Esterification Of Amides Research Articles

Direct esterification of amides by the dimethylsulfate-mediated activation of amide C–N bonds

Amides are important intermediates in organic chemistry and the pharmaceutical industry, but their low reactivity requires catalysts and/or severe reaction conditions for esterification. Here, a novel approach was devised to convert amides into esters without the use of transition metals. The method effectively overcomes the inherent low reactivity of amides by employing dimethylsulfate-mediated reaction to activate the C-N bonds. To confirm the proposed reaction mechanism, control experiments and density functional theory (DFT) calculations were conducted. The method demonstrates a wide array of substrates, including amides with typical H/alkyl/aryl substitutions, N,N-disubstituted amides, amides derived from alkyl, aryl, or vinyl carboxylic acids, and even amino acid substrates with stereocentres. Furthermore, we have shown the effectiveness of dimethylsulfate in removing acyl protective groups in amino derivatives. This study presents a method that offers efficiency and cost-effectiveness in broadening the esterification capabilities of amides, thereby facilitating their increased utilization as synthetic compounds in diverse transformations.

DABCO-catalyzed esterification of N-pivaloyl-activated amides.

A previously elusive organocatalytic protocol for the esterification of amides is disclosed. DABCO (10 mol%) is identified as an effective catalyst for the esterification of N-pivaloyl amides. Although N-pivaloyl amides are nearly planar (amide bond twist (τ) = 4.54° and pyramidalization (χN = 6.39°)) and resonance stabilized, esterification is achieved with high efficiency. The developed protocol is generic, phenols, thiophenols, aliphatic alcohols, and thiols were identified as effective substrates. Furthermore, the reaction features a broad substrate scope and excellent functional group tolerance. To exemplify the practical applicability of the developed protocol, the esterification of bioactive natural products, pterostilbene and menthol, is demonstrated. In addition, a series of competitive experiments were conducted to establish the reactivity pattern of alcohols, thiols, and phenols, which could serve as selectivity principles for future synthetic design. Our findings signify a notable advancement in utilizing amides as versatile synthetic building blocks in organic synthesis under metal-free conditions.

Catalytic Esterification of Amides by Using a Zirconium-Based Metal–Organic Framework

Catalytic Esterification of Amides by Using a Zirconium-Based Metal–Organic Framework

Transition‐Metal‐Free DMAP‐Mediated Aromatic Esterification of Amides with Organoboronic Acids

AbstractA new, transition‐metal‐free, effective method for aromatic esterification of amides with organoboronic acids has been developed. A wide range of benzoate derivatives were obtained with yields ranging from moderate to good. The catalytic reaction shows a broad substrate scope and excellent functional group tolerance. Conceptually, DMAP mediates the reaction and is crucial for this transformation.

Cover Feature: Zr‐MOF‐808 as Catalyst for Amide Esterification (Chem. Eur. J. 14/2021)

Cover Feature: Zr‐MOF‐808 as Catalyst for Amide Esterification (Chem. Eur. J. 14/2021)

Zr-MOF-808 as Catalyst for Amide Esterification.

In this work, zirconium-based metal-organic framework Zr-MOF-808-P has been found to be an efficient and versatile catalyst for amide esterification. Comparing with previously reported homogeneous and heterogeneous catalysts, Zr-MOF-808-P can promote the reaction for a wide range of primary, secondary and tertiary amides with n-butanol as nucleophilic agent. Different alcohols have been employed in amide esterification with quantitative yields. Moreover, the catalyst acts as a heterogeneous catalyst and could be reused for at least five consecutive cycles. The amide esterification mechanism has been studied on the Zr-MOF-808 at molecular level by in situ FTIR spectroscopic technique and kinetic study.

Hydrogen-bond-assisted transition-metal-free catalytic transformation of amides to esters

The amide C-N cleavage has drawn a broad interest in synthetic chemistry, biological process and pharmaceutical industry. Transition-metal, luxury ligand or excess base were always vital to the transformation. Here, we developed a transition-metal-free hydrogen-bond-assisted esterification of amides with only catalytic amount of base. The proposed crucial role of hydrogen bonding for assisting esterification was supported by control experiments, density functional theory (DFT) calculations and kinetic studies. Besides broad substrate scopes and excellent functional groups tolerance, this base-catalyzed protocol complements the conventional transition-metal-catalyzed esterification of amides and provides a new pathway to catalytic cleavage of amide C-N bonds for organic synthesis and pharmaceutical industry.

