- Biocatalytic Synthesis of Moclobemide Using the Amide Bond Synthetase McbA Coupled with an ATP Recycling System
-
The biocatalytic synthesis of amides from carboxylic acids and primary amines in aqueous media can be achieved using the ATP-dependent amide bond synthetase McbA, via an adenylate intermediate, using only 1.5 equiv of the amine nucleophile. Following earlier studies that characterized the broad carboxylic acid specificity of McbA, we now show that, in addition to the natural amine substrate 2-phenylethylamine, a range of simple aliphatic amines, including methylamine, butylamine, and hexylamine, and propargylamine are coupled efficiently to the native carboxylic acid substrate 1-acetyl-9H-β-carboline-3-carboxylic acid by the enzyme, to give amide products with up to >99% conversion. The structure of wild-type McbA in its amidation conformation, coupled with modeling and mutational studies, reveal an amine access tunnel and a possible role for residue D201 in amine activation. Amide couplings were slower with anilines and alicyclic secondary amines such as pyrrolidine and piperidine. The broader substrate specificity of McbA was exploited in the synthesis of the monoamine oxidase A inhibitor moclobemide, through the reaction of 4-chlorobenzoic acid with 1.5 equiv of 4-(2-aminoethyl)morpholine, and utilizing polyphosphate kinases SmPPK and AjPPK in the presence of polyphosphoric acid and 0.1 equiv of ATP, required for recycling of the cofactor.
- Fairlamb, Ian J. S.,Grogan, Gideon,Lloyd, Richard C.,Petchey, Mark R.,Rowlinson, Benjamin
-
-
Read Online
- Reaction-based two-photon probes for in vitro analysis and cellular imaging of monoamine oxidase activity
-
Reaction-based fluorescent probes for monoamine oxidases A and B are developed based on a new two-photon absorbing compound and its precursor. The probes show turn-on fluorescence response to the enzymes owing to the two-photon absorbing compound produced by the enzymatic activity, as monitored by one- as well as two-photon microscopy for the first time. The Royal Society of Chemistry 2012.
- Kim, Dokyoung,Sambasivan, Sunderraman,Nam, Hyoseok,Ki, Hean Kim,Jin, Yong Kim,Joo, Taiha,Lee, Kyung-Ha,Kim, Kyong-Tai,Han Ahn, Kyo
-
-
Read Online
- Amide Bond Formation via the Rearrangement of Nitrile Imines Derived from N-2-Nitrophenyl Hydrazonyl Bromides
-
We report how the rearrangement of highly reactive nitrile imines derived from N-2-nitrophenyl hydrazonyl bromides can be harnessed for the facile construction of amide bonds. This amidation reaction was found to be widely applicable to the synthesis of primary, secondary, and tertiary amides and was used as the key step in the synthesis of the lipid-lowering agent bezafibrate. The orthogonality and functional group tolerance of this approach was exemplified by the N-acylation of unprotected amino acids.
- Boyle, Mhairi,Livingstone, Keith,Henry, Martyn C.,Elwood, Jessica M. L.,Lopez-Fernandez, J. Daniel,Jamieson, Craig
-
supporting information
p. 334 - 338
(2022/01/20)
-
- Photochemical Activation of Aromatic Aldehydes: Synthesis of Amides, Hydroxamic Acids and Esters
-
A cheap, facile and metal-free photochemical protocol for the activation of aromatic aldehydes has been developed. Utilizing thioxanthen-9-one as the photocatalyst and cheap household lamps as the light source, a variety of aromatic aldehydes have been activated and subsequently converted in a one-pot reaction into amides, hydroxamic acids and esters in good to high yields. The applicability of this method was highlighted in the synthesis of Moclobemide, a drug against depression and social anxiety. Extended and detailed mechanistic studies have been conducted, in order to determine a plausible mechanism for the reaction.
- Nikitas, Nikolaos F.,Apostolopoulou, Mary K.,Skolia, Elpida,Tsoukaki, Anna,Kokotos, Christoforos G.
-
supporting information
p. 7915 - 7922
(2021/05/03)
-
- Water-removable ynamide coupling reagent for racemization-free syntheses of peptides, amides, and esters
-
A novel ynamide coupling reagent, the by-product of which can be removed by water, was reported. It promotes the direct coupling between carboxylic acids and amines, alcohols or thiols to provide amides, peptides, esters and thioesters, respectively. No detectable racemization was observed for all the coupling reactions of carboxylic acids containing an α-chiral center. Importantly, a simple acidic aqueous work-up removed the by-product readily to afford pure coupling products in good to excellent yields without the use of column chromatography, thus making this method more environmentally benign, user friendly and cost-effective. The robustness of the water-removable ynamide coupling reagent was further exemplified by the racemization/epimerization-free synthesis of carfilzomib, in which no column chromatography purification was involved for the entire 12-step synthesis.
- Liu, Tao,Zhang, Xue,Peng, Zejun,Zhao, Junfeng
-
supporting information
p. 9916 - 9921
(2021/12/24)
-
- A CO2-Catalyzed Transamidation Reaction
-
Transamidation reactions are often mediated by reactive substrates in the presence of overstoichiometric activating reagents and/or transition metal catalysts. Here we report the use of CO2as a traceless catalyst: in the presence of catalytic amounts of CO2, transamidation reactions were accelerated with primary, secondary, and tertiary amide donors. Various amine nucleophiles including amino acid derivatives were tolerated, showcasing the utility of transamidation in peptide modification and polymer degradation (e.g., Nylon-6,6). In particular,N,O-dimethylhydroxyl amides (Weinreb amides) displayed a distinct reactivity in the CO2-catalyzed transamidation versus a N2atmosphere. Comparative Hammett studies and kinetic analysis were conducted to elucidate the catalytic activation mechanism of molecular CO2, which was supported by DFT calculations. We attributed the positive effect of CO2in the transamidation reaction to the stabilization of tetrahedral intermediates by covalent binding to the electrophilic CO2
- Yang, Yang,Liu, Jian,Kamounah, Fadhil S.,Ciancaleoni, Gianluca,Lee, Ji-Woong
-
p. 16867 - 16881
(2021/11/18)
-
- Cobalt catalysed aminocarbonylation of thiols in batch and flow for the preparation of amides
-
The synthesis of amides from thiols through a cobalt-catalyzed aminocarbonylation is shown. After optimizing all the reaction parameters, the methodology makes possible the obtention of amides with variable yields, while competing reactions such as the formation of disulfides and ureas can be limited. The process works well with aromatic thiols with electron donating groups (EDG) whereas other thiols give reaction with lower yields. The previous process has been transferred and optimized into flow equipment, thus allowing using less CO in a safer way, and permitting the scaling up of the synthesis. Two drugs, moclobemide and itopride were prepared with this methodology, albeit only in the second case with good results. A mechanistic pathway is proposed.
