- N -Heterocyclic carbene (NHC) catalyzed amidation of aldehydes with amines via the tandem N -hydroxysuccinimide ester formation
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A facile method for the amidation of aldehydes by a cascade approach was developed. This methodology, reported for the first time, uses a N-heterocyclic carbene (NHC) as the catalyst, and N-hydroxysuccinimide (NHS) mediated synthesis of amides utilising TBHP as the oxidant. Various substituted aldehydes reacted smoothly with NHS giving the corresponding active esters in moderate to good yields, which facilely converted into amides in one pot. In addition, the drug moclobemide was synthesized to represent the practical utility of the developed methodology. This journal is
- Singh, Ashmita,Narula
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supporting information
p. 7486 - 7490
(2021/05/13)
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- Copper and N-Heterocyclic Carbene-Catalyzed Oxidative Amidation of Aldehydes with Amines
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A one-pot two-step oxidative process has been developed for the tert-butyl hydroperoxide mediated transformation of aldehydes and amines into amides catalyzed by copper(I) iodide and an N-heterocyclic carbene. The process is additive-free and does not require the amine to be transformed into its hydrochloride salts. The method is simple and practicable, has a broad substrate scope, and uses economical, feasible, and abundant reagents.
- Singh, Ashmita,Narula, Anudeep Kumar
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supporting information
p. 718 - 722
(2021/02/26)
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- Dehydrogenative amide synthesis from alcohols and amines utilizing N-heterocyclic carbene-based ruthenium complexes as efficient catalysts: The influence of catalyst loadings, ancillary and added ligands
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The metal-catalyzed dehydrogenative coupling of alcohols and amines to access amides has been recognized as an atom-economic and environmental-friendly process. Apart from the formation of the amide products, three other kinds of compounds (esters, imines and amines) may also be produced. Therefore, it is of vital importance to investigate product distribution in this transformation. Herein, N-heterocyclic carbene-based Ru (NHC/Ru) complexes [Ru-1]-[Ru-5] with different ancillary ligands were prepared and characterized. Based on these complexes, we selected condition A (without an added NHC precursor) and condition B (with an added NHC precursor) to comprehensively explore the selectivity and yield of the desired amides. After careful evaluation of various parameters, the Ru loadings, added NHC precursors and the electronic/steric properties of ancillary NHC ligands were found to have considerable influence on this catalytic process.
- Wang, Wan-Qiang,Wang, Zhi-Qin,Sang, Wei,Zhang, Rui,Cheng, Hua,Chen, Cheng,Peng, Da-Yong
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- Well-defined N-heterocyclic carbene/ruthenium complexes for the alcohol amidation with amines: The dual role of cesium carbonate and improved activities applying an added ligand
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Dehydrogenative amide bond formation from alcohols and amines has been regarded as an atom-economic and sustainable process. Among various catalytic systems, N-heterocyclic carbene (NHC)-based Ru catalytic systems have attracted growing interest due to the outstanding properties of NHCs as ligands. Herein, an NHC/Ru complex (1) was prepared and its structure was further confirmed with X-ray crystallography. In the presence of Cs2CO3, two NHC/Ru-based catalytic systems were disclosed to be active for this amide synthesis. System A, which did not contain any added ligand, required a catalyst loading of 1.00 mol%. Interestingly, improved catalytic performance was realized by the addition of an NHC precursor (L). Optimization of the amounts of L and other conditions gave rise to system B, a much more potent system with the Ru loading as low as 0.25 mol%. Moreover, an NHC-Ru-carbonate complex 6 was identified from the refluxing toluene of 1 and Cs2CO3, and further investigations revealed that 6 was an important intermediate for this catalytic reaction. Based on the above results, we claimed that the role of Cs2CO3 was to facilitate the formation of key intermediate 6. On the other hand, it provided the optimized basicity for the selective amide formation.
- Wang, Wan-Qiang,Yuan, Ye,Miao, Yang,Yu, Bao-Yi,Wang, Hua-Jing,Wang, Zhi-Qin,Sang, Wei,Chen, Cheng,Verpoort, Francis
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- Nickel-Catalyzed C-F/N-H Annulation of Aromatic Amides with Alkynes: Activation of C-F Bonds under Mild Reaction Conditions
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The Ni-catalyzed reaction of ortho-fluoro-substituted aromatic amides with alkynes results in C-F/N-H annulation to give 1(2H)-isoquinolinones. A key to the success of the reaction is the use of KOtBu or even weak base, such as Cs2CO3. The reaction proceeds in the absence of a ligand and under mild reaction conditions (40-60 °C). DFT calculations suggest that the pathway for this Ni-catalyzed C-F/N-H annulation involves N-H deprotonation, oxidative addition of a C-F bond, migratory insertion of an alkyne, and reductive elimination to form 1(2H)-isoquinolinone derivatives.
