Direct Synthesis Of Amides Research Articles

Desulfonation-associated direct amide bond formation between N-sulfonyl-1,2,3-triazoles with carboxylic acids

We have developed a highly N2-regioselective method for direct construction of amide bond from N-sulfonyl-1,2,3-triazoles and carboxylic acids in the presence of bases at 60 °C in air. The developed reaction provides the corresponding products with high yields (up to 90 %) and a broad substrate compatibility including aryl acids, heterocyclic acids, and alkyl acids. Mechanistic studies show that the reaction proceeds through a direct nucleophilic attack of N-sulfonyl-1,2,3-triazoles to carboxylate anions via a base- and water-involved synergistic desulfonation process. This work presents an unusual water-involved example for direct synthesis of amides utilizing readily available starting materials under mild conditions.

Direct Synthesis of Sugar Amides by Aerobic One-Pot Oxidative Amidation of Unprotected Carbohydrates

Direct Synthesis of Sugar Amides by Aerobic One-Pot Oxidative Amidation of Unprotected Carbohydrates

Nickel-catalysed reductive C-N bond cross-coupling between aryl halides and N-chloroamides.

A method for the direct synthesis of N-aryl lactams and amides with aryl halides and N-chloroamides through a Ni-catalyzed reductive C-N coupling reaction has been developed. The reaction features the advantages of mild conditions, good functional group tolerance and broad substrate scope including drug-derived substrates, and also provided direct access to the key synthetic intermediates for some bioactive molecules, suggesting the practicability of this method. Finally, DFT calculations were performed to shed further light on the reaction mechanism and it was found that an amidyl radical might be involved.

Redox-Neutral Decarboxylative Cross-Coupling of Oxamates with Aryl Bromides.

Dual nickel-photoredox-enabled direct synthesis of amides through cross-coupling of cesium oxamates with aryl bromides has been developed. This methodology's key advantages are mild reaction conditions, utilizing organic dye as a photocatalyst, employing readily available starting chemicals as coupling partners, and late-stage carbamoylation of pharmaceutically relevant molecules. DFT studies suggested that the nickel catalytic cycle proceeds via a radical addition pathway prior to the oxidative insertion.

A Strategy for Improving the Efficiency of Boronic Acid Catalysis in the Synthesis of Amides

AbstractThis study outlines the development of novel boronic acids as catalysts for the direct synthesis of amides from carboxylic acids and amines. The Lewis acidity of the boronic acids was estimated by means of computational techniques, and the observed increase in catalytic activity was corroborated by kinetic data derived from a model reaction. Our investigations led to the discovery of a set of ortho‐(sulfonyloxy)benzeneboronic acids that compared favorably with the established state‐of‐the‐art. These newly developed catalysts demonstrated efficacy in the coupling of aliphatic, aromatic, and heteroaromatic acids, as well as primary and secondary amines.

Streamlining the synthesis of amides using Nickel-based nanocatalysts

The synthesis of amides is a key technology for the preparation of fine and bulk chemicals in industry, as well as the manufacture of a plethora of daily life products. Furthermore, it constitutes a central bond-forming methodology for organic synthesis and provides the basis for the preparation of numerous biomolecules. Here, we present a robust methodology for amide synthesis compared to traditional amidation reactions: the reductive amidation of esters with nitro compounds under additives-free conditions. In the presence of a specific heterogeneous nickel-based catalyst a wide range of amides bearing different functional groups can be selectively prepared in a more step-economy way compared to previous syntheses. The potential value of this protocol is highlighted by the synthesis of drugs, as well as late-stage modifications of bioactive compounds. Based on control experiments, material characterizations, and DFT computations, we suggest metallic nickel and low-valent Ti-species to be crucial factors that makes this direct amide synthesis possible.

A Co‐Ni‐CM Heterogeneous Catalyst for the Direct Synthesis of Amides from the Oxidative Coupling of Aldehydes with N‐Substituted Formamides

AbstractGiven the importance of amides in pharmaceutical and chemical industries, a Co−Ni composites (Co−Ni‐CM) heterogeneous catalytic system for the synthesis of amides from the oxidative coupling of aldehydes with N‐substituted formamides has been developed under mild conditions. The catalyst was prepared by pyrolysis under ambient atmosphere using Co‐BTC supported NiCl2 as a precursor. The catalytic system possesses good catalytic ability and good compatibility with functional groups. The surface morphology and internal element composition of the catalyst were characterized by powder X‐ray diffraction (XRD), BET adsorption, high resolution transmission electron microscope (HRTEM), scanning electron microscope (SEM), inductively coupled plasma emission spectroscopy (ICP‐OES) and X‐ray photoelectron spectroscopy (XPS). The results show that the interaction of Co−Ni is a key factor for the good catalytic activity of the catalyst. Then control experiments related to the mechanism of this transformation indicate a free radical process is involved in this transformation. More importantly, the catalyst has an excellent recycling performance and can be recycled seven times without obvious loss of catalytic activity.

