Research

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19 pages, 5960 KiB

Open AccessArticle

Fast Amide Bond Cleavage Assisted by a Secondary Amino and a Carboxyl Group—A Model for yet Unknown Peptidases?

by Igor V. Komarov, Aleksandr Yu. Ishchenko, Aleksandr Hovtvianitsa, Viacheslav Stepanenko, Serhii Kharchenko, Andrew D. Bond and Anthony J. Kirby

Molecules 2019, 24(3), 572; https://doi.org/10.3390/molecules24030572 - 05 Feb 2019

Cited by 8 | Viewed by 5593

Abstract

Unconstrained amides that undergo fast hydrolysis under mild conditions are valuable sources of information about how amide bonds may be activated in enzymatic transformations. We report a compound possessing an unconstrained amide bond surrounded by an amino and a carboxyl group, each mounted [...] Read more.

Unconstrained amides that undergo fast hydrolysis under mild conditions are valuable sources of information about how amide bonds may be activated in enzymatic transformations. We report a compound possessing an unconstrained amide bond surrounded by an amino and a carboxyl group, each mounted in close proximity on a bicyclic scaffold. Fast amide hydrolysis of this model compound was found to depend on the presence of both the amino and carboxyl functions, and to involve a proton transfer in the rate-limiting step. Possible mechanisms for the hydrolytic cleavage and their relevance to peptide bond cleavage catalyzed by natural enzymes are discussed. Experimental observations suggest that the most probable mechanisms of the model compound hydrolysis might include a twisted amide intermediate and a rate-determining proton transfer. Full article

(This article belongs to the Special Issue Amide Bond Activation)

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9 pages, 2220 KiB

Open AccessCommunication

Selective C-N σ Bond Cleavage in Azetidinyl Amides under Transition Metal-Free Conditions

by Hengzhao Li, Zemin Lai, Adila Adijiang, Hongye Zhao and Jie An

Molecules 2019, 24(3), 459; https://doi.org/10.3390/molecules24030459 - 28 Jan 2019

Cited by 11 | Viewed by 4279

Abstract

Functionalization of amide bond via the cleavage of a non-carbonyl, C-N σ bond remains under-investigated. In this work, a transition-metal-free single-electron transfer reaction has been developed for the C-N σ bond cleavage of N-acylazetidines using the electride derived from sodium dispersions and [...] Read more.

Functionalization of amide bond via the cleavage of a non-carbonyl, C-N σ bond remains under-investigated. In this work, a transition-metal-free single-electron transfer reaction has been developed for the C-N σ bond cleavage of N-acylazetidines using the electride derived from sodium dispersions and 15-crown-5. Of note, less strained cyclic amides and acyclic amides are stable under the reaction conditions, which features the excellent chemoselectivity of the reaction. This method is amenable to a range of unhindered and sterically encumbered azetidinyl amides. Full article

(This article belongs to the Special Issue Amide Bond Activation)

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12 pages, 2616 KiB

Open AccessArticle

[2+2+2] Annulation of N-(1-Naphthyl)acetamide with Two Alkynoates via Cleavage of Adjacent C–H and C–N Bonds Catalyzed by an Electron-Deficient Rhodium(III) Complex

by Jyunichi Terasawa, Yu Shibata, Miho Fukui and Ken Tanaka

Molecules 2018, 23(12), 3325; https://doi.org/10.3390/molecules23123325 - 14 Dec 2018

Cited by 12 | Viewed by 3674

Abstract

It has been established that an electron-deficient cationic Cp^E-rhodium(III) complex catalyzes the non-oxidative [2+2+2] annulation of N-(1-naphthyl)acetamide with two alkynoates via cleavage of the adjacent C–H and C–N bonds to give densely substituted phenanthrenes under mild conditions (at 40 °C [...] Read more.

It has been established that an electron-deficient cationic Cp^E-rhodium(III) complex catalyzes the non-oxidative [2+2+2] annulation of N-(1-naphthyl)acetamide with two alkynoates via cleavage of the adjacent C–H and C–N bonds to give densely substituted phenanthrenes under mild conditions (at 40 °C under air). In this reaction, a dearomatized spiro compound was isolated, which may support the formation of a cationic spiro rhodacycle intermediate in the catalytic cycle. The use of N-(1-naphthyl)acetamide in place of acetanilide switched the reaction pathway from the oxidative [2+2+2] annulation-lactamization via C–H/C–H cleavage to the non-oxidative [2+2+2] annulation via C–H/C–N cleavage. This chemoselectivity switch may arise from stabilization of the carbocation in the above cationic spiro rhodacycle by the neighboring phenyl and acetylamino groups, resulting in the nucleophilic C–C bond formation followed by β-nitrogen elimination. Full article

(This article belongs to the Special Issue Amide Bond Activation)

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20 pages, 1995 KiB

Open AccessArticle

Understanding the Exceptional Properties of Nitroacetamides in Water: A Computational Model Including the Solvent

by Giovanni La Penna and Fabrizio Machetti

Molecules 2018, 23(12), 3308; https://doi.org/10.3390/molecules23123308 - 13 Dec 2018

Cited by 3 | Viewed by 3219

Abstract

Proton transfer in water involving C–H bonds is a challenge and nitro compounds have been studied for many years as good examples. The effect of substituents on acidity of protons geminal to the nitro group is exploited here with new p [...] Read more.