- Domínguez, Gema,Ordu?a, Jose Maria,Pérez-Castells, Javier
-
p. 30398 - 30406
(2021/10/20)
-
- Direct Amidation of Esters by Ball Milling**
-
The direct mechanochemical amidation of esters by ball milling is described. The operationally simple procedure requires an ester, an amine, and substoichiometric KOtBu and was used to prepare a large and diverse library of 78 amide structures with modest to excellent efficiency. Heteroaromatic and heterocyclic components are specifically shown to be amenable to this mechanochemical protocol. This direct synthesis platform has been applied to the synthesis of active pharmaceutical ingredients (APIs) and agrochemicals as well as the gram-scale synthesis of an active pharmaceutical, all in the absence of a reaction solvent.
- Barreteau, Fabien,Battilocchio, Claudio,Browne, Duncan L.,Godineau, Edouard,Leitch, Jamie A.,Nicholson, William I.,Payne, Riley,Priestley, Ian
-
supporting information
p. 21868 - 21874
(2021/09/02)
-
- Near-Ambient-Temperature Dehydrogenative Synthesis of the Amide Bond: Mechanistic Insight and Applications
-
The current existing methods for the amide bond synthesis via acceptorless dehydrogenative coupling of amines and alcohols all require high reaction temperatures for effective catalysis, typically involving reflux in toluene, limiting their potential practical applications. Herein, we report a system for this reaction that proceeds under mild conditions (reflux in diethyl ether, boiling point 34.6 °C) using ruthenium PNNH complexes. The low-temperature activity stems from the ability of Ru-PNNH complexes to activate alcohol and hemiaminals at near-ambient temperatures through the assistance of the terminal N-H proton. Mechanistic studies reveal the presence of an unexpected aldehyde-bound ruthenium species during the reaction, which is also the catalytic resting state. We further utilize the low-temperature activity to synthesize several simple amide bond-containing commercially available pharmaceutical drugs from the corresponding amines and alcohols via the dehydrogenative coupling method.
- Kar, Sayan,Xie, Yinjun,Zhou, Quan Quan,Diskin-Posner, Yael,Ben-David, Yehoshoa,Milstein, David
-
p. 7383 - 7393
(2021/06/30)
-
- Photocatalytic synthesis method of N-(2-morpholinoethyl) substituted benzamide compound
-
The invention relates to a photocatalytic synthesis method of an N-(2-morpholinoethyl) substituted benzamide compound, wherein the method is characterized in that benzyl alcohol with a structure represented by a formula (I) or a benzaldehyde compound with a structure represented by a formula (II) and N-(2-aminoethyl) morpholine are used as raw materials, and under the condition of existence of an oxygen-containing atmosphere, an organic solvent, alkali and a transition metal oxide/C3N4 composite photocatalyst, a photocatalytic reaction is carried out to prepare the N-(2-morpholinoethyl) substituted benzamide compound with a structure represented by a formula (III). Benzyl alcohol or benzaldehyde compounds are used as raw materials, acyl chloride and hydrobromic acid are not used, and the N-(2-morpholinoethyl) substituted benzamide compound is prepared in a green and economical mode.
- -
-
Paragraph 0035-0042; 0065-0071
(2021/11/26)
-
- N -Heterocyclic carbene (NHC) catalyzed amidation of aldehydes with amines via the tandem N -hydroxysuccinimide ester formation
-
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
-
supporting information
p. 7486 - 7490
(2021/05/13)
-
- Visible Light-Driven Efficient Synthesis of Amides from Alcohols using Cu?N?TiO2 Heterogeneous Photocatalyst
-
Amides were synthesized from alcohols and amines in high yields using an in situ generated active ester of N-hydroxyimide with our developed Cu?N?TiO2 catalyst at room temperature using oxygen as a sole oxidant under visible light. The catalyst can be easily prepared, robust, and recycled four times without a considerable change in catalytic activity. This developed protocol applies to a wide substrate scope and has good functional group tolerance. The application of this amidation reaction has been successfully demonstrated for the synthesis of moclobemide, an antidepressant drug, and an analog of the itopride drug on a gram scale.
- Singha, Krishnadipti,Ghosh, Subhash Chandra,Panda, Asit Baran
-
supporting information
p. 657 - 662
(2021/02/02)
-
- A practical and sustainable protocol for direct amidation of unactivated esters under transition-metal-free and solvent-free conditions
-
In this paper, a NaOtBu-mediated synthesis approach was developed for direct amidation of unactivated esters with amines under transition-metal-free and solvent-free conditions, affording a series of amides in good to excellent yields at room temperature. In particular, an environmentally friendly and practical workup procedure, which circumvents the use of organic solvents and chromatography in most cases, was disclosed. Moreover, the gram-scale production of representative products3a,3wand3auwas efficiently realized by applying operationally simple, sustainable and practical procedures. Furthermore, this approach was also applicable to the synthesis of valuable molecules such as moclobemide (a powerful antidepressant), benodanil and fenfuram (two commercial agricultural fungicides). These results demonstrate that this protocol has the potential to streamline amide synthesis in industry. Meanwhile, quantitative green metrics of all the target products were evaluated, implying that the present protocol is advantageous over the reported ones in terms of environmental friendliness and sustainability. Finally, additional experiments and computational calculations were carried out to elucidate the mechanistic insight of this transformation, and one plausible mechanism was provided on the basis of these results and the related literature reports.
