- Br?nsted acid catalysed chemo- andortho-selective aminomethylation of phenol
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We have developed a Br?nsted acid catalysed highlyortho-selective functionalization of free phenols with readily availableN,O-acetals under mild conditions, furnishing various corresponding aminomethylated phenol products in moderate to excellent yields. The salient features of this transformation include mild conditions, good substrate scope, excellentortho-selectivity, high efficiency, and ease of further transformation.
- Li, Dongdong,Liu, Lu,Peng, Dan,Tang, Zhiqiong,Yue, Yidi
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supporting information
p. 5777 - 5781
(2021/07/12)
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- Ruthenium-Catalyzed Aminomethylation and Methylation of Phenol Derivatives Utilizing Methanol as the C1 Source
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A reaction involving ortho-aminomethylation of phenol was developed via ruthenium-catalyzed dehydrogenation of methanol, an environmentally benign C1 building block, without the use of reactive reagents. The reaction was successfully applied to a range of substrates. When naphthol was employed instead of phenol, only methylation was observed. On the basis of various mechanistic studies, we propose that formamide barely participates in the reaction, which mainly occurs through an iminium cation intermediate. The difference in the reactivities of phenol and naphthol is attributable to stronger basicity of naphtholate as a conjugate base owing to its lower aromaticity. Plausible reaction pathways were proposed for both reactions. (Figure presented.).
- Kim, Seoksun,Hong, Soon Hyeok
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p. 798 - 810
(2017/03/11)
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- Novel bis-arylalkylamines as myeloperoxidase inhibitors: Design, synthesis, and structure-activity relationship study
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Human myeloperoxidase (MPO) plays an important role in innate immunity but also aggravates tissue damage by oxidation of biomolecules at sites of inflammation. As a result from a recent high-throughput virtual screening approach for MPO inhibitors, bis-2,2′-[(dihydro-1,3(2H,4H) pyrimidinediyl)bis(methylene)]phenol was detected as a promising lead compound for inhibition of the MPO-typical two-electron oxidation of chloride to hypochlorous acid (IC50= 0.5 μM). In the present pharmacomodulation study, 37 derivatives of this lead compound were designed and synthesized driven by comprehensive docking studies and the impact on the chlorination activity of MPO. We describe the structural requirements for optimum (i) binding to the heme periphery and (ii) inhibition capacity. Finally, the best three inhibitors (bis-arylalkylamine derivatives) were probed for interaction with the MPO redox intermediates Compound I and Compound II. Determined apparent bimolecular rate constants together with determination of reduction potential and nucleophilicity of the selected compounds allowed us to propose a mechanism of inhibition. The best inhibitor was found to promote the accumulation of inactive form of MPO-Compound II and has IC50= 54 nM, demonstrating the successful approach of the drug design. Due to the similarity of ligand interactions between MPO and serotonine transporter, the selectivity of this inhibitor was also tested on the serotonin transporter providing a selectivity index of 14 (KiSERT/IC50MPO).
- Aldib, Iyas,Gelbcke, Michel,Soubhye, Jalal,Prévost, Martine,Furtmüller, Paul G.,Obinger, Christian,Elfving, Betina,Alard, Ibaa Chikh,Roos, Goedele,Delporte, Cédric,Berger, Gilles,Dufour, Damien,Zouaoui Boudjeltia, Karim,Nève, Jean,Dufrasne, Francois,Van Antwerpen, Pierre
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supporting information
p. 746 - 762
(2016/08/18)
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- Copper(I)-catalyzed coupling reaction of aryl boronic acids with N,O-acetals and N,N-aminals under atmosphere leading to α-aryl glycine derivatives and diarylmethylamine derivatives
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We demonstrated a copper(I)-catalyzed coupling reaction of aryl boronic acids with N,O-acetals and N,N-aminals leading to the synthesis of α-aryl glycines and diarylmethylamines. Under an ambient atmosphere, this catalytic system could be applied to the activation of a C(sp3)-O bond of N,O-acetals with an ester and an aryl group, or without a coordinating substituent, as well as to a C(sp3)-N bond of N,N-aminals.