Proton transfer in water involving C–H bonds is a challenge and nitro compounds have been studied for many years as good examples. The effect of substituents on acidity of protons geminal to the nitro group is exploited here with new p

K_{a}

measurements and electronic structure models, the latter including explicit water environment. Substituents with the amide moiety display an exceptional combination of acidity and solubility in water. In order to find a rationale for the unexpected p

K_{a}

changes in the (ZZ

^{'}

)NCO- substituents, we measured and modeled the p

K_{a}

with Z=Z

^{'}

=H and Z=Z

^{'}

=methyl. The dominant contribution to the observed p

K_{a}

can be understood with advanced computational experiments, where the geminal proton is smoothly moved to the solvent bath. These models, mostly based on density-functional theory (DFT), include the explicit solvent (water) and statistical thermal fluctuations. As a first approximation, the change of p

K_{a}

can be correlated with the average energy difference between the two tautomeric forms (aci and nitro, respectively). The contribution of the solvent molecules interacting with the solute to the proton transfer mechanism is made evident. Full article

(This article belongs to the Special Issue Amide Bond Activation)

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10 pages, 3205 KiB

Open AccessFeature PaperCommunication

Pd-Catalyzed Suzuki-Miyaura Cross-Coupling of Pentafluorophenyl Esters

by Jonathan Buchspies, Daniel J. Pyle, Huixin He and Michal Szostak

Molecules 2018, 23(12), 3134; https://doi.org/10.3390/molecules23123134 - 29 Nov 2018

Cited by 16 | Viewed by 6451

Abstract

Although the palladium-catalyzed Suzuki-Miyaura cross-coupling of aryl esters has received significant attention, there is a lack of methods that utilize cheap and readily accessible Pd-phosphane catalysts, and can be routinely carried out with high cross-coupling selectivity. Herein, we report the first general method [...] Read more.

Although the palladium-catalyzed Suzuki-Miyaura cross-coupling of aryl esters has received significant attention, there is a lack of methods that utilize cheap and readily accessible Pd-phosphane catalysts, and can be routinely carried out with high cross-coupling selectivity. Herein, we report the first general method for the cross-coupling of pentafluorophenyl esters (pentafluorophenyl = pfp) by selective C–O acyl cleavage. The reaction proceeds efficiently using Pd(0)/phosphane catalyst systems. The unique characteristics of pentafluorophenyl esters are reflected in the fully selective cross-coupling vs. phenolic esters. Of broad synthetic interest, this report establishes pentafluorophenyl esters as new, highly reactive, bench-stable, economical, ester-based, electrophilic acylative reagents via acyl-metal intermediates. Mechanistic studies strongly support a unified reactivity scale of acyl electrophiles by C(O)–X (X = N, O) activation. The reactivity of pfp esters can be correlated with barriers to isomerization around the C(acyl)–O bond. Full article

(This article belongs to the Special Issue Amide Bond Activation)

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10 pages, 2334 KiB

Open AccessArticle

Computational Study of Mechanism and Thermodynamics of Ni/IPr-Catalyzed Amidation of Esters

by Chong-Lei Ji, Pei-Pei Xie and Xin Hong

Molecules 2018, 23(10), 2681; https://doi.org/10.3390/molecules23102681 - 18 Oct 2018

Cited by 18 | Viewed by 5038

Abstract

Nickel catalysis has shown remarkable potential in amide C–N bond activation and functionalization. Particularly for the transformation between ester and amide, nickel catalysis has realized both the forward (ester to amide) and reverse (amide to ester) reactions, allowing a powerful approach for the [...] Read more.

