Activity Of Amides Research Articles

Regioselective Synthesis of 3-Aminoimidazo[1,2-a]pyrimidines with Triflic Anhydride

The regioselective synthesis of 3-aminoimidazo[1,2-a]pyrimidines via triflic anhydride mediated amide activation and intramolecular cyclisation is reported. The nature of the added pyridine base allows access to both regioisomers from a simple common precursor. The method tolerates a range of functional groups and provides access to novel heterocyclic scaffolds.

Palladium-catalyzed 2-pyridylmethyl-directed β-C(sp3)[sbnd]H activation and cyclization of aliphatic amides with gem-dibromoolefins: A rapid access to γ-lactams

The direct Pd-catalyzed β-C(sp3)H activation and cyclization of aliphatic amides bearing a removable 2-pyridylmethyl directing group with gem-dibromoolefins is described for the first time to construct a variety of γ-lactams. The resulting products with Z- and E-configurations can be easily separated and purified after the reaction, demonstrating the effectiveness and applicability of the method herein developed.

Total Synthesis of Cordyheptapeptide A

The first total synthesis of cordyheptapeptide A is described. The synthesis is accomplished by a convergent approach featuring a combination of peptide coupling and the Ugi reaction for the preparation of the main building blocks and the acyclic precursor. The assembly of an N-methylated fragment by the Ugi reaction comprised the utilization of a convertible isonitrile followed by activation of the C-terminal amide. Two different macrocyclization sites were evaluated, proving greater efficacy the macrolactamization at the site Ile-Tyr, likely due of a more suitable conformational bias of the acyclic precursor having an internal β-turn centered at the N-Me-d-Phe-Pro moiety.

Direct Regioselective Synthesis of Tetrazolium Salts by Activation of Secondary Amides under Mild Conditions

Tetrazolium salts are biologically active molecules that have found broad applications in biochemical assays. A regioselective synthesis of tetrazolium salts is described through a formal (3 + 2) cycloaddition. The possibility of employing simple amides and azides as starting material and the mild conditions allow a broad functional group tolerance.

Ni-mediated C–N activation of amides and derived catalytic transformations

Amide, as a ubiquitous functional group, is essential in various aspects of chemistry and biology. Although the history of studying amide is rich and fruitful, the synthetic application of amide is very limited due to the inertness of amide C–N bond. Recently, significant advances have been achieved towards the nickel-mediated C–N activation of amides. This approach allows a facile generation of acyl-nickel intermediates, and a number of unique transformations have been designed and realized based on the amide C–N bond activation. Focused on the catalytic transformation, this review summarizes and categorizes the recent advances on the synthetic applications of Ni-mediated C–N bond activation of amides.

Metal-chelating properties and antiviral activity of some 2-hydroxyphenyl amides

Influenza virus is an hot topic in medicinal chemistry and great efforts are ongoing for the discover of new antivirals able to overcome problems related to resistant strains and adverse side effects of current drugs. Influenza virus endonuclease is an attractive target for antiviral drug development and in particular the strategy to chelate the metal ion(s) within the active site proved to be an efficient mode to inhibit enzymatic activity. Our previous findings revealed that 2-hydroxyamide derivatives are able to chelate Mg2+ ions, forming complexes with different stoichiometric ratios. Here we report on the activity of the three ligands N-(4-fluorobenzyl)-2-hydroxybenzamide, N-(4-fluorobenzyl)-2,3-dihydroxybenzamide, and N1,N3-bis(4-fluorobenzyl)-2-hydroxyisophthalamide, containing the salicylic group, and their Mg2+ complexes (7)–(9), evaluated by means of virus yield assay in influenza virus-infected MDCK cells and vRNP reconstitution assay in HEK293T cells. In some cases, promising anti-influenza activities with EC50 values in the low micromolar range were found. As a contribute to clarify the activity in cells of the ligands, here we also present a study on the their coordinating properties towards the other essential metal ion Cu(II), carried out by potentiometric and calorimetric measurements.

