractant being selected from the group consisting of unsubstituted and substituted cyclic secondary amines and unsubstituted and substituted aromatic cyclic amines having a distribution coefficient of at least about 0.70 or a separation factor of at least about 1.0. The invention further provides a process for obtaining substantially anhydrous oxygenated organic material from a dilute aqueous solution thereof in which the stream is subjected to liquid-liquid extraction to provide an oxygenated organic material poor raffinate phase and an oxygenated organic material rich extract phase, the oxygenated organic material present in said latter phase is concentrated in a rectifying column to provide an aqueous oxygenated organic material of high concentration and, if desired or necessary, the concentrated stream is azeotropically distilled in an anhydrous column operated under substantially superatmospheric pressure with thermal values recovered from said anhydrous column being used to satisfy part of all of the thermal operating requirements of the rectifying column.
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- Process for recovering ethanol from dilute aqueous solutions employing liquid extraction media
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A thermally efficient process for recovering ethanol present in dilute aqueous solution is disclosed which comprises contacting said dilute aqueous ethanol solution with at least one inert extractant which is liquid at ambient temperature and pressure, said extractant being selected from the group consisting of unsubstituted and substituted cyclic secondary amines and unsubstituted and substituted aromatic cyclic amines having a distribution coefficient of at least about 0.70 or a separation factor of at least about 1.0. The invention further provides a process for obtaining substantially anhydrous ethanol from a dilute aqueous ethanol solution in which the ethanol stream is subjected to liquid-liquid extraction to provide an ethanol-poor raffinate phase and an ethanol-rich extract phase, the ethanol present in said latter phase is concentrated in a rectifying column to provide an aqueous ethanol of high proof and the concentrated ethanol is azeotropically distilled in an anhydrous column operated under substantially superatmospheric pressure with thermal values recovered from said anhydrous column being used to satisfy part of all of the thermal operating requirements of the rectifying column.
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- Synthetic Applications of N-N Linked Heterocycles. Part 13. N-(2,5-Dimethylpyrrol-1-yl)pyridinium Salts in the Synthesis of 4-Alkyl and 4-Aryl-pyridines via Regiospecific Attack of Grignard Reagents and Organolithium Compounds.
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The reaction between N-(2,5-dimethylpyrrol-1-yl)pyridinium salts and alkyl- or aryl-Grignard reagents, or organolithium compounds, gives regiospecifically 1,4-dihydro-intermediates.These may be isolated and decomposed under free-radical conditions to give moderate to good yields of 4-alkyl- and 4-aryl-pyridines.Results are compared with those obtained from a related reaction sequence involving N-(2,6-dimethyl-4-oxopyridin-1-yl)pyridinium salts.
- Katritzky, Alan R.,Beltrami, Hector,Sammes, Michael P.
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p. 1684 - 1696
(2007/10/02)
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- Synthetic Applications of N-N Linked Heterocycles. Part 7. The Preparation of 4-Alkyl- and 4-Aryl-pyridines by Regiospecific Attack of Grignard Reagents γ to Quaternary Nitrogen in N-(2,6-Dimethyl-4-oxopyridin-1-yl)pyridinium Salts
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N-(2,6-Dimethyl-4-oxopyridin-1-yl)pyridinium salts (4), new reagents for the regiospecific synthesis of 4-substituted pyridines, give moderate to high yields of 4-alkyl- and 4-aryl-pyridines (8) - (10) on reaction with Grignard reagents.The scope and limitations on the reaction, which proceeds via 1,4-dihydro-intermediates (5) - (7), are explored.No 2-substituted pyridines were detected.Some reactions with organolithium compounds are also described.
- Katritzky, Alan R.,Beltrami, Hector,Sammes, Michael P.
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p. 2480 - 2484
(2007/10/02)
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- Substituted 2,2'-bipyridyl compounds and process for preparing same
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A process for preparing substituted 2,2'-bipyridyl compounds and several compounds so prepared, the process comprising the steps of first selecting a substituted pyridine of the formula defined herein, then mixing a stoichiometric excess of the substituted pyridine with an amount of sodamide, causing the resultant mixture to be at a temperature sufficiently high to cause substituted 2,2'-bipyridyl formation, and isolating the substituted 2,2'-bipyridyl thereby formed. The new substituted 2,2'-bipyridyl compounds are selected from the group consisting of 4,4'-di-(5-nonyl)-2,2'-bipyridyl; 4,4'-di-(3-pentyl)-2,2'-bipyridyl; 6,6'-di-(3-pentyl)-2,2'-bipyridyl; 6,6'-di-(5-nonyl)-2,2'-bipyridyl; 4,4'-di-(cyclohexylmethyl)-2,2'-bipyridyl; 5,5'-di-(5-nonyl)-2,2'-bipyridyl; 4,4'-di-(3-phenylpropyl)-2,2'-bipyridyl; 4,4'-di-(4-tetrahydropyranyl)-2,2'-bipyridyl; 4,4'-di-benzyl-2,2'-bipyridyl; 6,6'-di-isoamyl-2,2'-bipyridyl; and 4,4'-di-(t-butyl)-2,2'-bipyridyl.
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