Nickel catalysis has shown remarkable potential in amide C–N bond activation and functionalization. Particularly for the transformation between ester and amide, nickel catalysis has realized both the forward (ester to amide) and reverse (amide to ester) reactions, allowing a powerful approach for the ester and amide synthesis. Based on density functional theory (DFT) calculations, we explored the mechanism and thermodynamics of Ni/IPr-catalyzed amidation with both aromatic and aliphatic esters. The reaction follows the general cross-coupling mechanism, involving sequential oxidative addition, proton transfer, and reductive elimination. The calculations indicated the reversible nature of amidation, which highlights the importance of reaction thermodynamics in related reaction designs. To shed light on the control of thermodynamics, we also investigated the thermodynamic free energy changes of amidation with a series of esters and amides. Full article

(This article belongs to the Special Issue Amide Bond Activation)

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12 pages, 1463 KiB

Open AccessArticle

Synthesis of Gemcitabine-Threonine Amide Prodrug Effective on Pancreatic Cancer Cells with Improved Pharmacokinetic Properties

by Sungwoo Hong, Zhenghuan Fang, Hoi-Yun Jung, Jin-Ha Yoon, Soon-Sun Hong and Han-Joo Maeng

Molecules 2018, 23(10), 2608; https://doi.org/10.3390/molecules23102608 - 11 Oct 2018

Cited by 22 | Viewed by 5861

Abstract

To investigate the amino acid transporter-based prodrug anticancer strategy further, several amino acid-conjugated amide gemcitabine prodrugs were synthesized to target amino acid transporters in pancreatic cancer cells. The structures of the synthesized amino acid-conjugated prodrugs were confirmed by ¹H-NMR and LC-MS. The [...] Read more.

To investigate the amino acid transporter-based prodrug anticancer strategy further, several amino acid-conjugated amide gemcitabine prodrugs were synthesized to target amino acid transporters in pancreatic cancer cells. The structures of the synthesized amino acid-conjugated prodrugs were confirmed by ¹H-NMR and LC-MS. The pancreatic cancer cells, AsPC1, BxPC-3, PANC-1 and MIAPaCa-2, appeared to overexpress the amino acid transporter LAT-1 by conventional RT-PCR. Among the six amino acid derivatives of gemcitabine, threonine derivative of gemcitabine (Gem-Thr) was more effective than free gemcitabine in the pancreatic cancer cells, BxPC-3 and MIAPaCa-2, respectively, in terms of anti-cancer effects. Furthermore, Gem-Thr was metabolically stable in PBS (pH 7.4), rat plasma and liver microsomal fractions. When Gem-Thr was administered to rats at 4 mg/kg i.v., Gem-Thr was found to be successfully converted to gemcitabine via amide bond cleavage. Moreover, the Gem-Thr showed the increased systemic exposure of formed gemcitabine by 1.83-fold, compared to free gemcitabine treatment, due to the significantly decreased total clearance (0.60 vs. 4.23 mL/min/kg), indicating that the amide prodrug approach improves the metabolic stability of gemcitabine in vivo. Taken together, the amino acid transporter-targeting gemcitabine prodrug, Gem-Thr, was found to be effective on pancreatic cancer cells and to offer an efficient potential means of treating pancreatic cancer with significantly better pharmacokinetic characteristics than gemcitabine. Full article

(This article belongs to the Special Issue Amide Bond Activation)

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19 pages, 5644 KiB

Open AccessArticle

Density Functional Studies on Secondary Amides: Role of Steric Factors in Cis/Trans Isomerization

by Balmukund S. Thakkar, John Sigurd M. Svendsen and Richard A. Engh

Molecules 2018, 23(10), 2455; https://doi.org/10.3390/molecules23102455 - 25 Sep 2018

Cited by 7 | Viewed by 6573

Abstract

Cis/trans isomerization of amide bonds is a key step in a wide range of biological and synthetic processes. Occurring through C-N amide bond rotation, it also coincides with the activation of amides in enzymatic hydrolysis. In recently described QM studies of cis/trans isomerization [...] Read more.

Cis/trans isomerization of amide bonds is a key step in a wide range of biological and synthetic processes. Occurring through C-N amide bond rotation, it also coincides with the activation of amides in enzymatic hydrolysis. In recently described QM studies of cis/trans isomerization in secondary amides using density functional methods, we highlighted that a peptidic prototype, such as glycylglycine methyl ester, can suitably represent the isomerization and complexities arising out of a larger molecular backbone, and can serve as the primary scaffold for model structures with different substitution patterns in order to assess and compare the steric effect of the substitution patterns. Here, we describe our theoretical assessment of such steric effects using tert-butyl as a representative bulky substitution. We analyze the geometries and relative stabilities of both trans and cis isomers, and effects on the cis/trans isomerization barrier. We also use the additivity principle to calculate absolute steric effects with a gradual increase in bulk. The study establishes that bulky substitutions significantly destabilize cis isomers and also increases the isomerization barrier, thereby synergistically hindering the cis/trans isomerization of secondary amides. These results provide a basis for the rationalization of kinetic and thermodynamic properties of peptides with potential applications in synthetic and medicinal chemistry. Full article

(This article belongs to the Special Issue Amide Bond Activation)

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10 pages, 1260 KiB

Open AccessCommunication

Ruthenium-Based Catalytic Systems Incorporating a Labile Cyclooctadiene Ligand with N-Heterocyclic Carbene Precursors for the Atom-Economic Alcohol Amidation Using Amines

by Cheng Chen, Yang Miao, Kimmy De Winter, Hua-Jing Wang, Patrick Demeyere, Ye Yuan and Francis Verpoort

Molecules 2018, 23(10), 2413; https://doi.org/10.3390/molecules23102413 - 20 Sep 2018

Cited by 11 | Viewed by 3810

Abstract

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 [...] Read more.