- Sakai, Norio,Hori, Hiroaki,Yoshida, Yoshihiro,Konakahara, Takeo,Ogiwara, Yohei
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p. 4722 - 4729
(2015/07/27)
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- Syntheses and in Vitro Antiplasmodial Activity of Aminoalkylated Chalcones and Analogues
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(Chemical Equqation Presented). A series of readily synthesized and inexpensive aminoalkylated chalcones and diarylpropane analogues (1-55) were synthesized and tested against chloroquinone-sensitive (D10 and NF54) and -resistant (Dd2 and K1) strains of Plasmodium falciparum. Hydrogenation of the enone to a diarylpropane moiety increased antiplasmodial bioactivity significantly. The influence of the structure of the amine moiety, A-ring substituents, propyl vs ethyl linker, and chloride salt formation on further enhancing antiplasmodial activity was investigated. Several compounds have IC50 values similar to or better than chloroquine (CQ). The most active compound (26) had an IC50 value of 0.01 μM. No signs of resistance were detected, as can be expected from compounds with structures unrelated to CQ and other currently used antimalarial drugs. Toxicity tests (in vitro CHO cell assay) gave high SI indices.
- Wilhelm, Anke,Kendrekar, Pravin,Noreljaleel, Anwar E. M.,Abay, Efrem T.,Bonnet, Susan L.,Wiesner, Lubbe,De Kock, Carmen,Swart, Kenneth J.,Van Der Westhuizen, Jan Hendrik
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supporting information
p. 1848 - 1858
(2015/09/08)
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- Highly efficient and eco-friendly synthesis of tertiary amines by reductive alkylation of aldehydes with secondary amines over a Pt nanowires catalyst
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Plentiful tertiary amine derivates are synthesized by direct formation of tertiary amines by the interaction of aldehydes with secondary amines over Pt nanowires under mild conditions. This method offers a green and rapid approach to transform secondary amines into various tertiary amines.
- Wu, Junjie,Lu, Shuanglong,Ge, Danhua,Gu, Hongwei
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p. 81395 - 81398
(2015/10/06)
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- Structural and medium effects on the reactions of the cumyloxyl radical with intramolecular hydrogen bonded phenols. the interplay between hydrogen-bonding and acid-base interactions on the hydrogen atom transfer reactivity and selectivity
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A time-resolved kinetic study on the reactions of the cumyloxyl radical (CumO?) with intramolecularly hydrogen bonded 2-(1-piperidinylmethyl)phenol (1) and 4-methoxy-2-(1-piperidinylmethyl)phenol (2) and with 4-methoxy-3-(1-piperidinylmethyl)phenol (3) has been carried out. In acetonitrile, intramolecular hydrogen bonding protects the phenolic O-H of 1 and 2 from attack by CumO? and hydrogen atom transfer (HAT) exclusively occurs from the C-H bonds that are α to the piperidine nitrogen (α-C-H bonds). With 3 HAT from both the phenolic O-H and the α-C-H bonds is observed. In the presence of TFA or Mg(ClO 4)2, protonation or Mg2+ complexation of the piperidine nitrogen removes the intramolecular hydrogen bond in 1 and 2 and strongly deactivates the α-C-H bonds of the three substrates. Under these conditions, HAT to CumO? exclusively occurs from the phenolic O-H group of 1-3. These results clearly show that in these systems the interplay between intramolecular hydrogen bonding and Br?nsted and Lewis acid-base interactions can drastically influence both the HAT reactivity and selectivity. The possible implications of these findings are discussed in the framework of the important role played by tyrosyl radicals in biological systems.
- Salamone, Michela,Amorati, Riccardo,Menichetti, Stefano,Viglianisi, Caterina,Bietti, Massimo
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p. 6196 - 6205
(2014/07/21)
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- Divergent reaction: Metal & oxidant free direct C-H aryloxylation and hydride free formal reductive N-benzylation of N-heterocycles
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Metal, oxidant and other additive-free novel methods for direct C-H aryloxylation of aliphatic amines are developed. In the presence of excess amine, the course of the reaction was diverted, producing various arylmethylamines via hydride-free formal reductive amination. Involvement of a quinone methide intermediate was revealed from mechanistic studies. This journal is
- Mahato, Sujit,Haque, Md Ashraful,Dwari, Soumita,Jana, Chandan K.