- Chen, Cheng,Cheng, Hua,Du, Min-Chen,Qian, Liang,Qin, Xin,Sang, Wei,Yao, Wei-Zhong,Yuan, Ye,Zhang, Rui
-
supporting information
p. 3972 - 3982
(2021/06/17)
-
- Zirconium Oxide-Catalyzed Direct Amidation of Unactivated Esters under Continuous-Flow Conditions
-
A sustainable and environmentally benign direct amidation reaction of unactivated esters with amines has been developed in a continuous-flow system. A commercially available amorphous zirconium oxide was found to be an efficient catalyst for this reaction. While the typical amidation of esters with amines requires a stoichiometric amount of a promoter or metal activator, the present continuous-flow method enabled the direct amidation reaction under additive-free conditions with an extensive diversity towards various functional groups. High yields of the products were obtained with a nearly equimolar proportion of starting materials to reduce byproduct formation, which renders this process applicable for use in a sequential-flow system. (Figure presented.).
- Rashed, Md. Nurnobi,Masuda, Koichiro,Ichitsuka, Tomohiro,Koumura, Nagatoshi,Sato, Kazuhiko,Kobayashi, Shū
-
p. 2529 - 2535
(2021/02/01)
-
- Discovery and Design of Family VIII Carboxylesterases as Highly Efficient Acyltransferases
-
Promiscuous acyltransferase activity is the ability of certain hydrolases to preferentially catalyze acyl transfer over hydrolysis, even in bulk water. However, poor enantioselectivity, low transfer efficiency, significant product hydrolysis, and limited substrate scope represent considerable drawbacks for their application. By activity-based screening of several hydrolases, we identified the family VIII carboxylesterase, EstCE1, as an unprecedentedly efficient acyltransferase. EstCE1 catalyzes the irreversible amidation and carbamoylation of amines in water, which enabled the synthesis of the drug moclobemide from methyl 4-chlorobenzoate and 4-(2-aminoethyl)morpholine (ca. 20 % conversion). We solved the crystal structure of EstCE1 and detailed structure–function analysis revealed a three-amino acid motif important for promiscuous acyltransferase activity. Introducing this motif into an esterase without acetyltransferase activity transformed a “hydrolase” into an “acyltransferase”.
- Müller, Henrik,Godehard, Simon P.,Palm, Gottfried J.,Berndt, Leona,Badenhorst, Christoffel P. S.,Becker, Ann-Kristin,Lammers, Michael,Bornscheuer, Uwe T.
-
supporting information
p. 2013 - 2017
(2020/11/30)
-
- Efficient cleavage of tertiary amide bonds: Via radical-polar crossover using a copper(ii) bromide/Selectfluor hybrid system
-
A novel approach for the efficient cleavage of the amide bonds in tertiary amides is reported. Based on the selective radical abstraction of a benzylic hydrogen atom by a CuBr2/Selectfluor hybrid system followed by a selective cleavage of an N-C bond, an acyl fluoride intermediate is formed. This intermediate may then be derivatized in a one-pot fashion. The reaction proceeds under mild conditions and exhibits a broad substrate scope with respect to the tertiary amide moiety as well as to nitrogen, oxygen, and carbon nucleophiles for the subsequent derivatization. Mechanistic studies suggest that the present reaction proceeds via a radical-polar crossover process that involves benzylic carbon radicals generated by the selective radical abstraction of a benzylic hydrogen atom by the CuBr2/Selectfluor hybrid system. Furthermore, a synthetic application of this method for the selective cleavage of peptides is described. This journal is
- Maruoka, Keiji,Matsumoto, Akira,Wang, Zhe
-
p. 12323 - 12328
(2020/12/08)
-
- Palladium nanoparticles on a pyridinium supported ionic liquid phase: a recyclable and low-leaching palladium catalyst for aminocarbonylation reactions
-
A new SILP (Supported Ionic Liquid Phase) palladium catalyst was prepared and characterized by 13C and 29Si CP MAS NMR, DTG, FTIR and TEM. The presence of the grafted pyridinium cations on the surface of the support was found to result in the formation of highly dispersed Pd nanoparticles with their diameter in the range of 1-2 nm. The catalyst was proved to be active not only in the aminocarbonylation of some model compounds but also in the synthesis of active pharmaceutical ingredients. Catalyst recycling and palladium leaching studies were carried out for the first time in aminocarbonylations leading to CX-546(1-(1,4-benzodioxan-6-ylcarbonyl)piperidine), Moclobemide, Nikethamide and a precursor of Finasteride. The latter reaction proves that not only aryl iodides but also an iodoalkene can be converted into the products with the help of the heterogeneous catalyst. The results show that the conditions should be always fine-tuned in the reactions of different substrates to achieve optimal results. Palladium loss was also observed to depend considerably on the nature of the reaction partners. This journal is
- Adamcsik, Bernadett,Nagy, Enik?,Pekker, Péter,Skoda-F?ldes, Rita,Szabó, Péter,Urbán, Béla
-
p. 23988 - 23998
(2020/07/14)
-
- Amide Synthesis by Nickel/Photoredox-Catalyzed Direct Carbamoylation of (Hetero)Aryl Bromides
-
Herein, we report a one-electron strategy for catalytic amide synthesis that enables the direct carbamoylation of (hetero)aryl bromides. This radical cross-coupling approach, which is based on the combination of nickel and photoredox catalysis, proceeds at ambient temperature and uses readily available dihydropyridines as precursors of carbamoyl radicals. The method's mild reaction conditions make it tolerant of sensitive-functional-group-containing substrates and allow the installation of an amide scaffold within biologically relevant heterocycles. In addition, we installed amide functionalities bearing electron-poor and sterically hindered amine moieties, which would be difficult to prepare with classical dehydrative condensation methods.