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. Full article

(This article belongs to the Special Issue Amide Bond Activation)

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10 pages, 1067 KiB

Open AccessArticle

Palladium-Catalyzed Room Temperature Acylative Cross-Coupling of Activated Amides with Trialkylboranes

by Weijia Shi and Gang Zou

Molecules 2018, 23(10), 2412; https://doi.org/10.3390/molecules23102412 - 20 Sep 2018

Cited by 12 | Viewed by 3268

Abstract

A highly efficient acylative cross-coupling of trialkylboranes with activated amides has been effected at room temperature to give the corresponding alkyl ketones in good to excellent yields by using 1,3-bis(2,6-diisopropyl)phenylimidazolylidene and 3-chloropyridine co-supported palladium chloride, the PEPPSI catalyst, in the presence of K [...] Read more.

A highly efficient acylative cross-coupling of trialkylboranes with activated amides has been effected at room temperature to give the corresponding alkyl ketones in good to excellent yields by using 1,3-bis(2,6-diisopropyl)phenylimidazolylidene and 3-chloropyridine co-supported palladium chloride, the PEPPSI catalyst, in the presence of K₂CO₃ in methyl tert-butyl ether. The scope and limitations of the protocol were investigated, showing good tolerance of acyl, cyano, and ester functional groups in the amide counterpart while halo group competed via the classical Suzuki coupling. The trialkylboranes generated in situ by hydroboration of olefins with BH₃ or 9-BBN performed similarly to those separately prepared, making this protocol more practical. Full article

(This article belongs to the Special Issue Amide Bond Activation)

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22 pages, 7508 KiB

Open AccessArticle

Unexpected Resistance to Base-Catalyzed Hydrolysis of Nitrogen Pyramidal Amides Based on the 7-Azabicyclic[2.2.1]heptane Scaffold

by Diego Antonio Ocampo Gutiérrez de Velasco, Aoze Su, Luhan Zhai, Satowa Kinoshita, Yuko Otani and Tomohiko Ohwada

Molecules 2018, 23(9), 2363; https://doi.org/10.3390/molecules23092363 - 15 Sep 2018

Cited by 6 | Viewed by 5602

Abstract

Non-planar amides are usually transitional structures, that are involved in amide bond rotation and inversion of the nitrogen atom, but some ground-minimum non-planar amides have been reported. Non-planar amides are generally sensitive to water or other nucleophiles, so that the amide bond is [...] Read more.

Non-planar amides are usually transitional structures, that are involved in amide bond rotation and inversion of the nitrogen atom, but some ground-minimum non-planar amides have been reported. Non-planar amides are generally sensitive to water or other nucleophiles, so that the amide bond is readily cleaved. In this article, we examine the reactivity profile of the base-catalyzed hydrolysis of 7-azabicyclo[2.2.1]heptane amides, which show pyramidalization of the amide nitrogen atom, and we compare the kinetics of the base-catalyzed hydrolysis of the benzamides of 7-azabicyclo[2.2.1]heptane and related monocyclic compounds. Unexpectedly, non-planar amides based on the 7-azabicyclo[2.2.1]heptane scaffold were found to be resistant to base-catalyzed hydrolysis. The calculated Gibbs free energies were consistent with this experimental finding. The contribution of thermal corrections (entropy term, –TΔS^‡) was large; the entropy term (ΔS^‡) took a large negative value, indicating significant order in the transition structure, which includes solvating water molecules. Full article

(This article belongs to the Special Issue Amide Bond Activation)

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14 pages, 3688 KiB

Open AccessArticle

Electronic Effect on the Molecular Motion of Aromatic Amides: Combined Studies Using VT-NMR and Quantum Calculations

by Sungsoo Kim, Jungyu Kim, Jieun Kim, Daeun Won, Suk-Kyu Chang, Wansik Cha, Keunhong Jeong, Sangdoo Ahn and Kyungwon Kwak

Molecules 2018, 23(9), 2294; https://doi.org/10.3390/molecules23092294 - 08 Sep 2018

Cited by 7 | Viewed by 4982

Abstract

Rotational barrier energy studies to date have focused on the amide bond of aromatic compounds from a kinetic perspective using quantum calculations and nuclear magnetic resonance (NMR). These studies provide valuable information, not only regarding the basic conformational properties of amide bonds but [...] Read more.

