- A General, Selective, High-Yield N-Demethylation Procedure for Tertiary Amines by Solid Reagents in a Convenient Column Chromatography-like Setup
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(Equation presented) A traditional preparative chromatographic column can be used to achieve quantitative N-demethylation of tertiary N-methylamines and alkaloids. The filling is the crucial part and is loaded with different solid reagents in three reaction zones. The parent compound is charged on the column, and the neat N-demethylated secondary amine leaves the column some minutes later.
- Rosenau, Thomas,Hofinger, Andreas,Potthast, Antje,Kosma, Paul
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- Novel Family of (1-aminoalkyl)(trifluoromethyl)- and -(difluoromethyl) phosphinic Acids - Analogues of α-Amino Acids
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A series of novel (1-aminoalkyl)(trifluoromethyl)- and -(difluoromethyl) phosphinic acids - analogues of proteinogenic and nonproteinogenic α-amino acids were prepared. The synthetic methodology was based on nucleophilic addition of (trifluoromethyl)phosphinic acid or (difluoromethyl)phosphinic acid or its ethyl ester to substrates with C=N or activated C=C double bonds. Analogues of glycine, phenylglycine, alanine, valine, proline, aminomalonic and aspartic acids were thus prepared. Three-component one-pot reactions of (trifluoromethyl)phosphinic acid and dibenzylamine with aldehydes were also tested to prepare the title compounds.
- Pavlenko, Natalia V.,Oos, Tatiana I.,Yagupolskii, Yurii L.,Gerus, Igor I.,Doeller, Uwe,Willms, Lothar
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- Lithium compound catalyzed deoxygenative hydroboration of primary, secondary and tertiary amides
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A selective and efficient route for the deoxygenative reduction of primary to tertiary amides to corresponding amines has been achieved with pinacolborane (HBpin) using simple and readily accessible 2,6-di-tert-butyl phenolate lithium·THF (1a) as a catalyst. Both experimental and DFT studies provide mechanistic insight. This journal is
- Bisai, Milan Kumar,Gour, Kritika,Das, Tamal,Vanka, Kumar,Sen, Sakya S.
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supporting information
p. 2354 - 2358
(2021/03/03)
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- Selenoxide elimination triggers enamine hydrolysis to primary and secondary amines: A combined experimental and theoretical investigation
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We discuss a novel selenium-based reaction mechanism consisting in a selenoxide elimination-triggered enamine hydrolysis. This one-pot model reaction was studied for a set of substrates. Under oxidative conditions, we observed and characterized the formation of primary and secondary amines as elimination products of such compounds, paving the way for a novel strategy to selectively release bioactive molecules. The underlying mechanism was investigated using NMR, mass spectrometry and density functional theory (DFT).
- Bortoli, Marco,Gianoncelli, Alessandra,Ongaro, Alberto,Orian, Laura,Oselladore, Erika,Ribaudo, Giovanni,Zagotto, Giuseppe
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- A practical catalytic reductive amination of carboxylic acids
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We report reductive alkylation reactions of amines using carboxylic acids as nominal electrophiles. The two-step reaction exploits the dual reactivity of phenylsilane and involves a silane-mediated amidation followed by a Zn(OAc)2-catalyzed amide reduction. The reaction is applicable to a wide range of amines and carboxylic acids and has been demonstrated on a large scale (305 mmol of amine). The rate differential between the reduction of tertiary and secondary amide intermediates is exemplified in a convergent synthesis of the antiretroviral medicine maraviroc. Mechanistic studies demonstrate that a residual 0.5 equivalents of carboxylic acid from the amidation step is responsible for the generation of silane reductants with augmented reactivity, which allow secondary amides, previously unreactive in zinc/phenylsilane systems, to be reduced.
- Andrews, Keith G.,Denton, Ross M.,Hirst, David J.,Stoll, Emma L.,Tongue, Thomas,Valette, Damien
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p. 9494 - 9500
(2020/10/02)
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- Computationally forecasting the effect of dibenzylammonium substituents on pseudorotaxane formation with dibenzo[24]crown-8
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The ability to predict the relative stabilities of analogous pseudorotaxanes is essential for the synthetic chemist yet simplified computational forecasting approaches remain scarce. Consequently, ten [2]pseudorotaxanes have been assembled (from a series of para-substituted dibenzylammonium ions and dibenzo[24]crown-8) and their experimentally-determined stabilities correlated with two computational parameters closely related to complexation energy. The strongest relationship was obtained from density functional theory calculation of binding energy (R2 = 0.92) while determination of the maximum surface electrostatic potential on the dibenzylammonium ions (a proxy indicator of complex stability) afforded comparable results (R2 = 0.88) with great reduction in computational expense.
