Unactivated Esters Research Articles

Direct Synthesis of Artificial Esterase through Molecular Imprinting Using a Substrate-Mimicking Acylthiourea Template.

Most reported artificial esterases hydrolyze only activated esters. We here report a one-pot synthesis of artificial esterases via molecular imprinting. An acylthiourea template hydrogen bonds with 4-vinylbenzoic acid and coordinates to a polymerizable zinc complex inside a cross-linkable surfactant micelle. Double cross-linking of the micelle yields a polymeric nanoparticle catalyst that mimics a metalloenzyme to activate a water molecule for nucleophilic attack on the bound ester. The catalyst hydrolyzes both activated and unactivated esters under mild conditions with selectivity.

Intramolecular Reductive Amidation of Unactivated Esters with Nitroarenes: A Telescoped Synthesis of Tetrahydropyrrolo/Pyrido[1,2-a]quinoxalinones.

A reductive amidation of unactivated esters with nitroarenes, a key step in the telescopic synthesis of tetrahydropyrrolo[1,2-a]quinoxalinones and tetrahydropyrido[1,2-a]quinoxalinones, is reported. The process involves an intermolecular base-mediated SNAr reaction, followed by intramolecular reductive amidation employing sodium dithionite. The substrate scope coupled with the demonstration of the synthesis of pharmaceuticals is reported. The key features include nitro reduction at room temperature, easy purification without chromatography, amidation of unactivated esters without any externally added activating agent, and a telescopic process.

Cesium Carbonate Promoted Direct Amidation of Unactivated Esters with Amino Alcohol Derivatives.

Cesium carbonate promoted direct amidation of unactivated esters with amino alcohols was developed without the use of transition-metal catalysts and coupling reagents. This method enabled the synthesis of several serine-containing oligopeptides and benzamide derivatives with yields up to 90%. The methodology proceeds under mild reaction conditions and exhibits no racemization for most naturally occurring amino acid substrates. The reaction demonstrates good compatibility with primary alkyl and benzyl esters and broad tolerance for a range of amino acid substrates with nonpolar and protected side chains. The hydroxy group on the amine nucleophile was found to be critical for the reaction to be successful. A likely mechanism involving cesium coordination to the substrates enabling the subsequent proximity-driven acyl transfer was proposed. The practicality of this approach was demonstrated in the preparation of a biologically active nicotinamide derivative in a reasonable yield.

Ti-Catalyzed Modular Ketone Synthesis from Carboxylic Derivatives and gem-Dihaloalkanes.

Ketones are ubiquitous in organic synthesis. However, the general method to convert widely available carboxylic acids, unactivated esters, and amides into ketones remains elusive. Herein, we describe the Ti-catalyzed modular ketone synthesis from carboxylic derivatives and easily accessed gem-dihaloalkanes. Notably, this protocol could achieve the direct catalytic olefination of carboxylic acids. This method features a sequence of olefination and electrophilic transformation and good functional group compatibility and allows rapid access to various functionalized ketones. Preliminary mechanistic studies provide insights into the reaction pathway and support the intermediacy of plausible alkylidene titanocene and gem-bimetallic complexes.

Synthesis of Anilides by Aminolysis of Unactivated Esters using MnCl2 in Combination with strong Bases as Catalyst

AbstractAnilides are often found in pharmaceuticals and active ingredients in crop protection. Although of great interest, the atom‐ and step economic formation of the amide bond between a less nucleophilic aniline with an acid or ester remains still a major challenge. Herein, we report an aminolysis of aromatic and alkyl esters with anilines catalyzed by a readily available catalytic system comprising of an earth‐abundant Mn‐salt in combination with an inexpensive base.

Accessing Unusual Reactivity through Chelation-Promoted Bond Weakening.

Highly reducing Sm(II) reductants and protic ligands were used as a platform to ascertain the relationship between low-valent metal-protic ligand affinity and degree of ligand X-H bond weakening with the goal of forming potent proton-coupled electron transfer (PCET) reductants. Among the Sm(II)-protic ligand reductant systems investigated, the samarium dibromide N-methylethanolamine (SmBr2-NMEA) reagent system displayed the best combination of metal-ligand affinity and stability against H2 evolution. The use of SmBr2-NMEA afforded the reduction of a range of substrates that are typically recalcitrant to single-electron reduction including alkynes, lactones, and arenes as stable as biphenyl. Moreover, the unique role of NMEA as a chelating ligand for Sm(II) was demonstrated by the reductive cyclization of unactivated esters bearing pendant olefins in contrast to the SmBr2-water-amine system. Finally, the SmBr2-NMEA reagent system was found to reduce substrates analogous to key intermediates in the nitrogen fixation process. These results reveal SmBr2-NMEA to be a powerful reductant for a wide range of challenging substrates and demonstrate the potential for the rational design of PCET reagents with exceptionally weak X-H bonds.