- Bai, Ruopeng,Chatani, Naoto,Lan, Yu,Liu, Song,Nohira, Itsuki
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supporting information
p. 17306 - 17311
(2020/11/13)
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- An Efficient Catalytic Amidation of Esters Promoted by N-Heterocyclic Carbenes
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An efficient NHC-catalyzed amidation between esters and amines or hydrazines is described. This strategy was tolerant for a wide scope of substrates, affording a series of amides (or hydrazides) in good to excellent yields (60-96%) under simple conditions. The approach was also used to synthesize the pharmaceutically relevant antidepressant moclobemide in 85% yield.
- Chen, Ling-Yan,Wu, Mei-Fang
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p. 1595 - 1602
(2019/03/26)
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- Tert -Butyl nitrite promoted transamidation of secondary amides under metal and catalyst free conditions
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A mild and efficient method is demonstrated for the transamidation of secondary amides with various amines including primary, secondary, cyclic and acyclic amines in the presence of tert-butyl nitrite. The reaction proceeds through the N-nitrosamide intermediate and provides the transamidation products in good to excellent yields at room temperature. Moreover, the developed methodology does not require any catalyst or additives.
- Sureshbabu, Popuri,Azeez, Sadaf,Chaudhary, Priyanka,Kandasamy, Jeyakumar
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p. 845 - 850
(2019/01/30)
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- Design and synthesis of arylamidine derivatives as serotonin/norepinephrine dual reuptake inhibitors
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To improve the in vivo antidepressant activity of previously reported serotonin (5-HT) and norepinephrine (NE) dual reuptake inhibitors, three series of arylamidine derivatives were designed and synthesized. The in vitro 5-HT and NE reuptake inhibitory activities of these compounds were evaluated, and compound II-5 was identified as the most potent 5-HT (IC50 = 620 nM) and NE (IC50 = 10 nM) dual reuptake inhibitor. Compound II-5 exhibited potent antidepressant activity in the rat tail suspension test and showed an acceptable safety profile in a preliminary acute toxicity test in mice. Our results show that these arylamidine derivatives exhibit potent 5-HT/NE dual reuptake inhibition and should be explored further as antidepressant drug candidates.
- Wen, Hui,Qin, Wen,Yang, Guangzhong,Guo, Yanshen
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- Formamide catalyzed activation of carboxylic acids-versatile and cost-efficient amidation and esterification
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A novel, broadly applicable method for amide C-N and ester C-O bond formation is presented based on formylpyrrolidine (FPyr) as a Lewis base catalyst. Herein, trichlorotriazine (TCT), which is the most cost-efficient reagent for OH-group activation, was employed in amounts of ≤40 mol% with respect to the starting material (100 mol%). The new approach is distinguished by excellent cost-efficiency, waste-balance (E-factor down to 3) and scalability (up to >80 g). Moreover, high levels of functional group compatibility, which includes acid-labile acetals and silyl ethers, are demonstrated and even peptide C-N bonds can be formed. In comparison to reported amidation procedures using TCT, yields are considerably improved (for instance from 26 to 91%) and esterification is facilitated for the first time in synthetically useful yields. These significant enhancements are rationalized by activation by means of acid chlorides instead of less electrophilic acid anhydride intermediates.
- Huy, Peter H.,Mbouhom, Christelle
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p. 7399 - 7406
(2019/08/20)
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- Hydrogen Bond Directed ortho-Selective C?H Borylation of Secondary Aromatic Amides
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Reported is an iridium catalyst for ortho-selective C?H borylation of challenging secondary aromatic amide substrates, and the regioselectivity is controlled by hydrogen-bond interactions. The BAIPy-Ir catalyst forms three hydrogen bonds with the substrate during the crucial activation step, and allows ortho-C?H borylation with high selectivity. The catalyst displays unprecedented ortho selectivities for a wide variety of substrates that differ in electronic and steric properties, and the catalyst tolerates various functional groups. The regioselective C?H borylation catalyst is readily accessible and converts substrates on gram scale with high selectivity and conversion.
- Bai, Shao-Tao,Bheeter, Charles B.,Reek, Joost N. H.
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supporting information
p. 13039 - 13043
(2019/07/31)
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- Synthesis of amides from acid chlorides and amines in the bio-based solvent Cyrene
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Cyrene as a bio-alternative dipolar aprotic solvent: a waste minimizing and molar efficient protocol for the synthesis of amides from acid chlorides and primary amines in the bio-available solvent Cyrene is disclosed. This protocol removed the use of toxic solvents, such as dimethylformamide and dichloromethane. A simple aqueous work-up procedure for the removal of the high boiling solvent Cyrene resulted in up to a 55-fold increase in molar efficiency (Mol E.%) versus standard operating procedures. In order to rapidly compare the molar efficiency of this process against other methodologies an Excel based Mol. E% calculator was developed that automates many of the calculations. An investigation into the hydration of Cyrene found that it readily hydrates to form a geminal diol in the presence of water and that this process is exothermic.