A Sustainable Green Enzymatic Method for Amide Bond Formation.

A sustainable enzymatic strategy for the preparation of amides by using Candida antarctica lipase B as the biocatalyst and cyclopentyl methyl ether as a green and safe solvent was devised. The method is simple and efficient and it produces amides with excellent conversions and yields without the need for intensive purification steps. The scope of the reaction was extended to the preparation of 28 diverse amides using four different free carboxylic acids and seven primary and secondary amines, including cyclic amines. This enzymatic methodology has the potential to become a green and industrially reliable process for direct amide synthesis.

Oxidative Cleavage and Ammoxidation of Unsaturated Hydrocarbons via Heterogeneous Auto-Tandem Catalysis.

The oxidative cleavage and functionalization of unsaturated C-C bonds are important processes for synthesis of carbonyl compounds from hydrocarbon feedstocks, yet there has been no report of direct amidation of unsaturated hydrocarbons via an oxidative cleavage of unsaturated C-C bonds with molecular oxygen as an environmentally benign oxidant. Herein, for the first time, we describe a manganese oxide-catalyzed auto-tandem catalysis strategy that enables direct synthesis of amides from unsaturated hydrocarbons by coupling oxidative cleavage with amidation. With oxygen as an oxidant and ammonia as a nitrogen source, a wide range of structurally diverse mono- and multisubstituted activated and unactivated alkenes or alkynes can smoothly undergo unsaturated C-C bond cleavage to deliver one- or multiple-carbon shorter amides. Moreover, a slight modification of the reaction conditions also allows for the direct synthesis of sterically hindered nitriles from alkenes or alkynes. This protocol features excellent functional group tolerance, a broad substrate scope, flexible late-stage functionalization, facile scalability, and a cost-effective and recyclable catalyst. Detailed characterizations reveal that the high activity and selectivity of the manganese oxides are attributed to the large specific surface area, abundant oxygen vacancies, better reducibility, and moderate acid sites. Mechanistic studies and density functional theory calculations indicate that the reaction proceeds through divergent pathways depending on the structure of substrates.

NiH-catalyzed anti-Markovnikov hydroamidation of unactivated alkenes with 1,4,2-dioxazol-5-ones for the direct synthesis of N-alkyl amides

The addition of a nitrogen-based functional group to alkenes via a direct catalytic method is an attractive way of synthesizing value-added amides. The regioselective hydroamidation of unactivated alkenes is considered one of the easiest ways to achieve this goal. Herein, we report the NiH-catalyzed anti-Markovnikov intermolecular hydroamidation of unactivated alkenes enabled by using 2,9-dibutylphenathroline (diBuphen) as the ligand. This protocol provides a platform for the direct synthesis of over 90 structurally diverse N-alkyl amides using dioxazolones, which can be easily derived from abundant carboxylic acid feedstocks. This method succeeds for both terminal and internal unactivated alkenes and some natural products. Mechanistic studies including DFT calculations reveal an initial reversible insertion/elimination of the [NiH] to the alkene, followed by the irreversible amidation to furnish the N-alkyl amides. By crossover experiments and deuterium labeling studies, the observed anti-Markovnikov regioselectivities are suggested to be controlled by the sterical environment of the coupling reaction.