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p. 46214 - 46217
(2015/02/19)
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- Aerobic oxidative heck/dehydrogenation reactions of cyclohexenones: Efficient access to meta-substituted phenols
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Jockeying for the (meta)position: A new dicationic palladium(II) catalyst, employing a 6,6′-dimethyl-2,2′-bipyridine ligand, promotes both the aerobic oxidative Heck coupling and dehydrogenation reactions of cyclohexenones. These reactions may be combined in a one-pot sequence to enable the straightforward synthesis of meta-substituted phenols (see scheme). Copyright
- Izawa, Yusuke,Zheng, Changwu,Stahl, Shannon S.
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supporting information
p. 3672 - 3675
(2013/04/23)
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- Anionic ortho-fries rearrangement, a facile route to arenol-based mannich bases
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Phenol and 1-naphthol-based carbamates undergo the anionic ortho-Fries rearrangement to their corresponding amides. Bulky substitution at position 8 of 1-naphthol-based carbamates makes the rearrangement an exclusive reaction, even at -90 C, under a variety of conditions. The amides can be efficiently reduced to the corresponding Mannich bases. A novel route to 7-[(dialkylamino)methyl]-8- hydroxy-1-naphthaldehydes is presented.
- Assimomytis, Nikos,Sariyannis, Yiannis,Stavropoulos, Georgios,Tsoungas, Petros G.,Varvounis, George,Cordopatis, Paul
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experimental part
p. 2777 - 2782
(2010/03/03)
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- Exploiting tautomerism for switching and signaling
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Good form: Attaching a flexible piperidine unit to 4-(phenyldiazenyl) naphthalen-1-ol allows construction of a tautomeric switch, where directed shift of the tautomeric equilibrium can be achieved through protonation and deprotonation (see picture). The developed molecular switch shows acceptable complexation with small alkali- and alkaline-earth-metal ions and forms a promising base for further development of effective molecular sensors.
- Antonov, Liudmil,Deneva, Vera,Simeonov, Svilen,Kurteva, Vanya,Nedeltcheva, Daniela,Wirz, Jakob
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supporting information; experimental part
p. 7875 - 7878
(2010/04/06)
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- Regioselective mannich reaction of phenols under high pressure using dichloromethane as C1 unit
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Regioselectivity in Mannich reaction of 4-, 3-, and 2-substituted phenols with typical heterocyclic amines are investigated under reaction conditions developed by us. Phenol and 4-alkyl, and 4-chlorophenols in the title reaction predominantly gave the corresponding 2-(aminomethyl)phenols, while 4-methoxyphenol afforded, in addition to the mono(aminomethyl)phenols, a considerable amount of the bis adducts. Peculiarly enough, 3-methylphenol with amines afforded 3-methyl-4-(aminomethyl)phenols whereas 2-methylphenol produced 2-methyl-6-(aminomethyl)phenols.
- Matsumoto, Kiyoshi,Joho, Kouta,Mimori, Seisuke,Iida, Hirokazu,Hamana, Hiroshi,Kakehi, Akikazu
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scheme or table
p. 1061 - 1067
(2009/06/28)
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- Synthesis and cholinesterase activity of phenylcarbamates related to Rivastigmine, a therapeutic agent for Alzheimer's disease
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In order to develop new cholinesterase agents effective against Alzheimer's disease (AD) we synthesized some phenylcarbamates structurally related to Rivastigmine and evaluated their in vitro and in vivo biological activity. Among the compounds which displayed the most significant in vitro activity, 1-[1-(3-dimethylcarbamoyloxyphenyl)ethyl]piperidine (31b), in addition to a simple and cheaper synthesis, showed lower toxicity and very similar therapeutic index in comparison with Rivastigmine.
