Amide Bond Synthesis Research Articles

Microwave-assisted One-pot Synthesis of Amide Bond using WEB

Background: Amide bond plays a key role in medicinal chemistry, and the analysis of bioactive molecular database revealed that the carboxamide group appears in more than 25% of the existing database drugs. Typically amide bonds are formed from the union of carboxylic acid and amine; however, the product formation does not occur spontaneously. Several synthetic methods have been reported for amide bond formation in literature. Present work demonstrated simple and eco-friendly amide bond formation using carboxylic acid and primary amines through in situ generation of O-acylurea. The reaction was found to be more efficient, faster reaction rate; simple work-up gave pure compound isolation in moderate to excellent yield using microwave irradiation as compared to conventional heating. Methods: Developed one-pot synthesis of amide compounds using agro-waste derived greener catalyst under microwave irradiation. Results: Twenty amide bond containing organic compounds are synthesized from carboxylic acid with primary amine catalyzed by agro-waste derived medium under microwave irradiation. First, the reaction involved carboxylic acid activation using EDC.HCl, which is the required base for the neutralization and coupling. The method employed natural agro-waste derived from banana peel ash (WEB) for the coupling gave target amide product without the use of an external organic or inorganic base. Conclusion: In the present work, we demonstrated that agro-waste extract is an alternative greener catalytic medium for the condensation of organic carboxylic acid and primary amine under microwave irradiation. The method found several advantages compared to reported methods like solventfree, non-toxic, cheaper catalyst, and simple reaction condition. The final isolated product achieved chromatographically pure by simple recrystallization and did not require further purification.

Nickel‐Catalyzed Synthesis of Dialkyl Ketones from the Coupling of N‐Alkyl Pyridinium Salts with Activated Carboxylic Acids

AbstractWhile ketones are among the most versatile functional groups, their synthesis remains reliant upon reactive and low‐abundance starting materials. In contrast, amide formation is the most‐used bond‐construction method in medicinal chemistry because the chemistry is reliable and draws upon large and diverse substrate pools. A new method for the synthesis of ketones is presented here that draws from the same substrates used for amide bond synthesis: amines and carboxylic acids. A nickel terpyridine catalyst couples N‐alkyl pyridinium salts with in situ formed carboxylic acid fluorides or 2‐pyridyl esters under reducing conditions (Mn metal). The reaction has a broad scope, as demonstrated by the synthesis of 35 different ketones bearing a wide variety of functional groups with an average yield of 60±16 %. This approach is capable of coupling diverse substrates, including pharmaceutical intermediates, to rapidly form complex ketones.

Nickel-Catalyzed Synthesis of Dialkyl Ketones from the Coupling of N-Alkyl Pyridinium Salts with Activated Carboxylic Acids.

While ketones are among the most versatile functional groups, their synthesis remains reliant upon reactive and low-abundance starting materials. In contrast, amide formation is the most-used bond-construction method in medicinal chemistry because the chemistry is reliable and draws upon large and diverse substrate pools. A new method for the synthesis of ketones is presented here that draws from the same substrates used for amide bond synthesis: amines and carboxylic acids. A nickel terpyridine catalyst couples N-alkyl pyridinium salts with in situ formed carboxylic acid fluorides or 2-pyridyl esters under reducing conditions (Mn metal). The reaction has a broad scope, as demonstrated by the synthesis of 35 different ketones bearing a wide variety of functional groups with an average yield of 60±16 %. This approach is capable of coupling diverse substrates, including pharmaceutical intermediates, to rapidly form complex ketones.

Oxidative Amide Coupling from Functionally Diverse Alcohols and Amines Using Aerobic Copper/Nitroxyl Catalysis

AbstractThe aerobic Cu/ABNO catalyzed oxidative coupling of alcohols and amines is highlighted in the synthesis of amide bonds in diverse drug‐like molecules (ABNO=9‐azabicyclo[3.3.1]nonane N‐oxyl). The robust method leverages the privileged reactivity of alcohols bearing electronegative hetero‐ atoms (O, F, N, Cl) in the β‐position. The reaction tolerates over 20 unique functional groups and is demonstrated on a 15 mmol scale under air. Steric constraints of the catalyst allow for chemoselective amidation of primary amines in the presence of secondary amines. All catalyst components are commercially available, and the reaction proceeds under mild conditions with retention of stereocenters in both reaction partners, while producing only water as a by‐product.

Oxidative Amide Coupling from Functionally Diverse Alcohols and Amines Using Aerobic Copper/Nitroxyl Catalysis.

The aerobic Cu/ABNO catalyzed oxidative coupling of alcohols and amines is highlighted in the synthesis of amide bonds in diverse drug-like molecules (ABNO=9-azabicyclo[3.3.1]nonane N-oxyl). The robust method leverages the privileged reactivity of alcohols bearing electronegative hetero- atoms (O, F, N, Cl) in the β-position. The reaction tolerates over 20 unique functional groups and is demonstrated on a 15 mmol scale under air. Steric constraints of the catalyst allow for chemoselective amidation of primary amines in the presence of secondary amines. All catalyst components are commercially available, and the reaction proceeds under mild conditions with retention of stereocenters in both reaction partners, while producing only water as a by-product.