Strychnos alkaloids: total synthesis, characterization, DFT investigations, and molecular docking with AChE, BuChE, and HSA

An efficient five steps, the protection-deprotection synthetic a novel synthetic routes to(±) noruleine (±)-uleine, are reported starting from tetrahydrocarbazole fused monoalkyl nitrile at C-2 position that is prepared on multigram scale from 2-(3-ethyl-1-oxo-2,3,4,9-tetrahydro-1H-carbazol-2-yl)acetonitrile (1) as well as the key azocino[4,3-b]indole skeleton is constructed via the tetrafluoro-1,4-benzoquinone (TFB)-mediated cyclization of a tetrahydrocarbazole derivative possessing direct amide synthesis from nitrile. As a result, Total synthesis of noruleine and uleine has been developed, which is accomplished in 4 and 5- steps synthesis of the ABCD tetracyclic of the strychnos alkaloids with an overall yield of 44% and 39%, respectively. The DFT computations were performed with B3LYP/6-311g(d,p) level to determine inter and intramolecular interactions and reactivity features of the compound 3–6. Also, TD-DFT computations were performed to characterize the electronic absorption spectra of all compounds. Last, the interactions of compounds 3–6 with selected targets AChE, BuChE, and HSA were evaluated in light of the molecular dockings. The bioactivity and drug-likeness scores revealed that compound 6 3–6 can be proper candidate for future drug-design studies more than the other compounds.

Preparation of N-Aryl Amides by Epimerization-Free Umpolung Amide Synthesis.

Amide synthesis is one of the most widely practiced chemical reactions, owing to its use in drug development and peptide synthesis. Despite the importance of these applications, the attendant effort to eliminate waste associated with these protocols has met with limited success, and pernicious α-epimerization is most often minimized but not eliminated when targeting challenging amides (e.g., N-aryl amides). This effort has focused on what is essentially a single paradigm in amide formation wherein an electrophilic acyl donor reacts with a nucleophilic amine. Umpolung amide synthesis (UmAS) emerged from α-halo nitroalkane reactions with amines and has since been developed into a method for the synthesis of enantiopure amides using entirely catalytic, enantioselective synthesis. However, its inability to forge N-aryl amides has been a longstanding problem, one limiting its application more broadly in drug development where α-chiral N-aryl amides are increasingly common. We report here the reaction of α-fluoronitroalkanes and N-aryl hydroxyl amines for the direct synthesis of N-aryl amides using a simple Brønsted base as the promoter. No other activating agents are required, and experiments guided by mechanistic hypotheses outline a mechanism based on the UmAS paradigm and confirm that the N-aryl amide, not the N-aryl hydroxamic acid, is the direct product. Ultimately, select chiral α-amino-N-aryl amides were prepared with complete conservation of enantioenrichment, in contrast to a parallel demonstration of their ability to epimerize using the conventional amide synthesis alternative.

Direct Synthesis of Amides from Benzonitriles and Benzylic Alcohols via a KOt-Bu-Mediated MPV-type Hydrogen Transfer Process

Meerwein-Ponndorf-Verley (MPV)-type reduction between benzonitriles and benzylic alcohols under transition-metal-free conditions has been demonstrated for the first time. Using simple KOt-Bu as the base, various benzonitriles can be efficiently reduced by benzylic alcohols via hydrogen transfer reduction, and the resultant phenyl imine can react further with benzylic alcohols to give amides as the final product in which both the alcohols and the nitriles are incorporated. Preliminary mechanistic investigations indicated that the reaction may go through multiple MPV-type hydrogen transfer processes.

Heterogeneous manganese-oxide-catalyzed successive cleavage and functionalization of alcohols to access amides and nitriles

•Amidation and cyanation of alcohols via successive cleavage of C–C bonds •Amorphous manganese oxide as catalyst and oxygen as oxidant •Wide substrate scope and application to late-stage functionalization •A significant advancement in developing heterogeneous catalyst for lignin valorization The successive cleavage and functionalization of C–C bonds in alcohols has become a rapidly growing field for the discovery of new transformations. However, achieving it in a direct and selective manner remains challenging because of the intrinsic inertness of C–C bonds. Herein, we report a novel and efficient protocol that enables the direct synthesis of amides via heterogeneous manganese-oxide-catalyzed successive cleavage and amidation of C–C bonds in alcohols. A wide range of primary and secondary alcohols, 1,2-diols, and even β-O-4 and β-1 lignin model compounds can undergo C–C bond cleavage smoothly to deliver one- or multiple-carbon shorter amides. Moreover, a slight modification of reaction conditions allows for the cleavage and cyanation of alcohols to access sterically hindered nitriles. Detailed characterizations and density functional theory (DFT) calculations indicate that high specific surface area, abundant oxygen vacancies, and moderate acid sites contribute to the high catalytic performance of the manganese oxides. The successive cleavage and functionalization of C–C bonds in alcohols has become a rapidly growing field for the discovery of new transformations. However, achieving it in a direct and selective manner remains challenging because of the intrinsic inertness of C–C bonds. Herein, we report a novel and efficient protocol that enables the direct synthesis of amides via heterogeneous manganese-oxide-catalyzed successive cleavage and amidation of C–C bonds in alcohols. A wide range of primary and secondary alcohols, 1,2-diols, and even β-O-4 and β-1 lignin model compounds can undergo C–C bond cleavage smoothly to deliver one- or multiple-carbon shorter amides. Moreover, a slight modification of reaction conditions allows for the cleavage and cyanation of alcohols to access sterically hindered nitriles. Detailed characterizations and density functional theory (DFT) calculations indicate that high specific surface area, abundant oxygen vacancies, and moderate acid sites contribute to the high catalytic performance of the manganese oxides.