- Payne, Nicholas A.,Delmas, Luke C.,McDowell, Sean A.C.,Williams, Avril R.
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supporting information
p. 5175 - 5179
(2015/08/18)
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- Magnesium-catalyzed mild reduction of tertiary and secondary amides to amines
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The first example of a catalytic hydroboration of amides for their deoxygenation to amines is reported. This transformation employs an earth-abundant magnesium-based catalyst. Tertiary and secondary amides are reduced to amines at room temperature in the presence of pinacolborane (HBpin) and catalytic amounts of ToMMgMe (ToM = tris(4,4-dimethyl-2-oxazolinyl)phenylborate). Catalyst initiation and speciation is complex in this system, as revealed by the effects of concentration and order of addition of the substrate and HBpin in the catalytic experiments. ToMMgH2Bpin, formed from ToMMgMe and HBpin, is ruled out as a possible catalytically relevant species by its reaction with N,N-dimethylbenzamide, which gives Me2NBpin and PhBpin through C-N and C-C bond cleavage pathways, respectively. In that reaction, the catalytic product benzyldimethylamine is formed in only low yield. Alternatively, the reaction of ToMMgMe and N,N-dimethylbenzamide slowly gives decomposition of ToMMgMe over 24 h, and this interaction is also ruled out as a catalytically relevant step. Together, these data suggest that catalytic activation of ToMMgMe requires both HBpin and amide, and ToMMgH2Bpin is not a catalytic intermediate. With information on catalyst activation in hand, tertiary amides are selectively reduced to amines in good yield when catalytic amounts of ToMMgMe are added to a mixture of amide and excess HBpin. In addition, secondary amides are reduced in the presence of 10 mol % ToMMgMe and 4 equiv of HBpin. Functional groups such as cyano, nitro, and azo remain intact under the mild reaction conditions. In addition, kinetic experiments and competition experiments indicate that B-H addition to amide C-O is fast, even faster than addition to ester C=O, and requires participation of the catalyst, whereas the turnover-limiting step of the catalyst is deoxygenation.
- Lampland, Nicole L.,Hovey, Megan,Mukherjee, Debabrata,Sadow, Aaron D.
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p. 4219 - 4226
(2015/11/11)
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- Copper-catalysed reductive amination of nitriles and organic-group reductions using dimethylamine borane
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A heterogeneous copper catalyst, formed in situ, has been shown to dehydrocouple commercially available amine boranes whilst transferring hydrogen for the reduction of selected organic functional groups in an aqueous medium. The catalytic system has also been shown to promote the reductive amination of aryl nitriles. This journal is
- Van Der Waals, Dominic,Pettman, Alan,Williams, Jonathan M. J.
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p. 51845 - 51849
(2014/12/10)
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- A practical procedure for reduction of primary, secondary and tertiary amides to amines
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A mild and general procedure for reduction of primary, secondary, and tertiary amides using catalytic triruthenium dodecacarbonyl and 1,1,3,3-tetramethyldisiloxane as reductant is described. The reaction is tolerant of numerous functional groups, and the amine products can often be isolated by direct crystallization as hydrochloride salts. The catalyst and silane are commercially available, air stable, and inexpensive, making the procedure accessible for both laboratory and large-scale applications. Copyright
- Reeves, Jonathan T.,Tan, Zhulin,Marsini, Maurice A.,Han, Zhengxu S.,Xu, Yibo,Reeves, Diana C.,Lee, Heewon,Lu, Bruce Z.,Senanayake, Chris H.