Methyl Esters as Cross-Coupling Electrophiles: Direct Synthesis of Amide Bonds

Amide bond formation and transition metal-catalyzed cross-coupling are two of the most frequently used chemical reactions in organic synthesis. Recently, an overlap between these two reaction families was identified when Pd and Ni catalysts were demonstrated to cleave the strong C–O bond present in esters via oxidative addition. When simple methyl and ethyl esters are used, this transformation provides a powerful alternative to classical amide bond formations, which commonly feature stoichiometric activating agents. Thus far, few redox-active catalysts have been demonstrated to activate the C(acyl)–O bond of alkyl esters, which makes it difficult to perform informed screening when a challenging reaction needs optimization. We demonstrate that Ni catalysts bearing diverse NHC, phosphine, and nitrogen-containing ligands can all be used to activate methyl esters and enable their use in direct amide bond formation.

Amide bond synthesis via silver(I) N-heterocyclic carbene-catalyzed and tert-butyl hydroperoxide-mediated oxidative coupling of alcohols with amines under base free conditions

We present a base free method for amide bond construction via oxidative coupling of alcohols with amines catalyzed by Silver(I) N-heterocyclic carbenes (Ag(I)-NHCs) and mediated by tert-butyl hydroperoxide (TBHP) in ethanol. The results of controlled experiments suggest that the oxidative coupling proceeds through the formation of aldehyde, then subsequent attack by amine to give hemiaminal, which can then be oxidized to amide.

Nickel‐Catalyzed Amide Bond Formation from Methyl Esters

AbstractDespite being one of the most important and frequently run chemical reactions, the synthesis of amide bonds is accomplished primarily by wasteful methods that proceed by stoichiometric activation of one of the starting materials. We report a nickel‐catalyzed procedure that can enable diverse amides to be synthesized from abundant methyl ester starting materials, producing only volatile alcohol as a stoichiometric waste product. In contrast to acid‐ and base‐mediated amidations, the reaction is proposed to proceed by a neutral cross coupling‐type mechanism, opening up new opportunities for direct, efficient, chemoselective synthesis.

Nickel-Catalyzed Amide Bond Formation from Methyl Esters.

Despite being one of the most important and frequently run chemical reactions, the synthesis of amide bonds is accomplished primarily by wasteful methods that proceed by stoichiometric activation of one of the starting materials. We report a nickel-catalyzed procedure that can enable diverse amides to be synthesized from abundant methyl ester starting materials, producing only volatile alcohol as a stoichiometric waste product. In contrast to acid- and base-mediated amidations, the reaction is proposed to proceed by a neutral cross coupling-type mechanism, opening up new opportunities for direct, efficient, chemoselective synthesis.

Mechanism of Integrated β-Lactam Formation by a Nonribosomal Peptide Synthetase during Antibiotic Synthesis

Modular nonribosomal peptide synthetases (NRPSs) are large, multidomain engines of bioactive natural product biosynthesis that function as molecular "assembly lines" in which monomer units are selectively bound, modified, and linked in a specific order and number dictated by their mega-enzyme templates. Recently, a condensation domain in an NRPS was discovered to carry out the synthesis of an integrated β-lactam ring from a substrate seryl residue during antibiotic biosynthesis. We report here a series of experiments supporting a mechanism that involves C-N bond formation by stepwise elimination/addition reactions followed by canonical NRPS-catalyzed amide bond synthesis to achieve β-lactam formation. Partitioning of reactive intermediates formed during the multistep catalytic cycle provided insight into the ability of the NRPS to overcome the reversibility of corresponding reactions in solution and enforce directionality during synthesis.

Decarboxylative alkenylation.

Olefin chemistry, through pericyclic reactions, polymerizations, oxidations, or reductions, plays an essential role in the foundation of how organic matter is manipulated.1 Despite its importance, olefin synthesis still largely relies upon chemistry invented more than three decades ago, with metathesis2 being the most recent addition. Here we describe a simple method to access olefins with any substitution pattern or geometry from one of the most ubiquitous and variegated building blocks of chemistry: alkyl carboxylic acids. The same activating principles used in amide-bond synthesis can thus be employed, under Ni- or Fe-based catalysis, to extract CO2 from a carboxylic acid and economically replace it with an organozinc-derived olefin on mole scale. Over sixty olefins across a range of substrate classes are prepared, and the ability to simplify retrosynthetic analysis is exemplified with the preparation of sixteen different natural products across a range of ten different families.

ChemInform Abstract: Enzymatic Strategies and Biocatalysts for Amide Bond Formation: Tricks of the Trade Outside of the Ribosome

AbstractReview: 147 refs.