- Bousfield, Thomas W.,Pearce, Katharine P. R.,Nyamini, Simbarashe B.,Angelis-Dimakis, Athanasios,Camp, Jason E.
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supporting information
p. 3675 - 3681
(2019/07/09)
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- Ruthenium-based catalytic systems incorporating a labile cyclooctadiene ligand with N-heterocyclic carbene precursors for the atom-economic alcohol amidation using amines
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Transition-metal-catalyzed amide-bond formation from alcohols and amines is an atom-economic and eco-friendly route. Herein, we identified a highly active in situ N-heterocyclic carbene (NHC)/ruthenium (Ru) catalytic system for this amide synthesis. Various substrates, including sterically hindered ones, could be directly transformed into the corresponding amides with the catalyst loading as low as 0.25 mol.%. In this system, we replaced the p-cymene ligand of the Ru source with a relatively labile cyclooctadiene (cod) ligand so as to more efficiently obtain the corresponding poly-carbene Ru species. Expectedly, the weaker cod ligand could be more easily substituted with multiple mono-NHC ligands. Further high-resolution mass spectrometry (HRMS) analyses revealed that two tetra-carbene complexes were probably generated from the in situ catalytic system.
- Chen, Cheng,Miao, Yang,De Winter, Kimmy,Wang, Hua-Jing,Demeyere, Patrick,Yuan, Ye,Verpoort, Francis
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- Efficient N-Heterocyclic Carbene/Ruthenium Catalytic Systems for the Alcohol Amidation with Amines: Involvement of Poly-Carbene Complexes?
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The atom-economic direct amidation of alcohols with amines has been recently highlighted as an attractive and promising transformation. Among the versatile reported catalytic systems, in situ generated N-heterocyclic carbene (NHC)/ruthenium (Ru) catalytic systems have demonstrated their advantages such as easy operation and use of commercial Ru compounds. However, the existing catalyst loadings are relatively high, and additional insights for the in situ catalyst generation are still not well-documented. In this work, a variety of benzimidazole-based NHC precursors were initially synthesized. Through the screening of various NHC precursors and other reaction conditions, active in situ catalytic systems were discovered for the efficient amide synthesis. Notably, the catalyst loading is as low as 0.5 mol %. Furthermore, additional experiments were performed to validate the rationale for the superiority of the current catalytic systems over our previous system. It was observed that the ligand structure is one of the reasons for the higher activity. In addition, the higher ratio of the NHC precursor/[Ru] is another important factor for the improvement. Further HR-MS analysis identified the formation of two mono-NHC-Ru species as major species and two Ru species bearing multiple NHC ligands as minor species. Hopefully, the efficient and readily-accessible catalytic systems reported herein could demonstrate great potential for further practical applications.
- Cheng, Hua,Xiong, Mao-Qian,Zhang, Ni,Wang, Hua-Jing,Miao, Yang,Su, Wei,Yuan, Ye,Chen, Cheng,Verpoort, Francis
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p. 4338 - 4345
(2018/09/06)
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- In situ Generated Ruthenium Catalyst Systems Bearing Diverse N-Heterocyclic Carbene Precursors for Atom-Economic Amide Synthesis from Alcohols and Amines
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The transition-metal-catalyzed direct synthesis of amides from alcohols and amines is herein demonstrated as a highly environmentally benign and atom-economic process. Among various catalyst systems, in situ generated N-heterocyclic carbene (NHC)-based ruthenium (Ru) halide catalyst systems have been proven to be active for this transformation. However, these existing catalyst systems usually require an additional ligand to achieve satisfactory results. In this work, through extensive screening of a diverse variety of NHC precursors, we discovered an active in situ catalyst system for efficient amide synthesis without any additional ligand. Notably, this catalyst system was found to be insensitive to the electronic effects of the substrates, and various electron-deficient substrates, which were not highly reactive with our previous catalyst systems, could be employed to afford the corresponding amides efficiently. Furthermore, mechanistic investigations were performed to provide a rationale for the high activity of the optimized catalyst system. NMR-scale reactions indicated that the rapid formation of a Ru hydride intermediate (signal at δ=?7.8 ppm in the 1H NMR spectrum) after the addition of the alcohol substrate should be pivotal in establishing the high catalyst activity. Besides, HRMS analysis provided possible structures of the in situ generated catalyst system.