- Mustazza, Carlo,Borioni, Anna,Giudice, Maria Rosaria Del,Gatta, Franco,Ferretti, Rosella,Meneguz, Annarita,Volpe, Maria Teresa,Lorenzini, Paola
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- Alkylation of amino acids and glutathione in water by o-Quinone methide. Reactivity and selectivity
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o-Quinone methide (1) has been produced in water both thermally and photochemically from (2-hydroxybenzyl)trimethylammonium iodide (2). Michael addition reactions of 1 to various amines, and sulfides, including amino acids and glutathione have been carried out, obtaining alkylated adducts (3-16) in fairly good to quantitative yields. The reaction rate and selectivity of 1 toward nitrogen and sulfur nucleophiles, in competition with the hydration reaction, have been investigated at different pH by laser flash photolysis technique. The observed reactivity spans 7 orders of magnitude on passing from water (kNu = 5.8 M-1 s-1) to the most reactive nucleophile (2.8 × 108 M-1 s-1, 2-mercaptoethanol under alkaline conditions). These are the first direct reaction rate measurements of nucleophilic addition to the parent o-quinone methide (1). Competition experiments provided strong kinetic support to the involvement of free 1 as an intermediate in both thermal and photochemical reactions. Furthermore, several alkylation adducts regenerate 1 either by heating (9, 10, 13, and 14) or by irradiation (9, 11-13, 16). Such a thermal and photochemical reversibility of the alkylation process opens a new perspective for the use and application of such adducts as o-QM molecular carriers.
- Modica,Zanaletti,Freccero,Mella
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- The activation of aminals and aminol ethers by sulfur dioxide and their reactions with electron rich aromatic compounds
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Reactions of bis(dialkylamino)methanes and ethoxydialkylaminomethanes with nucleophilic aromatic heterocycles in the presence of sulfur dioxide result in the formation of the expected Mannich bases in good yields. Reactions of phenols are similarly activated by sulfur dioxide which lead to improved regioselectivity: in particular the reactions of 2,5-dimethylphenol result in the formation of 2-dialkylaminomethyl-3,6-dimethylphenol whereas reaction occurs at the I-position using the classical procedures.
- Heaney, Harry,Papageorgiou, George,Wilkins, Robert F.
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p. 13361 - 13372
(2007/10/03)
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- PREPARATION AND PROPERTIES OF 2-(DIALKYLAMINOMETHYL)CYCLOHEXYL AND 2-(DIALKYLAMINOMETHYL)PHENYL CARBANILATES
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A series of 2-(dialkylaminomethyl)cyclohexyl and 2-(dialkylaminomethyl)phenyl esters of substituted carbanilic acid have been prepared and their identity verified by elemental analysis and evaluation of IR and 13C NMR spectra.The spectral results have bee
- Bradlerova, Alena,Pronayova, Nadezda,Misikova, Eva,Durinda, Jan
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p. 1854 - 1865
(2007/10/02)
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- THE EFFECT OF SULPHUR DIOXIDE ON THE MANNICH REACTIONS OF PHENOLS
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Regioselectivity in the ortho-dialkylaminomethylation of phenols in greatest, for example in reactions of 2,5-dimethylphenol, when a mixture of the phenol and sulphur dioxide is allowed to stand for several hours before the addition of a bis-(dialkylamino)methane (aminal) or an alkoxydialkylaminomethane (aminol ether).
- Fairhurst, Robin A.,Heaney, Harry,Papageorgiou, George,Wilkins, Robert F.
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p. 5801 - 5804
(2007/10/02)
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- Alkyl- and alkoxy-substituted lamtidine analogues: Synthesis and H2-antagonistic activity. 38th Communication: H2-antihistaminics
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In studies on the structure-activity relationships of histamine H2-receptor antagonists, lamtidine analogous derivatives of ortho-, meta- and para-substituted piperidinomethylphenoxypropylamines bearing an additional substituent on the aromatic
- Bonjean,Schunack
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p. 501 - 507
(2007/10/02)
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- New Mannich Base Ligands
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A series of low-molecular-weight aminomethylphenol compounds have been synthesized as model analogues of new Cu2+ and Fe3+ chelating polymers.Preliminary colour tests with these two ions were used to indicate the structural features
- Hodgkin, Jonathan H.
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p. 2371 - 2378
(2007/10/02)
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