Transesterification of cellulose with unactivated esters in superbase-acid conjugate ionic liquids.

A sustainable homogeneous transesterification protocol utilizing the superbase ionic liquid [mTBNH][OAc] and unactivated methyl esters has been developed for the preparation of cellulose esters with controllable degree of substitution. [mTBNH][OAc] shows excellent recyclability with a high recovery of sufficient purity for repeated use. This reaction media allows for cellulose transesterification reactions not only using activated or cyclic esters, but also with unactivated methyl esters, which extends the substrate and application scope. Furthermore, the solubility properties of the prepared cellulose materials were tested and some intrinsic trends were observed at low degrees of substitution.

Mechanistic Understanding of KOt Bu-Mediated Direct Amidation of Esters with Anilines: An Experimental Study and Computational Approach.

A sustainable and cost-effective protocol has been reported for the synthesis of amide bonds from unactivated esters and non-nucleophilic amines promoted by potassium tert-butoxide under aerobic conditions. The reaction proceeds under relatively mild conditions, encompassing wide substrate scope. A combined experimental and quantum chemical study has been performed to shed light on the mechanism, which implied that a radical pathway is operating for the present protocol.

Really biomimetic: A synthetic hydrolase matching the proficiency of enzymes

In this issue of Chem Catalysis , Zhao and co-workers describe an artificial metallohydrolase that is finally capable of matching the proficiency of enzymes. Using molecular imprinted polymeric nanoparticles, the authors have realized a catalytic system capable of cleaving activated and unactivated esters with shape selectivity. In this issue of Chem Catalysis , Zhao and co-workers describe an artificial metallohydrolase that is finally capable of matching the proficiency of enzymes. Using molecular imprinted polymeric nanoparticles, the authors have realized a catalytic system capable of cleaving activated and unactivated esters with shape selectivity.

Base-promoted direct amidation of esters: beyond the current scope and practical applications.

The base-promoted direct amidation of unactivated esters is among the most useful reactions for amide bond formation in contemporary organic chemistry. The intensive research in this area has led to the development of a number of new methods to achive this transformation. However, to date, the existing literature is more methodological and in many instances lacks practical directions. Therefore, the full potential of this transformation is yet to be revealed by broadening the substrate scope. In a search for new practical applications of the amidation reaction, herein we present a comprehensive study of a number of base-promoted direct amidations that encompass a wide range of amines and esters. Furthermore, we applied our findings in the synthesis of phosphoramidates and several industrially relevant products.

Zirconium Oxide‐Catalyzed Direct Amidation of Unactivated Esters under Continuous‐Flow Conditions

AbstractA sustainable and environmentally benign direct amidation reaction of unactivated esters with amines has been developed in a continuous‐flow system. A commercially available amorphous zirconium oxide was found to be an efficient catalyst for this reaction. While the typical amidation of esters with amines requires a stoichiometric amount of a promoter or metal activator, the present continuous‐flow method enabled the direct amidation reaction under additive‐free conditions with an extensive diversity towards various functional groups. High yields of the products were obtained with a nearly equimolar proportion of starting materials to reduce byproduct formation, which renders this process applicable for use in a sequential‐flow system.magnified image

A practical and sustainable protocol for direct amidation of unactivated esters under transition-metal-free and solvent-free conditions

An environmentally friendly and scalable protocol was developed for direct amidation of unactivated esters under transition-metal-free, solvent-free and chromatography-free conditions.

Reductive Cleavage of Azoarene as a Key Step in Nickel-Catalyzed Amidation of Esters with Nitroarenes

A nickel-catalyzed reductive amidation of unactivated esters was recently reported, employing readily available and low-cost nitroarenes as nitrogen sources. Here, we describe a comprehensive exper...

Metal-Free Cross-Dehydrogenative C-O Coupling of Carbonyl Compounds with N-Hydroxyimides: Unexpected Selective Behavior of Highly Reactive Free Radicals at an Elevated Temperature.

Cross-dehydrogenative C-O coupling of N-hydroxyimides with ketones, esters, and carboxylic acids was achieved employing the di-tert-butyl peroxide as a source of free radicals and a dehydrogenating agent. The proposed method is experimentally simple and demonstrates the outstanding efficiency for the challenging CH substrates, such as unactivated esters and carboxylic acids. It was shown that N-hydroxyphthalimide drastically affects the oxidative properties of t-BuOOt-Bu by intercepting the t-BuO• radicals with the formation of phthalimide-N-oxyl radicals, a species responsible for both hydrogen atom abstraction from the CH reagent and the selective formation of the C-O coupling product by selective radical cross-recombination. The practical applicability of the developed method was exemplified by the single-stage synthesis of commercial reagent (known as Baran aminating reagent precursor) from isobutyric acid and N-hydroxysuccinimide, whereas in the standard synthetic approach, four stages are necessary.