Rotational barrier energy studies to date have focused on the amide bond of aromatic compounds from a kinetic perspective using quantum calculations and nuclear magnetic resonance (NMR). These studies provide valuable information, not only regarding the basic conformational properties of amide bonds but also the molecular gear system, which has recently gained interest. Thus, we investigate the precise motion of the amide bonds of two aromatic compounds using an experimental rotational barrier energy estimation by NMR experiments and a theoretical evaluation of the density functional theory calculation. The theoretical potential energy surface scan method combined with the quadratic synchronous transit 3 method and consideration of additional functional group rotation with optimization and frequency calculations support the results of the variable temperature ¹H NMR, with deviations of less than 1 kcal/mol. This detailed experimental and theoretical research strongly supports molecular gear motion in the aromatic amide system, and the difference in kinetic energy indicates that the electronic effect from the aromatic structure has a key role in conformational movements at different temperatures. Our study provides an enhanced basis for future amide structural dynamics research. Full article

(This article belongs to the Special Issue Amide Bond Activation)

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10 pages, 2497 KiB

Open AccessArticle

K₂S₂O₈-Promoted Aryl Thioamides Synthesis from Aryl Aldehydes Using Thiourea as the Sulfur Source

by Yongjun Bian, Xingyu Qu, Yongqiang Chen, Jun Li and Leng Liu

Molecules 2018, 23(9), 2225; https://doi.org/10.3390/molecules23092225 - 01 Sep 2018

Cited by 8 | Viewed by 5073

Abstract

Thiourea as a sulfur atom transfer reagent was applied for the synthesis of aryl thioamides through a three-component coupling reaction with aryl aldehydes and N,N-dimethylformamide (DMF) or N,N-dimethylacetamide (DMAC). The reaction could tolerate various functional groups and [...] Read more.

Thiourea as a sulfur atom transfer reagent was applied for the synthesis of aryl thioamides through a three-component coupling reaction with aryl aldehydes and N,N-dimethylformamide (DMF) or N,N-dimethylacetamide (DMAC). The reaction could tolerate various functional groups and gave moderate to good yields of desired products under the transition-metal-free condition. Full article

(This article belongs to the Special Issue Amide Bond Activation)

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18 pages, 1200 KiB

Open AccessArticle

Asymmetric Primaquine and Halogenaniline Fumardiamides as Novel Biologically Active Michael Acceptors

by Zrinka Rajić, Maja Beus, Hana Michnová, Josipa Vlainić, Leentje Persoons, Ivan Kosalec, Josef Jampílek, Dominique Schols, Toma Keser and Branka Zorc

Molecules 2018, 23(7), 1724; https://doi.org/10.3390/molecules23071724 - 14 Jul 2018

Cited by 8 | Viewed by 4915

Abstract

Novel primaquine (PQ) and halogenaniline asymmetric fumardiamides 4a–f, potential Michael acceptors, and their reduced analogues succindiamides 5a–f were prepared by simple three-step reactions: coupling reaction between PQ and mono-ethyl fumarate (1a) or mono-methyl succinate (1b [...] Read more.

Novel primaquine (PQ) and halogenaniline asymmetric fumardiamides 4a–f, potential Michael acceptors, and their reduced analogues succindiamides 5a–f were prepared by simple three-step reactions: coupling reaction between PQ and mono-ethyl fumarate (1a) or mono-methyl succinate (1b), hydrolysis of PQ-dicarboxylic acid mono-ester conjugates 2a,b to corresponding acids 3a,b, and a coupling reaction with halogenanilines. 1-[bis(Dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU) was used as a coupling reagent along with Hünig′s base. Compounds 4 and 5 were evaluated against a panel of bacteria, several Mycobacterium strains, fungi, a set of viruses, and nine different human tumor cell lines. p-Chlorofumardiamide 4d showed significant activity against Staphylococcus aureus,Streptococcus pneumoniae and Acinetobacter baumannii, but also against Candida albicans (minimum inhibitory concentration (MIC) 6.1–12.5 µg/mL). Together with p-fluoro and p-CF₃ fumardiamides 4b,f, compound 4d showed activity against Mycobacterium marinum and 4b,f against M. tuberculosis. In biofilm eradication assay, most of the bacteria, particularly S. aureus, showed susceptibility to fumardiamides. m-CF₃ and m-chloroaniline fumardiamides 4e and 4c showed significant antiviral activity against reovirus-1, sindbis virus and Punta Toro virus (EC₅₀ = 3.1–5.5 µM), while 4e was active against coxsackie virus B4 (EC₅₀ = 3.1 µM). m-Fluoro derivative 4a exerted significant cytostatic activity (IC₅₀ = 5.7–31.2 μM). Acute lymphoblastic leukemia cells were highly susceptible towards m-substituted derivatives 4a,c,e (IC₅₀ = 6.7–8.9 μM). Biological evaluations revealed that fumardiamides 4 were more active than succindiamides 5 indicating importance of Michael conjugated system. Full article