Synthesis and anti-inflammatory activity of triazole-based macrocyclic amides through click chemistry

ABSTRACTTriazole-based macrocyclic amides 1–12 with amide group as the intrannular functionality has been synthesized through click chemistry. Triazole-based macrocyclic amides 1–12 show good anti-inflammatory activity even at low concentration (50 µg/mL) when compared to that of the reference drug prednisolone. BINOL-based chiral macrocyclic amides and pyridine-based macrocyclic amides show better anti-inflammatory activity than the other synthesized macrocyclic amides.

Neil K. Garg

Angewandte Chemie International EditionVolume 56, Issue 14 p. 3748-3748 Author ProfileFree Access Neil K. Garg First published: 31 January 2017 https://doi.org/10.1002/anie.201700568Citations: 1AboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat Graphical Abstract „I can never resist jelly beans. I would have liked to have discovered the wheel. ...“ This and more about Neil K. Garg can be found on page 3748. Neil K. Garg The author presented on this page has recently published his 10th article in Angewandte Chemie in 10 years: “Nickel-Catalyzed Esterification of Aliphatic Amides”: L. Hie, E. L. Baker, S. M. Anthony, J.-N. Desrosiers, C. Senanayake, N. K. Garg, Angew. Chem. Int. Ed. 2016, 55, 15129; Angew. Chem. 2016, 128, 15353. Date of birth: December 18, 1978 Position: Professor, Department of Chemistry and Biochemistry, University of California, Los Angeles E-mail: neilgarg@chem.ucla.edu Homepage: http://garg.chem.ucla.edu/ ORCID: 0000-0002-7793-2629 Education: 2000 BS, New York University 2005 PhD supervised by Professor Brian M. Stoltz, California Institute of Technology 2005–2007 Postdoctoral studies with Professor Larry E. Overman, University of California, Irvine Awards: 2015 Arthur C. Cope Scholar Award; 2016 Mitsui Chemicals Catalysis Science Award of Encouragement; 2016 Merck Award, Royal Society of Chemistry; 2016 Guggenheim Fellowship; 2016 Thieme–IUPAC Prize; 2016 Tetrahedron Young Investigator Award; 2017 Elias J. Corey Award for Outstanding Original Contribution in Organic Synthesis, American Chemical Society Research: Methodology, catalysis, total synthesis Hobbies: Hiking, editing videos, watching basketball I can never resist jelly beans. I would have liked to have discovered the wheel. The most exciting thing about my research is my co-workers and their ideas. Guaranteed to make me laugh is the movie Forgetting Sarah Marshall. The most enjoyable chemistry adventure in my career was chasing the dragmacidin alkaloids in cahoots with Richmond Sarpong and Daniel Caspi, as a graduate student in the Stoltz Lab. My top three films of all time are Zoolander, Cinema Paradiso, and Star Wars. The downside of my job is that it is fun and perhaps too addictive. My favorite quote is “I feel like I am taking crazy pills” (Mugatu from Zoolander). I like refereeing because it is a great way to engage in the newest science and be an advocate for my field. The biggest problem that scientists face is being overly critical of each other. What I look for first in a publication is something unexpected. My favorite piece of research is the Woodward/Eschenmoser synthesis of vitamin B12. If I won the lottery, I would invest the cash. When I'm frustrated, I try to have a good laugh. My 5 top papers: References 1“The First Total Synthesis of Dragmacidin D”: N. K. Garg, R. Sarpong, B. M. Stoltz, J. Am. Chem. Soc. 2002, 124, 13179. (Led to my current interests in complex-molecule synthesis and cross-coupling methods.) 2“Total Synthesis of (−)-Sarain A”: N. K. Garg, S. Hiebert, L. E. Overman, Angew. Chem. Int. Ed. 2006, 45, 2912; Angew. Chem. 2006, 118, 2978. (My contributions as a postdoc to the total synthesis of sarain A, which had been an ongoing pursuit in the Overman laboratory). 3“Cross-Coupling Reactions of Aryl Pivalates with Boronic Acids”: K. W. Quasdorf, X. Tian, N. K. Garg, J. Am. Chem. Soc. 2008, 130, 14422. (This was the first paper from my independent career. Demonstrated that phenol-derived esters can undergo cross-coupling reactions by using nickel catalysis.) 4“Total Synthesis of (−)-N-Methylwelwitindolinone C Isothiocyanate”: A. D. Huters, K. W. Quasdorf, N. K. Garg, J. Am. Chem. Soc. 2011, 133, 15797. (The first total synthesis of a long-standing target.) 5“Conversion of amides to esters by the nickel-catalysed activation of amide C−N bonds”: L. Hie, N. F. F. Nathel, T. K. Shah, E. L. Baker, X. Hong, Y.-F. Yang, P. Liu, K. N. Houk, N. K. Garg, Nature 2015, 524, 79 (An exciting “post-tenure” direction for my laboratory, involving the activation of amide C−N bonds). Citing Literature Volume56, Issue14March 27, 2017Pages 3748-3748 ReferencesRelatedInformation