- Alandini, Nurtalya,Buzzetti, Luca,Candish, Lisa,Collins, Karl D.,Favi, Gianfranco,Melchiorre, Paolo,Schulte, Tim
-
supporting information
p. 5248 - 5253
(2020/03/03)
-
- Visible Light-Induced Amide Bond Formation
-
A metal-, base-, and additive-free amide bond formation reaction was developed under an organic photoredox catalyst. This green approach showed excellent functional selectivity without affecting other functional groups such as alcohols, phenols, ethers, esters, halogens, or heterocycles. This method featured a broad substrate scope, good compatibility with water and air, and high yields (≤95%). The potential utilities were demonstrated by the synthesis of important drug molecules such as paracetamol, melatonin, moclobemide, and acetazolamide.
- Song, Wangze,Dong, Kun,Li, Ming
-
supporting information
p. 371 - 375
(2019/11/29)
-
- Rapid Organocatalytic Formation of Carbon Monoxide: Application towards Carbonylative Cross Couplings
-
Herein, the first organocatalytic method for the transformation of non-derivatized formic acid into carbon monoxide (CO) is introduced. Formylpyrrolidine (FPyr) and trichlorotriazine (TCT), which is a cost-efficient commodity chemical, enable this decarbonylation. Utilization of dimethylformamide (DMF) as solvent and catalyst even allows for a rapid CO generation at room temperature. Application towards four different carbonylative cross coupling protocols demonstrates the high synthetic utility and versatility of the new approach. Remarkably, this also comprehends a carbonylative Sonogashira reaction at room temperature employing intrinsically difficult electron-deficient aryl iodides. Commercial 13C-enriched formic acid facilitates the production of radiolabeled compounds as exemplified by the pharmaceutical Moclobemide. Finally, comparative experiments verified that the present method is highly superior to other protocols for the activation of carboxylic acids.
- Zoller, Ben,Zapp, Josef,Huy, Peter H.
-
supporting information
p. 9632 - 9638
(2020/07/13)
-
- Cyclooctatetraene: A Bioactive Cubane Paradigm Complement
-
Cubane was recently validated as a phenyl ring (bio)isostere, but highly strained caged carbocyclic systems lack π character, which is often critical for mediating key biological interactions. This electronic property restriction associated with cubane has been addressed herein with cyclooctatetraene (COT), using known pharmaceutical and agrochemical compounds as templates. COT either outperformed or matched cubane in multiple cases suggesting that versatile complementarity exists between the two systems for enhanced bioactive molecule discovery.
- Xing, Hui,Houston, Sevan D.,Chen, Xuejie,Ghassabian, Sussan,Fahrenhorst-Jones, Tyler,Kuo, Andy,Murray, Cody-Ellen P.,Conn, Kyna-Anne,Jaeschke, Kara N.,Jin, Da-Yun,Pasay, Cielo,Bernhardt, Paul V.,Burns, Jed M.,Tsanaktsidis, John,Savage, G. Paul,Boyle, Glen M.,De Voss, James J.,McCarthy, James,Walter, Gimme H.,Burne, Thomas H. J.,Smith, Maree T.,Tie, Jian-Ke,Williams, Craig M.
-
supporting information
p. 2729 - 2734
(2019/02/03)
-
- Formamide catalyzed activation of carboxylic acids-versatile and cost-efficient amidation and esterification
-
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
-
p. 7399 - 7406
(2019/08/20)
-
- Ti-superoxide catalyzed oxidative amidation of aldehydes with saccharin as nitrogen source: Synthesis of primary amides
-
A new heterogeneous catalytic system (Ti-superoxide/saccharin/TBHP) has been developed that efficiently catalyzes oxidative amidation of aldehydes to produce various primary amides. The protocol employs saccharin as amine source and was found to tolerate a wide range of substrates with different functional groups. Moderate to excellent yields, catalyst reusability and operational simplicity are the main highlights. A possible mechanism and the role of the catalyst in oxidative amidation have also been discussed.
- Kamble, Rohit B.,Mane, Kishor D.,Rupanawar, Bapurao D.,Korekar, Pranjal,Sudalai,Suryavanshi, Gurunath
-
p. 724 - 728
(2020/01/23)
-
- N-Doped Yellow TiO2 Hollow Sphere-Mediated Visible-Light-Driven Efficient Esterification of Alcohol and N-Hydroxyimides to Active Esters
-
Herein we report a simple synthetic protocol for N-doped yellow TiO2 (N-TiO2) hollow spheres as an efficient visible-light-active photocatalyst using aqueous titanium peroxocarbonate complex (TPCC) solution as precursor and NH4OH. In the developed strategy, the ammonium ion of TPCC and NH4OH acts as nitrogen source and structure-directing agent. The synthesized N-TiO2 hollow spheres are capable of promoting the synthesis of active esters of N-hydroxyimide and alcohol through simultaneous selective oxidation of alcohol to aldehyde followed by cross-dehydrogenative coupling (CDC) under ambient conditions upon irradiation of visible light. It is possible to develop a novel and cost-effective one-pot strategy for the synthesis of important esters and amides on gram scale using the developed strategy. The catalytic activity of N-TiO2 hollow spheres is much superior to that of other reported N-TiO2 samples as well as TiO2 with varying morphology.