(This article belongs to the Special Issue Amide Bond Activation)

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Review

Jump to: Research

22 pages, 4432 KiB

Open AccessReview

Weinreb Amides as Directing Groups for Transition Metal-Catalyzed C-H Functionalizations

by Jagadeesh Kalepu and Lukasz T. Pilarski

Molecules 2019, 24(5), 830; https://doi.org/10.3390/molecules24050830 - 26 Feb 2019

Cited by 45 | Viewed by 9971

Abstract

Weinreb amides are a privileged, multi-functional group with well-established utility in classical synthesis. Recently, several studies have demonstrated the use of Weinreb amides as interesting substrates in transition metal-catalyzed C-H functionalization reactions. Herein, we review this part of the literature, including the metal [...] Read more.

Weinreb amides are a privileged, multi-functional group with well-established utility in classical synthesis. Recently, several studies have demonstrated the use of Weinreb amides as interesting substrates in transition metal-catalyzed C-H functionalization reactions. Herein, we review this part of the literature, including the metal catalysts, transformations explored so far and specific insights from mechanistic studies. Full article

(This article belongs to the Special Issue Amide Bond Activation)

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17 pages, 11269 KiB

Open AccessFeature PaperReview

Chemistry of Bridged Lactams: Recent Developments

by Roman Szostak and Michal Szostak

Molecules 2019, 24(2), 274; https://doi.org/10.3390/molecules24020274 - 12 Jan 2019

Cited by 42 | Viewed by 6080

Abstract

Bridged lactams represent the most effective and wide-ranging method of constraining the amide bond in a non-planar conformation. A previous comprehensive review on this topic was published in 2013 (Chem. Rev. 2013, 113, 5701–5765). In the present review, which is [...] Read more.

Bridged lactams represent the most effective and wide-ranging method of constraining the amide bond in a non-planar conformation. A previous comprehensive review on this topic was published in 2013 (Chem. Rev. 2013, 113, 5701–5765). In the present review, which is published as a part of the Special Issue on Amide Bond Activation, we present an overview of the recent developments in the field of bridged lactams that have taken place in the last five years and present a critical assessment of the current status of bridged lactams in synthetic and physical organic chemistry. This review covers the period from 2014 until the end of 2018 and is intended as an update to Chem. Rev. 2013, 113, 5701–5765. In addition to bridged lactams, the review covers recent advances in the chemistry of bridged sultams, bridged enamines and related non-planar structures. Full article

(This article belongs to the Special Issue Amide Bond Activation)

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18 pages, 5815 KiB

Open AccessFeature PaperReview

Well-Defined Pre-Catalysts in Amide and Ester Bond Activation

by Sandeep R. Vemula, Michael R. Chhoun and Gregory R. Cook

Molecules 2019, 24(2), 215; https://doi.org/10.3390/molecules24020215 - 09 Jan 2019

Cited by 6 | Viewed by 5431

Abstract

Over the past few decades, transition metal catalysis has witnessed a rapid and extensive development. The discovery and development of cross-coupling reactions is considered to be one of the most important advancements in the field of organic synthesis. The design and synthesis of [...] Read more.

Over the past few decades, transition metal catalysis has witnessed a rapid and extensive development. The discovery and development of cross-coupling reactions is considered to be one of the most important advancements in the field of organic synthesis. The design and synthesis of well-defined and bench-stable transition metal pre-catalysts provide a significant improvement over the current catalytic systems in cross-coupling reactions, avoiding excess use of expensive ligands and harsh conditions for the synthesis of pharmaceuticals, agrochemicals and materials. Among various well-defined pre-catalysts, the use of Pd(II)-NHC, particularly, provided new avenues to expand the scope of cross-coupling reactions incorporating unreactive electrophiles, such as amides and esters. The strong σ-donation and tunable steric bulk of NHC ligands in Pd-NHC complexes facilitate oxidative addition and reductive elimination steps enabling the cross-coupling of broad range of amides and esters using facile conditions contrary to the arduous conditions employed under traditional catalytic conditions. Owing to the favorable catalytic activity of Pd-NHC catalysts, a tremendous progress was made in their utilization for cross-coupling reactions via selective acyl C–X (X=N, O) bond cleavage. This review highlights the recent advances made in the utilization of well-defined pre-catalysts for C–C and C–N bond forming reactions via selective amide and ester bond cleavage. Full article

(This article belongs to the Special Issue Amide Bond Activation)

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22 pages, 7685 KiB

Open AccessReview

Recent Advances in the Addition of Amide/Sulfonamide Bonds to Alkynes

by Fei Zhao, Pinyi Li, Xiaoyan Liu, Xiuwen Jia, Jiang Wang and Hong Liu

Molecules 2019, 24(1), 164; https://doi.org/10.3390/molecules24010164 - 04 Jan 2019

Cited by 11 | Viewed by 4512

Abstract

The addition of amide/sulfonamide bonds to alkynes is not only one of the most important strategies for the direct functionalization of carbon–carbon triple bonds, but also a powerful tool for the downstream transformations of amides/sulfonamides. The present review provides a comprehensive summary of [...] Read more.