Half‐Sandwich Ruthenium Complexes Bearing Hemilabile κ2‐(C,S)−Thioether‐Functionalized NHC Ligands: Application to Amide Synthesis from Alcohol and Amine

AbstractAmide synthesis is one of the most crucial transformations in chemistry and biology. Among various catalytic systems, N‐heterocyclic carbene (NHC)‐based ruthenium (Ru) catalyst systems have been proven to be active for direct synthesis of amides by sustainable acceptorless dehydrogenative Coupling of primary alcohols with amines. Most often, these catalytic systems usually use monodentate NHC and thus require an additional ligand to obtain high reactivity and selectivity. In this work, a series of cationic Ru(II)(η6‐p‐cymene) complexes with thioether‐functionalized N‐heterocyclic carbene ligands (imidazole and benzimidazole‐based) have been prepared and fully characterized. These complexes have then been used in the amidation reaction and the most promising one (i. e. 3 c) has been applied on a large range of substrates. High conversions albeit with moderate yields have generally been obtained.

NDTP Mediated Direct Rapid Amide and Peptide Synthesis without Epimerization.

Herein, we explored an unprecedented mild, nonirritating, conveniently available, and recyclable coupling reagent NDTP, which could activate the carboxylic acids via acyl thiocyanide and enable the rapid amide and peptide synthesis at very mild conditions. In addition, the methodology was compatible with Fmoc-SPPS, which may provide an alternative to peptide manufacturing.

Metal-free synthesis of secondary amides using N-Boc-O-tosylhydroxylamine as nitrogen source via Beckmann rearrangement

An efficient methodology for the direct synthesis of secondary amides from ketones has been developed by using N-Boc-O-tosylhydroxylamine (TsONHBoc).

Berichtigung: Asymmetric Direct Amide Synthesis by Kinetic Amine Resolution: A Chiral Bifunctional Aminoboronic Acid Catalyzed Reaction between a Racemic Amine and an Achiral Carboxylic Acid

In this Communication, structure 1 was incorrectly drawn with boron atom, rather than nitrogen atom, in the benzylic position, and should have had the revised structure shown below.

A Molecular Iron-Based System for Divergent Bond Activation: Controlling the Reactivity of Aldehydes

The direct synthesis of amides and nitriles from readily available aldehyde precursors provides access to functional groups of major synthetic utility. To date, most reliable catalytic methods have typically been optimized to supply one product exclusively. Herein, we describe an approach centered on an operationally simple iron-based system that, depending on the reaction conditions, selectively addresses either the C═O or C–H bond of aldehydes. This way, two divergent reaction pathways can be opened to furnish both products in high yields and selectivities under mild reaction conditions. The catalyst system takes advantage of iron’s dual reactivity capable of acting as (1) a Lewis acid and (2) a nitrene transfer platform to govern the aldehyde building block. The present transformation offers a rare control over the selectivity on the basis of the iron system’s ionic nature. This approach expands the repertoire of protocols for amide and nitrile synthesis and shows that fine adjustments of the catalyst system’s molecular environment can supply control over bond activation processes, thus providing easy access to various products from primary building blocks.

Direct Synthesis of N-Protected Serine- and Threonine-Derived Weinreb Amides via Diboronic Acid Anhydride-Catalyzed Dehydrative Amidation: Application to the Concise Synthesis of ­Garner’s Aldehyde

AbstractAn efficient method for the direct synthesis of Weinreb amides derived from serine and threonine derivatives via diboronic acid anhydride-catalyzed hydroxy-directed amidation is described. This is the first successful example of the synthesis of serine- or threonine-derived Weinreb amides using catalytic dehydrative amidations. The methodology could be applied to the concise synthesis of Garner’s aldehyde.