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supporting information
p. 47 - 52
(2013/03/13)
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- Cobalt carbonyl-based catalyst for hydrosilylation of carboxamides
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The cobalt carbonyl [Co2(CO)8] complex is employed as a useful catalyst for the reduction of tertiary amides to the corresponding tertiary amines using 1,1,3,3-tetramethyldisiloxane (TMDS) and poly(methylhydrosiloxane) (PMHS) as silane reagents under thermal (100 °C) or photo-assisted conditions (UV, 350 nm at room temperature). Of particular interest, a low catalytic amount (0.5 mol%) of [Co2(CO)8] is used to perform the reaction with 2.2 equiv. of PMHS at 100 °C for 3 h. This reaction is the first example of a cobalt-catalyzed hydrosilylation of amides. Copyright
- Dombray, Thomas,Helleu, Camille,Darcel, Christophe,Sortais, Jean-Baptiste
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supporting information
p. 3358 - 3362
(2013/12/04)
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- Hydrosiloxane-Ti(OiPr)4: An efficient system for the reduction of primary amides into primary amines as their hydrochloride salts
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A simple and useful method for the reduction of primary amides into the corresponding amines using a polymethylhydrosiloxane (PMHS)-Ti(OiPr)4 reducing system is described. Aromatic as well as aliphatic primary amides are reduced in high selectivity and excellent yields. The reduction could proceed via dehydration of the primary amide group into the corresponding nitrile which is then reduced into the corresponding primary amine.
- Laval, Stéphane,Dayoub, Wissam,Pehlivan, Leyla,Métay, Estelle,Favre-Réguillon, Alain,Delbrayelle, Dominique,Mignani, Gérard,Lemaire, Marc
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experimental part
p. 4072 - 4075
(2011/09/12)
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- Complexation equilibria involving salts in non-aqueous solvents: Ion pairing and activity considerations
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Complexation of anions, cations and even ion pairs is now an active area of investigation in supramolecular chemistry; unfortunately it is an area fraught with complications when these processes are examined in low polarity organic media. Using a pseudorotaxane complex as an example, apparent Ka2 values (=[complex]/{[salt]o-[complex]}{[host]o-[complex]}) for pseudorotaxane formation from dibenzylammonium salts (2-X) and dibenzo-[24]crown-8 (1, DB24C8) in CDCl3/CD3CN 3:2 vary with concentration. This is attributable to the fact that the salt is ion paired, but the complex is not. We report an equilibrium model that explicitly includes ion pair dissociation and is based upon activities rather than molar concentrations for study of such processes in non-aqueous media. Proper analysis requires both a dissociation constant, Kipd, for the salt and a binding constant for interaction of the free cation 2+ with the host, Ka5; Ka5 for pseudorotaxane complexation is independent of the counterion (500M-1), a result of the complex existing in solution as a free cation, but Kipd values for the salts vary by nearly two orders of magnitude from trifluoroacetate to tosylate to tetrafluoroborate to hexafluorophosphate anions. The activity coefficients depend on the nature of the predominant ions present, whether the pseudorotaxane or the ions from the salt, and also strongly on the molar concentrations; activity coefficients as low as 0.2 are observed, emphasizing the magnitude of their effect. Based on this type of analysis, a method for precise determination of relative binding constants, Ka5, for multiple hosts with a given guest is described. However, while the incorporation of activity coefficients is clearly necessary, it removes the ability to predict from the equilibrium constants the effects of concentration on the extent of binding, which can only be determined experimentally. This has serious implications for study of all such complexation processes in low polarity media.
- Gibson, Harry W.,Jones, Jason W.,Zakharov, Lev N.,Rheingold, Arnold L.,Slebodnick, Carla
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experimental part
p. 3192 - 3206
(2011/04/18)
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- Macrocyclic Ghrelin Receptor Antagonists and Inverse Agonists and Methods of Using the Same
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The present invention provides novel conformationally-defined macrocyclic compounds that have been demonstrated to be selective modulators of the ghrelin receptor (GRLN, growth hormone secretagogue receptor, GHS-R1a and subtypes, isoforms and/or variants thereof). Methods of synthesizing the novel compounds are also described herein. These compounds are useful as antagonists or inverse agonists of the ghrelin receptor and as medicaments for treatment and prevention of a range of medical conditions including, but not limited to, metabolic and/or endocrine disorders, obesity and obesity-associated disorders, appetite or eating disorders, addictive disorders, cardiovascular disorders, gastrointestinal disorders, genetic disorders, hyperproliferative disorders, central nervous system disorders and inflammatory disorders.