Synthesis, Characterization and Biological Activities of Creatinine Amides and Creatinine Schiff Bases.

In spite of substantial progress in scientific cognizance and medical technology, still infectious diseases are among the leading cause of morbidity and mortality. Creatinine and Schiff bases are well known for their diverse range of biological activities and thought to be emerging and useful therapeutic target for the treatment of several diseases. The present work was aimed to illustrate the influence of substitution of amides and Schiff bases on creatinine and their antimicrobial, antioxidant and anti-urease effectiveness was determined. Creatinine substituted amides (1-2) and creatinine Schiff bases (3-7) were synthesized and characterized by NMR and IR spectral data in combination with elemental analysis. All the compounds (1-7) were investigated on Jack bean urease for their urease inhibitory potential. Investigation of antimicrobial activity of the compounds was made by the agar dilution method. Moreover, 1,1-diphenyl-2- picrylhydrazyl (DPPH) method was used to determine their antioxidant potential. Molecular docking studies were also carried out to elucidate their relationship with the binding pockets of the enzyme. The compounds were found to be potent inhibitors of urease. The synthesized derivatives exhibited significant inhibition against Gram-positive and Gram-negative bacterial strains, as compared to standard, ciprofloxacin. Creatinine based derivatives exhibited potential antifungal activity when tested on infectious and pathogenic fungal strains. Similarly, most of the compounds exhibited good antioxidant activity. These derivatives may serve as a source of potential antioxidants and also help to retard microbial growth in food industry. Similarly, the studies provide a basis for further research to develop more potent urease inhibitory compounds of medicinal /agricultural interest.

Synthesis and biological activity of pyridazine amides, hydrazones and hydrazides.

Optimization studies on compounds initially designed to be herbicides led to the discovery of a series of [6-(3-pyridyl)pyridazin-3-yl]amides exhibiting aphicidal properties. Systematic modifications of the amide moiety as well as the pyridine and pyridazine rings were carried out to determine if these changes could improve insecticidal potency. Structure-activity relationship (SAR) studies showed that changes to the pyridine and pyridazine rings generally resulted in a significant loss of insecticidal potency against green peach aphids [Myzus persicae (Sulzer)] and cotton aphids [(Aphis gossypii (Glover)]. However, replacement of the amide moiety with hydrazines, hydrazones, or hydrazides appeared to be tolerated, with small aliphatic substituents being especially potent. A series of aphicidal [6-(3-pyridyl)pyridazin-3-yl]amides were discovered as a result of random screening of compounds that were intially investigated as herbicides. Follow-up studies of the structure-activity relationship of these [6-(3-pyridyl)pyridazin-3-yl]amides showed that biosteric replacement of the amide moiety was widely tolerated suggesting that further opportunities for exploitation may exist for this new area of insecticidal chemistry. Insecticidal efficacy from the original hit, compound 1, to the efficacy of compound 14 produced greater than 10-fold potency improvement against Aphis gossypii and greater than 14-fold potency improvement against Myzus persicae. © 2016 Society of Chemical Industry.

Direct Catalytic Asymmetric Aldol Reaction of α-Alkylamides.