The addition of amide/sulfonamide bonds to alkynes is not only one of the most important strategies for the direct functionalization of carbon–carbon triple bonds, but also a powerful tool for the downstream transformations of amides/sulfonamides. The present review provides a comprehensive summary of amide/sulfonamide bond addition to alkynes, including direct and metal-free aminoacylation, based-promoted aminoacylation, transition-metal-catalyzed aminoacylation, organocatalytic aminoacylation and transition-metal-catalyzed aminosulfonylation of alkynes up to December 2018. The reaction conditions, regio- and stereoselectivities, and mechanisms are discussed and summarized in detail. Full article

(This article belongs to the Special Issue Amide Bond Activation)

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Scheme 1

31 pages, 7066 KiB

Open AccessReview

Amide Activation in Ground and Excited States

by Ervin Kovács, Balázs Rózsa, Attila Csomos, Imre G. Csizmadia and Zoltán Mucsi

Molecules 2018, 23(11), 2859; https://doi.org/10.3390/molecules23112859 - 02 Nov 2018

Cited by 29 | Viewed by 13542

Abstract

Not all amide bonds are created equally. The purpose of the present paper is the reinterpretation of the amide group by means of two concepts: amidicity and carbonylicity. These concepts are meant to provide a new viewpoint in defining the stability and reactivity [...] Read more.

Not all amide bonds are created equally. The purpose of the present paper is the reinterpretation of the amide group by means of two concepts: amidicity and carbonylicity. These concepts are meant to provide a new viewpoint in defining the stability and reactivity of amides. With the help of simple quantum-chemical calculations, practicing chemists can easily predict the outcome of a desired process. The main benefit of the concepts is their simplicity. They provide intuitive, but quasi-thermodynamic data, making them a practical rule of thumb for routine use. In the current paper we demonstrate the performance of our methods to describe the chemical character of an amide bond strength and the way of its activation methods. Examples include transamidation, acyl transfer and amide reductions. Also, the method is highly capable for simple interpretation of mechanisms for biological processes, such as protein splicing and drug mechanisms. Finally, we demonstrate how these methods can provide information about photo-activation of amides, through the examples of two caged neurotransmitter derivatives. Full article

(This article belongs to the Special Issue Amide Bond Activation)

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39 pages, 10961 KiB

Open AccessReview

Heteroatom Substitution at Amide Nitrogen—Resonance Reduction and HERON Reactions of Anomeric Amides

by Stephen A. Glover and Adam A. Rosser

Molecules 2018, 23(11), 2834; https://doi.org/10.3390/molecules23112834 - 31 Oct 2018

Cited by 23 | Viewed by 9419

Abstract

This review describes how resonance in amides is greatly affected upon substitution at nitrogen by two electronegative atoms. Nitrogen becomes strongly pyramidal and resonance stabilisation, evaluated computationally, can be reduced to as little as 50% that of N,N-dimethylacetamide. However, this [...] Read more.

This review describes how resonance in amides is greatly affected upon substitution at nitrogen by two electronegative atoms. Nitrogen becomes strongly pyramidal and resonance stabilisation, evaluated computationally, can be reduced to as little as 50% that of N,N-dimethylacetamide. However, this occurs without significant twisting about the amide bond, which is borne out both experimentally and theoretically. In certain configurations, reduced resonance and pronounced anomeric effects between heteroatom substituents are instrumental in driving the HERON (Heteroatom Rearrangement On Nitrogen) reaction, in which the more electronegative atom migrates from nitrogen to the carbonyl carbon in concert with heterolysis of the amide bond, to generate acyl derivatives and heteroatom-substituted nitrenes. In other cases the anomeric effect facilitates S_N1 and S_N2 reactivity at the amide nitrogen. Full article

(This article belongs to the Special Issue Amide Bond Activation)

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43 pages, 10917 KiB

Open AccessReview

Amide Bond Activation of Biological Molecules

by Sriram Mahesh, Kuei-Chien Tang and Monika Raj

Molecules 2018, 23(10), 2615; https://doi.org/10.3390/molecules23102615 - 12 Oct 2018

Cited by 138 | Viewed by 12702

Abstract

Amide bonds are the most prevalent structures found in organic molecules and various biomolecules such as peptides, proteins, DNA, and RNA. The unique feature of amide bonds is their ability to form resonating structures, thus, they are highly stable and adopt particular three-dimensional [...] Read more.