- Singha, Krishnadipti,Ghosh, Subhash Ch.,Panda, Asit Baran
-
p. 3205 - 3212
(2019/09/09)
-
- Highly Chemoselective, Transition-Metal-Free Transamidation of Unactivated Amides and Direct Amidation of Alkyl Esters by N-C/O-C Cleavage
-
The amide bond is one of the most fundamental functional groups in chemistry and biology and plays a central role in numerous processes harnessed to streamline the synthesis of key pharmaceutical and industrial molecules. Although the synthesis of amides is one of the most frequently performed reactions by academic and industrial scientists, the direct transamidation of tertiary amides is challenging due to unfavorable kinetic and thermodynamic contributions of the process. Herein, we report the first general, mild, and highly chemoselective method for transamidation of unactivated tertiary amides by a direct acyl N-C bond cleavage with non-nucleophilic amines. This operationally simple method is performed in the absence of transition metals and operates under unusually mild reaction conditions. In this context, we further describe the direct amidation of abundant alkyl esters to afford amide bonds with exquisite selectivity by acyl C-O bond cleavage. The utility of this process is showcased by a broad scope of the method, including various sensitive functional groups, late-stage modification, and the synthesis of drug molecules (>80 examples). Remarkable selectivity toward different functional groups and within different amide and ester electrophiles that is not feasible using existing methods was observed. Extensive experimental and computational studies were conducted to provide insight into the mechanism and the origins of high selectivity. We further present a series of guidelines to predict the reactivity of amides and esters in the synthesis of valuable amide bonds by this user-friendly process. In light of the importance of the amide bond in organic synthesis and major practical advantages of this method, the study opens up new opportunities in the synthesis of pivotal amide bonds in a broad range of chemical contexts.
- Li, Guangchen,Ji, Chong-Lei,Hong, Xin,Szostak, Michal
-
supporting information
p. 11161 - 11172
(2019/08/07)
-
- COtab: Expedient and Safe Setup for Pd-Catalyzed Carbonylation Chemistry
-
Bench-stable tablets (COtabs) have been developed for the rapid and safe production of carbon monoxide. The tablets can be made in less than 5 min without the use of a glovebox and only require a stock solution of an amine base to liberate a specific quantity of CO in a two-chamber system. The COtabs were tested in five different carbonylation reactions and provided similar yields compared to literature procedures. Finally, a gram-scale reaction was conducted, as well as 13C-isotope labeling of the anticancer drug, olaparib.
- Collin, Hugo P.,Reis, Wallace J.,Nielsen, Dennis U.,Lindhardt, Anders T.,Valle, Marcelo S.,Freitas, Rossimiriam P.,Skrydstrup, Troels
-
supporting information
p. 5775 - 5778
(2019/08/26)
-
- Pd/PTABS: An Efficient Catalytic System for the Aminocarbonylation of a Sugar-Protected Nucleoside
-
A highly efficient and mild protocol for the aminocarbonylation of a nucleoside is developed by employing palladium/(1,3,5-Triaza-7-phosphaadamantan-1-ium-1-yl)butane-1-sulfonate (Pd/PTABS) as the catalytic system. The developed aminocarbonylation methodology employs CO gas at a relatively low temperature of 60? °C and is suitable for a wide range of amines, including (heteroaryl)benzylic, aliphatic acyclic, alicyclic and secondary amines. This protocol is also utilized for the synthesis of a sangivamycin precursor by carrying out the Pd-catalyzed amination and aminocarbonylation simultaneously. The utility of this protocol is further demonstrated by the synthesis of the drugs moclobemide and nikethamide.
- Bhanage, Bhalchandra M.,Bhilare, Shatrughn,Gaikwad, Vinayak,Gupta, Gaurav,Kapdi, Anant R.,Sanghvi, Yogesh S.,Shah, Jagrut
-
supporting information
p. 4239 - 4248
(2019/11/14)
-
- Monoamine oxidase-A targeting probe for prostate cancer imaging and inhibition of metastasis
-
Mitochondrial enzyme monoamine oxidase (MAO-A) is known to be overexpressed in prostate cancer (PCa) cells. Herein, we have developed a two-photon probe (PCP-1) for selectively targeting and imaging the MAO-A in PCa. Supported by enzymatic docking and in vitro experiments, PCP-1 showed efficiency to visualize MAO-A overexpressing cells and inhibit their growth and metastasis potential.
- Kim, Won Young,Won, Miae,Salimi, Abbas,Sharma, Amit,Lim, Jong Hyeon,Kwon, Seung-Hae,Jeon, Joo-Yeong,Lee, Jin Yong,Kim, Jong Seung
-
supporting information
p. 13267 - 13270
(2019/11/19)
-
- An Efficient Catalytic Amidation of Esters Promoted by N-Heterocyclic Carbenes
-
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
-
p. 1595 - 1602
(2019/03/26)
-
- Tetramethyl Orthosilicate (TMOS) as a Reagent for Direct Amidation of Carboxylic Acids
-
Tetramethyl orthosilicate (TMOS) is shown to be an effective reagent for direct amidation of aliphatic and aromatic carboxylic acids with amines and anilines. The amide products are obtained in good to quantitative yields in pure form directly after workup without the need for any further purification. A silyl ester as the putative activated intermediate is observed by NMR methods. Amidations on a 1 mol scale are demonstrated with a favorable process mass intensity.
- Braddock, D. Christopher,Lickiss, Paul D.,Rowley, Ben C.,Pugh, David,Purnomo, Teresa,Santhakumar, Gajan,Fussell, Steven J.
-
supporting information
p. 950 - 953
(2018/02/23)
-
- Air-stable Bis(pentamethylcyclopentadienyl) Zirconium Perfluorooctanesulfonate as an Efficient and Recyclable Catalyst for the Synthesis of N-substituted Amides
-
Bis(pentamethylcyclopentadienyl) zirconium perfluorooctanesulfonate is an air-stable and water-tolerant Lewis acid. This complex exhibited good thermal stability and high solubility in polar organic solvents. The compound showed relatively strong acidity, with an acid strength of 0.8Ho≤3.3, and high catalytic efficiency for the synthesis of N-substituted amides via the reaction of carboxylic acids with amines, the Ritter reaction of nitriles with alcohols, and the amination of alcohols with amides. Moreover, the complex had good reusability. This catalytic system affords a simple and efficient way to synthesize N-substituted amides.