ChemInform Abstract: Catalytic Chemical Amide Synthesis at Room Temperature: One More Step Toward Peptide Synthesis.

AbstractA direct amide bond synthesis between carbocyclic acids and amines is achieved in the presence of a highly active bench‐stable catalyst.

Catalytic chemical amide synthesis at room temperature: one more step toward peptide synthesis.

An efficient method has been developed for direct amide bond synthesis between carboxylic acids and amines via (2-(thiophen-2-ylmethyl)phenyl)boronic acid as a highly active bench-stable catalyst. This catalyst was found to be very effective at room temperature for a large range of substrates with slightly higher temperatures required for challenging ones. This methodology can be applied to aliphatic, α-hydroxyl, aromatic, and heteroaromatic acids as well as primary, secondary, heterocyclic, and even functionalized amines. Notably, N-Boc-protected amino acids were successfully coupled in good yields with very little racemization. An example of catalytic dipeptide synthesis is reported.

Amide Bond Formation through Iron-Catalyzed Oxidative Amidation of Tertiary Amines with Anhydrides

A general and efficient method for amide bond synthesis has been developed. The method allows for synthesis of tertiary amides from readily available tertiary amines and anhydrides in the presence of FeCl2 as catalyst and tert-butyl hydroperoxide in water (T-Hydro) as oxidant. Mechanistic studies indicated that the in situ-generated α-amino peroxide of tertiary amine and iminium ion act as key intermediates in this oxidative transformation.

Direct Nucleophilic Addition to N‐Alkoxyamides

While the synthesis of amide bonds is now one of the most reliable organic reactions, functionalization of amide carbonyl groups has been a long-standing issue due to their high stability. As an ongoing program aimed at practical transformation of amides, we developed a direct nucleophilic addition to N-alkoxyamides to access multisubstituted amines. The reaction enabled installation of two different functional groups to amide carbonyl groups in one pot. The N-alkoxy group played important roles in this reaction. First, it removed the requirement for an extra preactivation step prior to nucleophilic addition to activate inert amide carbonyl groups. Second, the N-alkoxy group formed a five-membered chelated complex after the first nucleophilic addition, resulting in suppression of an extra addition of the first nucleophile. While diisobutylaluminum hydride (DIBAL-H) and organolithium reagents were suitable as the first nucleophile, allylation, cyanation, and vinylation were possible in the second addition including inter- and intramolecular reactions. The yields were generally high, even in the synthesis of sterically hindered α-trisubstituted amines. The reaction exhibited wide substrate scope, including acyclic amides, five- and six-membered lactams, and macrolactams.

Mild and Efficient Cooper (II) Oxide-Catalyzed Acylation of Amines and Alcohols

Therefore, the development of a mild and efficient method for the synthesis of amide bonds in the absence of a base is strongly desired. In this communication, we report on a new and efficient method for the synthesis of amides from corres-ponding acyl chlorides and amines using a catalytic amount of cooper (II) oxide (CuO). To the best of our knowledge, this is the first demonstration of CuO-catalyzed acylation of amines and alcohols.Initially, we chose benzoyl chloride and cyclohexylamine as model compounds. When benzoyl chloride was treated with cyclohexylamine (1 equiv) and CuO (1 equiv) in CH

Synthesis and Mechanism Studies on Amide Bond Formation by Hexamethylphosphoramide (HMPA)

In this paper, hexamethylphosphoramide (HMPA) was used as the organic phosphorus coupling reagent for the synthesis of amide bond. The reaction mechanism was tracked and investigated through 31P NMR.

Staudinger Ligation of Peptides at Non-Glycyl Residues

The Staudinger ligation provides a means to form an amide bond between a phosphinothioester and azide. This reaction holds promise for the ligation of peptides en route to the total chemical synthesis of proteins. (Diphenylphosphino)methanethiol is the most efficacious of known reagents for mediating the Staudinger ligation of peptides, providing high (> 90%) isolated yields for equimolar couplings in which a glycine residue is at the nascent junction. Surprisingly, the yields are lower (< 50%) for non-glycyl couplings due to an aza-Wittig reaction that diverts the reaction toward a phosphonamide byproduct. Here, the partitioning of the reaction toward Staudinger ligation (and away from the aza-Wittig reaction) is shown to increase with increasing electron density on phosphorus. This electron density can be tuned either by installing functional groups on the phenyl substituents of (diphenylphosphino)methanethiol or by changing the polarity of the solvent. Installing p-methoxy groups and using a solvent of low polarity (such as toluene or dioxane) provide especially high (> 80%) isolated yields for the ligation of two non-glycyl residues. These conditions retain the high chemoselectivity of the reaction and do not lead to a substantial change in reaction rate. The traceless Staudinger ligation is now poised to enable the iterative ligation of peptides with little regard for their sequence, as well as the synthesis of amide bonds for other purposes.

Indium‐Mediated Mild and Facile Method for the Synthesis of Amides.

AbstractFor Abstract see ChemInform Abstract in Full Text.