Visible light-mediated transition metal-free esterification of amides with boronic acids

A novel strategy for visible light-mediated esterification of amides with boronic acids in air has been described. This method is characterized by mild reaction conditions and low cost owing to no need of any catalyst, which implies high potential utility in late-stage functionalization of amide drugs and materials.

Esterification of Tertiary Amides: Remarkable Additive Effects of Potassium Alkoxides for Generating Hetero Manganese-Potassium Dinuclear Active Species.

A catalyst system of mononuclear manganese precursor 3 combined with potassium alkoxide served as a superior catalyst compared with our previously reported manganese homodinuclear catalyst 2 a for esterification of not only tertiary aryl amides, but also tertiary aliphatic amides. On the basis of stoichiometric reactions of 3 and potassium alkoxide salt, kinetic studies, and density functional theory (DFT) calculations, we clarified a plausible reaction mechanism in which in situ generated manganese–potassium heterodinuclear species cooperatively activates the carbonyl moiety of the amide and the OH moiety of the alcohols. We also revealed details of the reaction mechanism of our previous manganese homodinuclear system 2 a, and we found that the activation free energy (ΔG ≠) for the manganese–potassium heterodinuclear complex catalyzed esterification of amides is lower than that for the manganese homodinuclear system, which was consistent with the experimental results. We further applied our catalyst system to deprotect the acetyl moiety of primary and secondary amines.

Ball-milling enables highly selective solvent-free N-tert-butoxycarbonylation for activation of amides

A ball-milling enabled chemoselective activation of amides via N-tert-butoxycarbonylation catalyzed by 4-dimethylaminopyridine is described under solvent-free conditions. High chemoselectivity with respect to NH acidity of amides has been observed. A one-pot two-step procedure for selective esterification of amides has been demonstrated in model reaction of benzamides with p-cresol and benzyl alcohol.

Nickel-Catalyzed Esterification of Amides Under Mild Conditions

The use of ligands to adjust the catalytic activity of the catalyst for esterification of amides is challenge in organic chemistry. In this paper, Nickel(II)-NHC-catalyzed the esterification reaction between N,N-di-Boc amide and alcohols at room temperature have been demonstrated. The imidazolium salt bearing a hydroxyl functionalized side arm showed high effective catalytic activity in the activation of the amide N–C bond in air atmosphere.

Catalytic Cleavage of Amide C-N Bond: Scandium, Manganese, and Zinc Catalysts for Esterification of Amides.

Amide C-N bonds are thermodynamically stable and their fission, such as by hydrolysis and alcoholysis, is considered a long-challenging organic reaction. In general, stoichiometric chemical transformations of amides into the corresponding esters and acids require harsh conditions, such as strong acids/bases at a high reaction temperature. Accordingly, the development of catalytic reactions that cleave not only primary and secondary amides, but also tertiary amides in mild conditions, is in high demand. Herein, we surveyed typical stoichiometric transformations of amides, and highlight our recent achievements in the catalytic esterification of amides using scandium, manganese, and zinc catalysts, together with some recent catalyst systems using late-transition metal reported by other groups.

Direct Phenolysis Reactions of Unactivated Amides into Phenolic Esters Promoted by a Heterogeneous CeO2 Catalyst.

The direct catalytic esterification of amides that leads to the construction of C-O bonds through the cleavage of amide C-N bonds is a highly attractive strategy in organic synthesis. While aliphatic and aromatic alcohols can be readily used for the alcoholysis of activated and unactivated amides, the introduction of phenols is more challenging due to their lower nucleophilicity in the phenolysis of unactivated amides. Herein, we demonstrate that phenols can be used for the phenolysis of unactivated amides into the corresponding phenolic esters using a simple heterogenous catalytic system based on CeO2 under additive-free reaction conditions. The method tolerates a broad variety of functional groups (>50 examples) in the substrates. Results of kinetic studies afforded mechanistic insights into the principles governing this reaction, suggesting that the cooperative effects of the acid-base functions of catalysts would be of paramount importance for the efficient progression of the C-N bond breaking process, and consequently, CeO2 showed the best catalytic performance among the catalysts explored.

Transition-Metal-Free Esterification of Amides via Selective N-C Cleavage under Mild Conditions.