- Li, Ningbo,Wang, Lingxiao,Zhang, Liting,Zhao, Wenjie,Qiao, Jie,Xu, Xinhua,Liang, Zhiwu
-
p. 3532 - 3538
(2018/08/01)
-
- Preparation method of acetylene amide mediated thioacid amide and application of acetylene amide mediated thioacid amide in thiopeptide synthesis
-
The invention discloses an acetylene amide mediated method for selectively synthesizing carbonyl thioesters and ordinary thioesters. The ordinary thioesters are further used for preparing amides and peptides, and the carbonyl thioesters are used for preparing thioamides and thiopeptides. An addition reaction is carried out between acetylene amide in m-xylene and thiocarboxylic acid to selectivelyobtain the carbonyl thioester and ordinary thioester of which the ratio is 3:1 under the condition of 40 DEG C below zero; the ordinary thioesters can carry out a combination reaction with amines to produce amides and peptides; and the carbonyl can carry out a combination reaction with the amines to produce thioamides and thiopeptides. The method disclosed by the invention is mild in reaction conditions, free of any metal catalyst, high in reaction speed, high in yield, simple in operation and wide in application range. With respect to chiral thiocarboxylic acid in a position alpha of carboxyl, when thioamide bonds or thiopeptide bonds are formed from the carbonyl thioesters or when amido bonds or peptide bonds are formed from the ordinary thioesters, any racemization phenomenon can be avoided.
- -
-
Paragraph 0057
(2018/09/21)
-
- Integration of co2 reduction with subsequent carbonylation: Towards extending chemical utilization of co2
-
Currently, it still remains a challenge to amplify the spectrum of chemical fixation of CO2, although enormous progress has been achieved in this field. In view of the widespread applications of CO in a myriad of industrial carbonylation processes, an alternative strategy is proposed in which CO2 reduction to CO is combined with carbonylation with CO generated ex situ, which affords efficiently pharmaceutically and agrochemically attractive molecules. As such, CO2 in this study was efficiently reduced by triphenysilane using CsF to CO in a sealed two-chamber reactor. Subsequently, palladium-catalyzed aminocar-bonylation, carbonylative Sonogashira coupling of aryl iodides, and rhodium(I)-mediated Pauson–Khand-type reaction proceeded smoothly to yield amides, alkynones, and bicyclic cy-clopentenones, respectively. Furthermore, the formed alkynones can further be successfully converted to a series of heterocycles, for example, pyrazoles, 3a-hydroxyisoxazolo[3,2-a]isoindol-8-(3aH)-one derivatives and pyrimidines in moderate yields. The striking features of this protocol include operational simplicity, high efficiency, and relatively broad application scope, which represents an alternative avenue for CO2 transformation.
- Lang, Xian-Dong,He, Liang-Nian
-
-
- Synthesis and pharmacological evaluation of benzamide derivatives as potent and selective sigma-1 protein ligands
-
A series of novel benzamide-derived compounds was designed, synthesized and pharmacologically evaluated. Among all 37 synthesized compounds, two series were developed with the modulation of the nature, the position of atoms or groups on the benzamide scaffold, but also the nature of the amine group separated from the benzamide with 2, 3 or 4 methylene groups. In vitro competition binding assays against sigma proteins (sigma-1 S1R and sigma-2 S2R) revealed that most of them conferred S2R/S1R selectivity toward without cytotoxic effects on SY5Y cells, especially with the first series with compounds 7a-z. Some selected compounds were also evaluated for their agonist and antagonist activities on a panel of 40 receptors. Results showed the importance of the nature and the position with halogeno atom on the benzamide scaffold, the length chain but also the contribution of the hydrophobic part on the amine group. Among them, compounds 7i, w, y with Cl, CN or NO2 groups at the 4-position of the benzamide scaffold showed excellent affinity for S1R (Ki = 1.2–3.6 nM), selectivity for S2R (Ki up to 1400 nM) and high selectivity index (IC50(SY5Y)/Ki (S1R) ratio from 28 000 to 83 000). Futhermore, these compounds presented an excellent safety profile over 40 other receptors. These derivatives will be selected for further biological investigations.
- Donnier-Maréchal, Marion,Carato, Pascal,Larchanché, Paul-Emmanuel,Ravez, Séverine,Boulahjar, Rajaa,Barczyk, Amélie,Oxombre, Bénédicte,Vermersch, Patrick,Melnyk, Patricia
-
p. 964 - 978
(2017/08/01)
-
- Copper-catalyzed one-pot oxidative amidation between methylarenes and amines
-
A new method for the direct one-pot oxidative amidation between methylarenes and amines catalyzed by copper has been developed. This method integrates methylarene oxidation and amide bond formation, which are usually accomplished separately, into a single operation. In addition, the reaction provides a relatively high yield and has a wide substrate scope. Moreover, the starting reagents are abundant and available in a convenient way at a cheaper price.
- Yang, Yuhang,Gu, Jiajia,Fang, Zheng,Yang, Zhao,Wei, Ping,Guo, Kai
-
p. 22797 - 22801
(2017/07/10)
-
- A Visible-Light-Driven, Metal-free Route to Aromatic Amides via Radical Arylation of Isonitriles
-
The photochemical metal-free carboamidation of aryl radicals has been exploited for the preparation of aromatic amides, including hetero- and polyaromatic derivatives, under visible light irradiation of arylazo sulfones in the presence of isocyanides in aqueous acetonitrile. The process was useful for the smooth preparation of the antidepressant moclobemide. (Figure presented.).
- Malacarne, Marco,Protti, Stefano,Fagnoni, Maurizio
-
supporting information
p. 3826 - 3830
(2017/11/15)
-
- Mono- and double carbonylation of aryl iodides with amine nucleophiles in the presence of recyclable palladium catalysts immobilised on a supported dicationic ionic liquid phase
-
Silica modified with organic dicationic moieties proved to be an excellent support for palladium catalysts used in the aminocarbonylation of aryl iodides. By an appropriate choice of the reaction conditions, the same catalyst could be used for selective mono- or double carbonylations leading to amide and α-ketoamide products, respectively. The best catalyst could be recycled for at least 10 consecutive runs with a loss of palladium below the detection limit. By the application of the new support, efficient catalyst recycling could be achieved under mild reaction conditions (under low pressure and in a short reaction time). Palladium-leaching data support a mechanism with dissolution - re-precipitation of the active palladium species.