A catalytic asymmetric aldol reaction directly employing amides as latent enolates has remained elusive because of the resistance of amides to enolization. A direct aldol reaction of α-alkylamides without any electron-withdrawing group harnessed by specific activation of 7-azaindoline amides under soft Lewis acid/Brønsted base cooperative catalysis is reported. Diastereo- and enantioselective coupling with ynals and aromatic aldehydes as well as divergent functional group interconversion of the amide provided expeditious access to a variety of aliphatic and aromatic chiral building blocks.

Ultrasound-assisted green bromination of N-cinnamoyl amino acid amides – Structural characterization and antimicrobial evaluation

N-phenylpropenoyl amino acid amides have been brominated using two alternative sonochemically activated green chemistry procedures. The first synthetic procedure has involved an ultrasound assisted bromination in an aqueous medium using ionic liquid as a catalyst of the reaction, whereas in the second one an in situ formation of Br2 via oxidation of HBr by H2O2 has been used. For comparison, the conventional bromination procedure was also used. The newly brominated compounds were characterized by appropriate analytical techniques. A detailed NMR spectroscopic analysis and quantum chemical calculations using Density Functional Theory (DFT) methods have been used to define the stereochemistry of the products. The results confirmed the physicochemical identity and similar yields of the products obtained by the three synthetic procedures employed, and reveal the co-existence of two diastereoisomeric forms of the newly synthesized products. The antibacterial and antifungal activities of the dibrominated amides were evaluated.

The synthesis of unsymmetric diamides through Rh-catalyzed selective C–H bond activation of amides with isocyanates

Synthetic and mechanistic studies on Rh-catalyzed C–H activation of amides with isocyanates, resulting in one of the unsymmetric diamine products showing promising anti-cancer activity.

Synthesis, characterization and catalytic activity of rare-earth metal amides incorporating cyclohexyl bridged bis(β-diketiminato) ligands

The bridged bis(β-diketiminato) ligands supported rare-earth amides exhibited high catalytic activity towards the hydrophosphination of β-nitroalkene and α,β-unsaturated carbonyl derivatives with an excellent regioselectivity.

Synthesis, Characterization and Antiproliferative Activity of Certain Meclofenamic Acid Amides

Synthesis, Characterization and Antiproliferative Activity of Certain Meclofenamic Acid Amides

Mechanism of Nickel-Catalyzed Selective C-N Bond Activation in Suzuki-Miyaura Cross-Coupling of Amides: A Theoretical Investigation.

In textbooks, the low reactivity of amides is attributed to the strong resonance stability. However, Garg and co-workers recently reported the Ni-catalyzed activation of robust amide C-N bonds, leading to conversions of amides into esters, ketones, and other amides with high selectivity. Among them, the Ni-catalyzed Suzuki-Miyaura coupling (SMC) of N-benzyl-N-tert-butoxycarbonyl (N-Bn-N-Boc) amides with pinacolatoboronate (PhBpin) was performed in the presence of K3PO4 and water. Water significantly enhanced the reaction. With the aid of density functional theory (DFT) calculations, the present study explored the mechanism of the aforementioned SMC reaction as well as analyzed the weakening of amide C-N bond by N-functionalization. The most favorable pathway includes four basic steps: oxidative addition, protonation, transmetalation, and reductive elimination. Comparing the base- and water-free process, the transmetalation step with the help of K3PO4 and water is significantly more facile. Water efficiently protonates the basic N(Boc) (Bn) group to form a neutral HN(Boc) (Bn), which is easily removed. The transmetalation step is the rate-determining step with an energy barrier of 25.6 kcal/mol. Further, a DFT prediction was carried out to investigate the full catalytic cycle of a cyclic (amino) (aryl)carbene in the Ni-catalyzed SMC of amides, which provided clues for further design of catalysts.