- Cheng, Hua,Xiong, Mao-Qian,Cheng, Chuan-Xiang,Wang, Hua-Jing,Lu, Qiang,Liu, Hong-Fu,Yao, Fu-Bin,Chen, Cheng,Verpoort, Francis
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p. 440 - 448
(2018/02/06)
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- Site-Selective Silylation of Aliphatic C-H Bonds Mediated by [1,5]-Hydrogen Transfer: Synthesis of α-Sila Benzamides
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The first example of site-selective silylation of C(sp3)-H bonds mediated by a [1,5]-hydrogen transfer is reported. This reaction occurs selectively at the α-position of benzamides with a combination of tert-butylmagnesium chloride and a catalytic amount of 4,4′-di-tert-butylbipyridine (dtbpy) ligand and provides a facile route for the creation of biologically interesting α-sila benzamides. Late-stage functionalization of the incorporated silyl moieties facilitates the synthesis of N-formyl, cis-enamine, β-hydroxyl, amino, and pyrrole-containing derivatives.
- Liu, Pei,Tang, Jinghua,Zeng, Xiaoming
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p. 5536 - 5539
(2016/11/17)
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- Selective catalytic sp3 C-O bond cleavage with C-N bond formation in 3-alkoxy-1-propanols
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The ruthenium catalyzed selective sp3 C-O cleavage with amide formation was reported in reactions of 3-alkoxy-1-propanol derivatives and amines. The cleavage only occurs at the C3-O position even with 3-benzyloxy-1-propanol. Based on the experimental results, O-bound and C-bound Ru enolate complexes were proposed as key intermediates for the unique selective sp3 C-O bond cleavage in 3-alkoxy-1-propanols.
- Chen, Cheng,Hong, Soon Hyeok
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supporting information; experimental part
p. 2992 - 2995
(2012/07/28)
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- An efficient route to 3-aminoindazoles and 3-amino-7-azaindazoles
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A non-acidic procedure for the preparation of 3-aminoindazoles and 3-amino-7-azaindazoles from 2-fluoroaryl carboxylic acids is reported. The synthesis starts from readily available starting materials and uses mild and practical reaction conditions in a three-step overall procedure. Products were isolated for a number of examples, but yields varied significantly depending on electronic nature of the substituents.
- Burke, Michael J.,Trantow, Brian M.
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p. 4579 - 4581
(2008/09/21)
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- N-nitrosamide-mediated ritter-type reactions. Part II - The operation of persistent steric and π*-acceptor agostic-type effects
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Benzyl cations were generated via thermolysis of N-benzyl-N-nitrosopivalamide in molten 2-R-substituted benzonitriles (R = MeO, Me, H, F, Cl, and Br). The corresponding N-2-R-benzonitrilium species, in contrast to their 4-R-benzonitrilium counterparts, underwent limited reaction with pivalate ion to form unsymmetrical diacylamines via rearrangement of their initial imidic anhydrides. The yield of diacylamines, though small, varied systematically with the nature of the R group in a manner suggesting the operation of interesting steric and/or electronic effects on the pivalate ion-nitrilium ion collapse. The ortho-substituent, though present on only one side of the benzonitrilium ion inhibits reaction at both sides via steric hindrance in the near-ground state and steric crowding in the transition state (a persistent steric effect). The proposed electronic effect involves a π*-acceptor agostic-type interaction between n or σ electrons (HOMO) and the π* system (LUMO) of the nitrilium ion. Additionally, in many cases, attack by water on the nitrilium ion occurred to a significantly larger extent than attack by the much more nucleophilic and positionally favored pivalate ion on the same species. This observation is interpreted in terms of the differences in the sizes and docking trajectories of both species with the nitrilium ion due to charge and charge distribution on both nucleophiles.
- Darbeau, Ron W.,Pease, Rebecca S.,Perez, Edson V.,Gibble, Rebekah E.,Ayo, Faith A.,Sweeney, Aaron W.
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p. 2146 - 2153
(2007/10/03)
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- POTENTIAL CENTRAL NERVOUS SYSTEM ACTIVE AGENTS. 3. SYNTHESIS OF SOME SUBSTITUTED BENZAMIDES AND PHENYLACETAMIDES.
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The preparation and special properties (IR, **1H NMR) are given for 45 benzamides and 10 phenylacetamides substituted on nitrogen with allyl, benzhydryl, benzyl, or cyclopropyl groups, and variously substituted on the acyl part with halo, methoxyl, methyl, or nitro groups. The benzamide derivatives were synthesized by the Schotten-Baumann method, and the phenylacetamide derivatives were prepared by heating the appropriate N-benzhydrylammonium salt in o-xylene. Thirty-one of the compounds are new.
- Agwada
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p. 231 - 235
(2007/10/02)
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