- Papp,Szabó,Srankó,Sáfrán,Kollár,Skoda-F?ldes
-
p. 44587 - 44597
(2017/09/26)
-
- Direct, efficient NHC-catalysed aldehyde oxidative amidation:: In situ formed benzils as unconventional acylating agents
-
A new N-heterocyclic carbene-catalysed oxidative amidation of aldehydes has been developed which converts the aldehyde to a benzil acylating agent in situ. The process uses an air-recyclable oxidant and a nucleophilic co-catalyst and does not require the use of a large excess of either one coupling partner or catalyst.
- Kumar, Vikas,Connon, Stephen J.
-
supporting information
p. 10212 - 10215
(2017/09/22)
-
- One-Pot Amide Bond Formation from Aldehydes and Amines via a Photoorganocatalytic Activation of Aldehydes
-
A mild, one-pot, and environmentally friendly synthesis of amides from aldehydes and amines is described. Initially, a photoorganocatalytic reaction of aldehydes with di-isopropyl azodicarboxylate leads to an intermediate carbonyl imide, which can react with a variety of amines to afford the desired amides. The initial visible light-mediated activation of a variety of monosubstituted or disubstituted aldehydes is usually fast, occurring in a few hours. Following the photocatalytic reaction, addition of the primary amine at room temperature or the secondary amine at elevated temperatures leads to the corresponding amide from moderate to excellent yields without epimerization. This methodology was applied in the synthesis of Moclobemide, a drug against depression and social anxiety.
- Papadopoulos, Giorgos N.,Kokotos, Christoforos G.
-
p. 7023 - 7028
(2016/08/30)
-
- Visible-Light-Mediated Synthesis of Amides from Aldehydes and Amines via in Situ Acid Chloride Formation
-
An efficient visible-light photocatalysis-based one-pot amide synthesis method was developed; visible-light irradiation of a mixture of an aldehyde, tert-butyl hydrogen peroxide, and N-chlorosuccinimide using a Ru(bpy)3Cl2 photocatalyst afforded an acid chloride, which subsequently reacted with amine to yield the corresponding amide. The reaction was used to synthesize moclobemide and a D3 receptor intermediate.
- Iqbal, Naeem,Cho, Eun Jin
-
p. 1905 - 1911
(2016/03/15)
-
- Mild and efficient preparation method of alpha-acyloxy alkenyl amide compound and application thereof to synthesis of amide and polypeptide
-
The invention discloses a mild and efficient preparation method of an alpha-acyloxy alkenyl amide compound and application thereof to synthesis of an amide and a polypeptide. The alpha-acyloxy alkenyl amide compound is obtained by an addition reaction of alkyne amide and carboxylic acid in dichloromethane under a condition that the temperature is 0 to 50 DEG C; the product alpha-acyloxy alkenyl amide compound can generate the amide or the polypeptide with amides through combination reaction; the two reactions can be carried out step by step and can also be carried out in one pot; when the two reactions are carried out in one pot, the product alpha-acyloxy alkenyl amide compound does not need to be purified from the former reaction and the amide compound is directly added to react, wherein in the reaction of generating the amide or the polypeptide, a solvent can also be water, so that a novel method for fixed-site decoration and marking of biological macromolecules including proteins, nucleic acid and the like in a water phase is provided. The mild and efficient preparation method has moderate reaction conditions and does not need a metal catalyst; when the carboxylic acid, which has chirality on an alpha site of carboxyl, forms an amide bond or a peptide bond, no racemization occurs; the mild and efficient preparation method is simple to operate and wide in application range.
- -
-
-
- Ynamides as Racemization-Free Coupling Reagents for Amide and Peptide Synthesis
-
A highly efficient, two-step, one-pot synthetic strategy for amides and peptides was developed by employing ynamides as novel coupling reagents under extremely mild reaction conditions. The ynamides not only are effective for simple amide and dipeptide synthesis but can also be used for peptide segment condensation. Importantly, no racemization was detected during the activation of chiral carboxylic acids. Excellent amidation selectivity toward amino groups in the presence of -OH, -SH, -CONH2, ArNH2, and the NH of indole was observed, making the protection of these functional groups unnecessary in amide and peptide synthesis.
- Hu, Long,Xu, Silin,Zhao, Zhenguang,Yang, Yang,Peng, Zhiyuan,Yang, Ming,Wang, Changliu,Zhao, Junfeng
-
supporting information
p. 13135 - 13138
(2016/10/22)
-
- Chloroform as a Carbon Monoxide Precursor: In or Ex Situ Generation of CO for Pd-Catalyzed Aminocarbonylations
-
Conditions for the rapid hydrolysis of chloroform to carbon monoxide (CO) using heterogeneous CsOH·H2O are described. CO and 13CO can be generated cleanly and rapidly under mild conditions and can be captured either in or ex situ in palladium-catalyzed aminocarbonylation reactions. Utilizing only 1-3 equiv of CO allows for the aminocarbonylation of aryl, vinyl, and benzyl halides with a wide variety of primary and secondary amines giving amide products in good to excellent yields. (Chemical Equation Presented).
- Gockel, Samuel N.,Hull, Kami L.
-
supporting information
p. 3236 - 3239
(2015/07/15)
-
- Iron-catalyzed benzamide formation. Application to the synthesis of moclobemide
-
A convenient and user-friendly method to yield benzamides from primary and secondary amines and various benzylic alcohols in the presence of a cheap iron salt (FeCl2$4H2O) and tert-butylhydroperoxide (70% in water) as a stoichiometric oxidant is described. Control experiments indicated that this reaction might involve radical species. This method proved to be general, generating a family of 30 benzamides and was applied to the preparative synthesis of anti-anxiety drug moclobemide.