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- Self-modulated highly chemoselective direct-reductive-amination (DRA) of benzaldehydes straightforward to N-monosubstituted benzylamine hydrochlorides
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An unprecedented efficient and chemoselective DRA of benzaldehydes and primary amines was developed to directly yield N-monosubstituted benzylamine hydrochlorides as single products in practically quantitative yields. The method was characterized by simply adding a few milliliters of CHCl3 in the conventional Pd-C catalytic hydrogenation system at atmospheric pressure and room temperature. A self-modulated system and a four-stage cyclic pathway were proposed.
- Xing, Lixin,Cheng, Chuanjie,Zhu, Rui,Zhang, Boyang,Wang, Xinyan,Hu, Yuefei
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supporting information; experimental part
p. 11783 - 11788
(2009/04/05)
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- Reaction of Dichlorotriphenylphosphorane with Bis(trimethylsilyl) Peroxide. A new Method for the Formation of Electrophilic Chlorine Source.
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Reactions of dichlorotriphenylphosphorane with bis(trimethylsilyl) peroxide in the presence of some organic compounds have been found to give chlorinated products.Aromatic hydrocarbons bearing electron-donating substituents give the corresponding monochloroarenes, while an enol silyl ether is converted into α-chloro-ketone.The mechanism is briefly discussed.
- Shibata, Kazusato,Itoh, Yukinori,Tokitoh, Norihiro,Okazaki, Renji,Inamoto, Naoki
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p. 3749 - 3751
(2007/10/02)
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- REACTIONS OF N-POLYFLUOROPHENYLCARBONIMIDOYL DICHLORIDES WITH PRIMARY AND SECONDARY AMINES. KINETICS AND MECHANISM. SYNTHESIS OF POLYFLUORINATED CABODIIMIDES, CHLOROFORMAMIDINES, GUANIDINES AND BENZIMIDAZOLES
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The reactions of N-polyfluorophenylcarbonimidoyl dichlorides with primary and secondary aliphatic and aromatic amines have been studied.With primary aliphatic amines, the reactions led to carbodiimides or guanidines, depending on the amount of amine.The carbodiimides obtained reacted with amines to form guanidines.The reactions with primary aromatic amines produced only triarylguanidines.N-Pentafluorophenylcarbonimidoyl dichloride (I) reacted with tetrafluoro-o-phenylene diamine to give 2-pentafluoroanilino-4,5,6,7-tetrafluorobenzimidazole.Polyfluorinated benzimidazole derivatives were also produced by the thermolysis of polyfluorinated triarylguanidines.Heating of N1,N2,N3-tris(pentafluorophenyl)guanidine with K2CO3 in dimethylformamide led to 1,2,3,4,7,8,9,10-octafluoro-5-pentafluorophenyl-5H-benzimidazobenzimidazole.N-Polyfluorophenylcarbonimidoyl dichlorides reacted with various secondary amines alredy at room temperature giving N-polyfluorophenylchloroformamidines in high yields.Elevated temperature and prolonged reaction time led to formation of N-polyfluorophenylguanidines.Kinetics and mechanism of the reactions of N-polyfluorophenylcarbonimidoyl dichlorides with primary and secondary amines in acetonitrile at 25 deg C have been studied.The reactions have been found to proceed by a bimolecular nucleophilic addition-elimination mechanism via a tetrahedral intermediate.Possible reasons of formation of different products in the above transformations are discussed in terms of this mechanism.
- Kolesnikova, I. V.,Petrova, T. D.,Platonov, V.E.,Mikhailov, V. A.,Popov, A. A.,Savelova, V.A.
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p. 217 - 246
(2007/10/02)
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- A DIRECT REDUCTIVE DEAMINATION OF AMIDINES WITH SODIUM BOROHYDRIDE. FORMATION OF DEAMINATED COMPOUNDS AND SECONDARY AMINES
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The reaction of 3-substituted-4-amino-1H-1,5-benzodiazepines (1a, b) with sodium borohydride afforded deaminated compounds (4a, b and 6a, b).On the other hand, acyclic amidines were converted by treatment with sodium borohydride to the corresponding secondary amines (13) under the same conditions.Keywords: 1,5-benzodiazepines; deamination; amidines; mass analysis; IR; absorption of cyano group; N-NMR; 13C-NMR
- Okamoto, Yoshihisa,Kinoshita, Toshio
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p. 1165 - 1169
(2007/10/02)
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