Amide bonds are the most prevalent structures found in organic molecules and various biomolecules such as peptides, proteins, DNA, and RNA. The unique feature of amide bonds is their ability to form resonating structures, thus, they are highly stable and adopt particular three-dimensional structures, which, in turn, are responsible for their functions. The main focus of this review article is to report the methodologies for the activation of the unactivated amide bonds present in biomolecules, which includes the enzymatic approach, metal complexes, and non-metal based methods. This article also discusses some of the applications of amide bond activation approaches in the sequencing of proteins and the synthesis of peptide acids, esters, amides, and thioesters. Full article

(This article belongs to the Special Issue Amide Bond Activation)

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17 pages, 5877 KiB

Open AccessReview

Direct Transamidation Reactions: Mechanism and Recent Advances

by Paola Acosta-Guzmán, Alejandra Mateus-Gómez and Diego Gamba-Sánchez

Molecules 2018, 23(9), 2382; https://doi.org/10.3390/molecules23092382 - 18 Sep 2018

Cited by 62 | Viewed by 10301

Abstract

Amides are undeniably some of the most important compounds in Nature and the chemical industry, being present in biomolecules, materials, pharmaceuticals and many other substances. Unfortunately, the traditional synthesis of amides suffers from some important drawbacks, principally the use of stoichiometric activators or [...] Read more.

Amides are undeniably some of the most important compounds in Nature and the chemical industry, being present in biomolecules, materials, pharmaceuticals and many other substances. Unfortunately, the traditional synthesis of amides suffers from some important drawbacks, principally the use of stoichiometric activators or the need to use highly reactive carboxylic acid derivatives. In recent years, the transamidation reaction has emerged as a valuable alternative to prepare amides. The reactivity of amides makes their direct reaction with nitrogen nucleophiles difficult; thus, the direct transamidation reaction needs a catalyst in order to activate the amide moiety and to promote the completion of the reaction because equilibrium is established. In this review, we present research on direct transamidation reactions ranging from studies of the mechanism to the recent developments of more applicable and versatile methodologies, emphasizing those reactions involving activation with metal catalysts. Full article

(This article belongs to the Special Issue Amide Bond Activation)

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16 pages, 4138 KiB

Open AccessReview

Transition-Metal-Free Activation of Amide Bond by Arynes

by Hideto Miyabe

Molecules 2018, 23(9), 2145; https://doi.org/10.3390/molecules23092145 - 27 Aug 2018

Cited by 12 | Viewed by 4635

Abstract

Highly reactive arynes activate the N–C and C=O bonds of amide groups under transition metal-free conditions. This review highlights the insertion of arynes into the N–C and C=O bonds of the amide group. The insertion of arynes into the N–C bond gives the [...] Read more.

Highly reactive arynes activate the N–C and C=O bonds of amide groups under transition metal-free conditions. This review highlights the insertion of arynes into the N–C and C=O bonds of the amide group. The insertion of arynes into the N–C bond gives the unstable four-membered ring intermediates, which are easily converted into ortho-disubstituted arenes. On the other hand, the selective insertion of arynes into the C=O bond is observed when the sterically less-hindered formamides are employed to give a reactive transient intermediate. Therefore, the trapping reactions of transient intermediates with a variety of reactants lead to the formation of oxygen atom-containing heterocycles. As relative functional groups are activated, the reactions of arynes with sulfinamides, phosphoryl amides, cyanamides, sulfonamides, thioureas, and vinylogous amides are also summarized. Full article

(This article belongs to the Special Issue Amide Bond Activation)

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31 pages, 16221 KiB

Open AccessFeature PaperReview

Recent Uses of N,N-Dimethylformamide and N,N-Dimethylacetamide as Reagents

by Jean Le Bras and Jacques Muzart

Molecules 2018, 23(8), 1939; https://doi.org/10.3390/molecules23081939 - 03 Aug 2018

Cited by 44 | Viewed by 10117

Abstract

N,N-Dimethylformamide and N,N-dimethylacetamide are multipurpose reagents which deliver their own H, C, N and O atoms for the synthesis of a variety of compounds under a number of different experimental conditions. The review mainly highlights the corresponding [...] Read more.

N,N-Dimethylformamide and N,N-dimethylacetamide are multipurpose reagents which deliver their own H, C, N and O atoms for the synthesis of a variety of compounds under a number of different experimental conditions. The review mainly highlights the corresponding literature published over the last years. Full article

(This article belongs to the Special Issue Amide Bond Activation)

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