Tf2O-TMDS combination for the direct reductive transformation of secondary amides to aldimines, aldehydes, and/or amines

The direct partial reduction of highly stable secondary amides to more reactive aldimines and aldehydes is a challenging yet highly demanding transformation. In this context, only three methods have been reported. We report herein an improved version of the Charette’s method. Our protocol consists of activation of secondary amides with triflic anhydride/2-fluoropyridine, and partial reduction of the resulting intermediates with 1,1,3,3-tetramethyldisiloxane (TMDS), which delivered aldimines or aldehydes upon acidic hydrolysis. Aromatic amides were reduced to the corresponding aldimines in 85%–100% NMR yields, and yields (NMR) from aliphatic amides were 72%–86%. Acidic hydrolysis of the aldimine intermediates afforded, in one-pot, the corresponding aldehydes in 80%–96% yields. A simple protocol was established to isolate labile aldimines in pure form in 92%–96% yields. The improved method gave generally higher yields as compared to the known ones, and features the use of cheaper and more atom-economical TMDS as a chemoselective reducing agent. In addition, a convenient extraction protocol has been established to allow the isolation of amines, which constitutes a mild method for the N-deacylation of amides, another highly desirable transformation. The extended method retains the advantages of the original method of Charette in terms of mild conditions, good functional group tolerance, and excellent chemoselectivity.

Nitroxyl-Radical-Catalyzed Oxidative Coupling of Amides with Silylated Nucleophiles through N-Halogenation.

A nitroxyl-radical-catalyzed oxidative coupling reaction between amines with an N-protecting electron-withdrawing group (EWG) and silylated nucleophiles was developed to furnish coupling products in high yields, thus opening up new frontiers in organocatalyzed reactions. This reaction proceeded through the activation of N-halogenated amides by a nitroxyl-radical catalyst, followed by carbon-carbon coupling with silylated nucleophiles. Studies of the reaction mechanism indicated that the nitroxyl radical activates N-halogenated amides, which are generated from N-EWG-protected amides and a halogenation reagent, to give the corresponding imines.

Metal-Free Intermolecular Coupling of Arenes with Secondary Amides: Chemoselective Synthesis of Aromatic Ketimines and Ketones, and N-Deacylation of Secondary Amides

The direct transformation of common secondary amides into aromatic ketimines and aromatic ketones with C-C bond formation is described. The reaction can also be used for N-deacylation of secondary amides to release amines. This method consists of in situ amide activation with triflic anhydride and intermolecular capture of the resulting highly electrophilic nitrilium intermediate with an arene. The reaction is applicable to various kinds of secondary amides (electrophiles), but only electron-rich and moderately electron-rich arenes can be used as nucleophiles. Thanks to the use of bench stable arenes instead of reactive and basic organometallics as nucleophiles, the reaction proceeded with high chemoselectivity at the secondary amido group in the presence of a series of sensitive functional groups such as aldehyde, ketone, ester, cyano, nitro, and tertiary amido groups. The reaction can be viewed as a Friedel-Crafts-type reaction using secondary amides as acylating agents or as an intermolecular version of the Bischler-Napieralski reaction.

Industrial landmarks in the development of sustainable production processes for the β-lactam antibiotic key intermediate 7-aminocephalosporanic acid (7-ACA)

Reflecting its importance as key intermediate for the large scale manufacture of β-lactam-type antibiotic drugs being widely used in antibacterial therapy, tremendous achievements have been made over the past decades in developing both, economically and ecologically attractive production routes for 7-aminocephalosporanic acid (7-ACA). Representative achievements and industrial landmarks thereof are described in this review. With cephalosporin C a starting material being accessible through fermentation is readily available in bulk quantities. Initially a chemical production process in organic medium based on various reagents for protection group chemistry and acyclic amide activation served as the large scale production technology for transforming cephalosporin C into 7-ACA. Subsequently, a bi-enzymatic production in aqueous reaction medium based on the use of a D-amino acid oxidase for side chain modification and glutaryl acylase for side chain cleavage was developed. This biocatalytic approach also turned out as an industrial scale solution and dramatically reduced the amount of waste from 31kg (for the "original chemical process") to less than 1kg. The latest innovation has been the extension of the two-step bi-enzymatic process towards a one-step monoenzymatic process based on a direct cleavage of the acyclic amide bond of cephalosporin C by means of a cephalosporin C acylase. This alternative, economically efficient and sustainable biotechnological process has already been established on industrial scale in recent years. These biotechnological achievements represent industrial landmarks in biocatalysis and examples that modern biocatalysis can contribute to the development and implementation of highly economical as well as sustainable industrial manufacturing processes.