- Bantreil, Xavier,Kanfar, Nasreddine,Gehin, Nicolas,Golliard, Ethan,Ohlmann, Pauline,Martinez, Jean,Lamaty, Frédéric
-
p. 5093 - 5099
(2014/12/10)
-
- Iron-catalyzed benzamide formation. Application to the synthesis of moclobemide
-
A convenient and user-friendly method to yield benzamides from primary and secondary amines and various benzylic alcohols in the presence of a cheap iron salt (FeCl2·4H2O) and tert-butylhydroperoxide (70% in water) as a stoichiometric oxidant is described. Control experiments indicated that this reaction might involve radical species. This method proved to be general, generating a family of 30 benzamides and was applied to the preparative synthesis of anti-anxiety drug moclobemide.
- Bantreil, Xavier,Kanfar, Nasreddine,Gehin, Nicolas,Golliard, Ethan,Ohlmann, Pauline,Martinez, Jean,Lamaty, Frédéric
-
p. 5093 - 5099
(2014/07/08)
-
- Mesoporous niobium oxide spheres as an effective catalyst for the transamidation of primary amides with amines
-
Mesoporous niobium oxide spheres (MNOS), conveniently prepared by a novel antisolvent precipitation approach, have been shown to be an effective catalyst for the transamidation of primary amides with amines. This novel transamidation can be efficiently carried out under solvent-free conditions and is applicable to a wide range of primary amides and amines to provide N-alkyl amides in good to excellent yields. The catalyst is highly stable and reusable. The application of this transamidation reaction has been demonstrated in the synthesis of antidepressant drug moclobemide and other druglike compounds.
- Ghosh, Subhash Chandra,Li, Cheng Chao,Zeng, Hua Chun,Ngiam, Joyce S. Y.,Seayad, Abdul M.,Chen, Anqi
-
p. 475 - 484
(2014/05/20)
-
- Efficient fluoride-catalyzed conversion of CO2 to CO at room temperature
-
A protocol for the efficient and selective reduction of carbon dioxide to carbon monoxide has been developed. Remarkably, this oxygen abstraction step can be performed with only the presence of catalytic cesium fluoride and a stoichiometric amount of a disilane in DMSO at room temperature. Rapid reduction of CO2 to CO could be achieved in only 2 h, which was observed by pressure measurements. To quantify the amount of CO produced, the reduction was coupled to an aminocarbonylation reaction using the two-chamber system, COware. The reduction was not limited to a specific disilane, since (Ph 2MeSi)2 as well as (PhMe2Si)2 and (Me3Si)3SiH exhibited similar reactivity. Moreover, at a slightly elevated temperature, other fluoride salts were able to efficiently catalyze the CO2 to CO reduction. Employing a nonhygroscopic fluoride source, KHF2, omitted the need for an inert atmosphere. Substituting the disilane with silylborane, (pinacolato)BSiMe2Ph, maintained the high activity of the system, whereas the structurally related bis(pinacolato)diboron could not be activated with this fluoride methodology. Furthermore, this chemistry could be adapted to 13C-isotope labeling of six pharmaceutically relevant compounds starting from Ba13CO 3 in a newly developed three-chamber system.
- Lescot, Camille,Nielsen, Dennis U.,Makarov, Ilya S.,Lindhardt, Anders T.,Daasbjerg, Kim,Skrydstrup, Troels
-
supporting information
p. 6142 - 6147
(2014/05/20)
-
- Efficient palladium-catalyzed aminocarbonylation of aryl iodides using palladium nanoparticles dispersed on siliceous mesocellular foam
-
A highly dispersed nanopalladium catalyst supported on mesocellular foam (MCF), was successfully used in the heterogeneous catalysis of aminocarbonylation reactions. During the preliminary evaluation of this catalyst it was discovered that the supported palladium nanoparticles exhibited a "release and catch" effect, meaning that a minor amount of the heterogeneous palladium became soluble and catalyzed the reaction, after which it re-deposited onto the support. It's catchy! An efficient palladium-catalyzed protocol for the aminocarbonylation of aryl iodides is reported in which the palladium immobilized on the amino-functionalized mesocellular foam (MCF) was found to operate through a "release and catch" mechanism (see scheme). A very low content of palladium was found in solution upon completion of the reaction and a variety of different aryl iodides were converted to the corresponding amides under mild conditions.
- Tinnis, Fredrik,Verho, Oscar,Gustafson, Karl P. J.,Tai, Cheuk-Wai,Baeckvall, Jan-E.,Adolfsson, Hans
-
supporting information
p. 5885 - 5889
(2014/05/20)
-
- Palladium nanoparticles supported on ZIF-8 as an efficient heterogeneous catalyst for aminocarbonylation
-
Pd nanoparticles supported on ZIF-8 (PdNPs/ZIF-8) are described as an efficient heterogeneous catalyst for the aminocarbonylation of bromoarenes in the presence of phosphines and iodoarenes under phosphine-free conditions. The catalyst can be readily prepared and is air-stable. The palladium loading can be as low as 1 wt %, and the catalyst was recycled four times with negligible change in catalytic performance. A variety of pharmaceutically important amides was readily synthesized. A TON of 2540 was easily achieved in a batch reaction by scaling up to a gram scale. The catalyst reported can also be applied to the synthesis of cyclic and primary amides as well as an alkoxycarbonylation reaction to form an ester.
- Dang, Tuan T.,Zhu, Yinghuai,Ngiam, Joyce S. Y.,Ghosh, Subhash C.,Chen, Anqi,Seayad, Abdul M.
-
p. 1406 - 1410
(2013/07/26)
-
- Direct amide formation from unactivated carboxylic acids and amines
-
The direct coupling of unactivated carboxylic acids with amines can be performed in toluene 110 °C in the absence of catalyst. The use of simple zirconium catalysts at 5 mol% loading gave amide formation in as little as 4 h.
- Allen, C. Liana,Chhatwal, A. Rosie,Williams, Jonathan M. J.
-
supporting information; experimental part
p. 666 - 668
(2012/01/13)
-