Methoxyacetic acid esters: Applications in protecting group and glycosylation chemistry

The methoxyacetate (MAc) protecting group was introduced over 50 years ago and has proved useful owing to its combination of stability and its ability to be selectively removed in the presence of unactivated esters and a wide variety of other protecting groups. Glycosyl methoxyacetates have been investigated as glycosyl donors under activation by lanthanoids. In this mini-review we highlight a range of useful transformations enabled by judicious application of the methoxyacetate group.

Bidentate Ru(II)‐NC Complexes as Catalysts for α‐Alkylation of Unactivated Amides and Esters

AbstractFive Ru(II)‐NC complexes were tested as catalysts for α‐alkylation of unactivated amides using alcohols as alkylating agents, and complex {(C5H4N)‐(C6H4)}RuCl(CO)(PPh3)2 (1) showed the highest activity. With 0.5 mol% catalyst loading, a series of α‐alkylated amides were isolated at 80 °C within 6 hours. Furthermore, under similar conditions, complex 1 was also active for α‐alkylation of unactivated esters with alcohols, and the reaction time was shortened to 1.5 hours. The catalytic performance of 1 is comparable to the best reported catalyst.

Transition State Analysis of the Reaction Catalyzed by the Phosphotriesterase from Sphingobium sp. TCM1.

Organophosphorus flame retardants are stable toxic compounds used in nearly all durable plastic products and are considered major emerging pollutants. The phosphotriesterase from Sphingobium sp. TCM1 ( Sb-PTE) is one of the few enzymes known to be able to hydrolyze organophosphorus flame retardants such as triphenyl phosphate and tris(2-chloroethyl) phosphate. The effectiveness of Sb-PTE for the hydrolysis of these organophosphates appears to arise from its ability to hydrolyze unactivated alkyl and phenolic esters from the central phosphorus core. How Sb-PTE is able to catalyze the hydrolysis of the unactivated substituents is not known. To interrogate the catalytic hydrolysis mechanism of Sb-PTE, the pH dependence of the reaction and the effects of changing the solvent viscosity were determined. These experiments were complemented by measurement of the primary and secondary 18-oxygen isotope effects on substrate hydrolysis and a determination of the effects of changing the p Ka of the leaving group on the magnitude of the rate constants for hydrolysis. Collectively, the results indicated that a single group must be ionized for nucleophilic attack and that a separate general acid is not involved in protonation of the leaving group. The Brønsted analysis and the heavy atom kinetic isotope effects are consistent with an early associative transition state with subsequent proton transfers not being rate limiting. A novel binding mode of the substrate to the binuclear metal center and a catalytic mechanism are proposed to explain the unusual ability of Sb-PTE to hydrolyze unactivated esters from a wide range of organophosphate substrates.

Sustainable Alkylation of Unactivated Esters and Amides with Alcohols Enabled by Manganese Catalysis

The first example of manganese-catalyzed C-alkylation of the carboxylic acid derivatives is reported. The bench-stable homogeneous manganese complex enables the transformation of the renewable alcohol and carboxylic acid derivative feedstock to higher value esters and amides. The reaction operates via hydrogen autotransfer and ideally produces water as the only side product. Importantly, aliphatic-, benzylic-, and heterocyclic-containing alcohols can be used as alkylating reagents, eliminating the need for mutagenic alkyl halides.

Cobalt catalyzed synthesis of α, β-unsaturated esters from esters and alcohols via mild O2-interrupted hydrogen borrowing

The implementation of direct and mild catalytic synthesis of products from benign materials using inexpensive catalysts is a major goal of chemists. Herein, a mild O2-interrupted hydrogen borrowing strategy using easily accessible and high efficient cobalt complex was reported for direct synthesis of α, β-unsaturated esters from unactivated esters and alcohols. This new route had good tolerance on broad substrate scope (alcohols, acetates, propionates and dios) and functional group with the highest yield of 89.1%. Systematic mechanism investigation revealed the cobalt complex was activated by t-BuOK via double deprotonation of PN5P ligand and removal of dichloro ligands, followed by two-fold alcohols activation and dehydrogenation. Also, the oxygen atmosphere was demonstrated very crucial for such interrupted hydrogen borrowing pathway.

Manganese-Catalyzed Direct Conversion of Ester to Amide with Liberation of H2.

A simple and efficient Mn-catalyzed acylation of amines is achieved using both acyl and alkoxy functions of unactivated esters with the liberation of molecular hydrogen as a sole byproduct. The present protocol provides an atom-economical and sustainable route for the synthesis of amides from esters by employing an earth-abundant manganese salt and inexpensive phosphine-free tridentate ligand.