A general, transition-metal-free, and operationally simple method for esterification of amides by a highly selective cleavage of N-C(O) bonds under exceedingly mild conditions is reported. The reaction is characterized by broad substrate scope and excellent functional group tolerance. The potential of this mild esterification is highlighted by late-stage diversification of natural products and pharmaceuticals. Conceptually, the metal-free acyl functionalization of amides represents a significant step forward as a practical alternative to ligand exchange in acylmetal intermediates.

Fluoride-Catalyzed Esterification of Amides.

In recent years, it has been demonstrated that amide carbon-nitrogen bonds can be activated and selectively cleaved using transition metal catalysts. However, these methodologies have been restricted to specific amides; a one-to-one relationship exists between the catalytic system and the amides and also uses large amounts of transition-metal catalysts and ligands. Hence, we now report a general strategy for esterification of common amides using fluoride as a catalyst. This method shows high functional group tolerance, and notably it requires only a slight excess of the alcohol nucleophile, which is a rare case in transition-metal-free amide transformations. Moreover, this approach may provide a new understanding for further studies on esterification of amides and is expected to stimulate the development of alternative methods for direct functionalization of amides.

Cobalt-Catalyzed Esterification of Amides.

The first cobalt-catalyzed amide activation of N-Boc-amides, and their conversion into esters, is reported here. This new methodology presents a very practical process that does not require an inert atmosphere, uses an inexpensive cobalt catalyst, and proceeds under mild reaction conditions. This catalytic system has a broad substrate scope and has been shown to be highly efficient, with catalyst loadings as low as 1 mol %.

Kinetic Modeling of the Nickel-Catalyzed Esterification of Amides.

Nickel-catalyzed coupling reactions provide exciting tools in chemical synthesis. However, most methodologies in this area require high catalyst loadings, which commonly range from 10–20 mol % nickel. Through an academic-industrial collaboration, we demonstrate that kinetic modeling can be used strategically to overcome this problem, specifically within the context of the Ni-catalyzed conversion of amides to esters. The successful application of this methodology to a multigram-scale coupling, using only 0.4 mol % Ni, highlights the impact of this endeavor.

Nickel‐Catalyzed Esterification of Aliphatic Amides

AbstractRecent studies have demonstrated that amides can be used in nickel‐catalyzed reactions that lead to cleavage of the amide C−N bond, with formation of a C−C or C−heteroatom bond. However, the general scope of these methodologies has been restricted to amides where the carbonyl is directly attached to an arene or heteroarene. We now report the nickel‐catalyzed esterification of amides derived from aliphatic carboxylic acids. The transformation requires only a slight excess of the alcohol nucleophile and is tolerant of heterocycles, substrates with epimerizable stereocenters, and sterically congested coupling partners. Moreover, a series of amide competition experiments establish selectivity principles that will aid future synthetic design. These studies overcome a critical limitation of current Ni‐catalyzed amide couplings and are expected to further stimulate the use of amides as synthetic building blocks in C−N bond cleavage processes.

Nickel-Catalyzed Esterification of Aliphatic Amides.

Recent studies have demonstrated that amides can be used in nickel-catalyzed reactions that lead to cleavage of the amide C-N bond, with formation of a C-C or C-heteroatom bond. However, the general scope of these methodologies has been restricted to amides where the carbonyl is directly attached to an arene or heteroarene. We now report the nickel-catalyzed esterification of amides derived from aliphatic carboxylic acids. The transformation requires only a slight excess of the alcohol nucleophile and is tolerant of heterocycles, substrates with epimerizable stereocenters, and sterically congested coupling partners. Moreover, a series of amide competition experiments establish selectivity principles that will aid future synthetic design. These studies overcome a critical limitation of current Ni-catalyzed amide couplings and are expected to further stimulate the use of amides as synthetic building blocks in C-N bond cleavage processes.

Direct Three‐Component Synthesis of α‐Cyano Acrylates Involving Cascade Knoevenagel Reaction and Esterification

AbstractA direct three‐component approach has been developed for the synthesis of α‐cyano acrylates starting from aldehydes, alcohols and α‐cyano acetamide by employing cyanuric chloride as an organocatalyst. A class of structurally diverse α‐cyano acrylates have been provided with good to excellent yields via the cascade transformation of Knoevenagel condensation and amide esterification.