Acylating Reagents Research Articles

Acid-Solvent Cluster-Promoted General and Regioselective Friedel-Crafts Acylation with Carboxylic Acids.

Carboxylic acids are considered to be the most ideal acylating reagents for Friedel-Crafts acylation. However, the low electrophilicity of carboxylic acids and the ability of their byproduct water to deactivate Lewis and Brønsted acids greatly limit their application in this reaction. In this work, we developed a general and regioselective Friedel-Crafts acylation with carboxylic acids, wherein unactivated/activated arenes and various aromatic and aliphatic carboxylic acids were viable starting materials. Key to this accomplishment is the use of trifluoromethanesulfonic acid-hexafluoroisopropanol clusters.

Palladium Catalyzed Direct Ortho C‐H Acylation of 4‐Phenylquinazoline Using Methylarenes as Acylation Reagents

AbstractA simple ortho‐acylation of 4‐phenylquinazoline by a Pd‐catalyzed oxidative C−H activation was developed, with moderate yields, in which no prefunctionalized methylarenes were used as acylation reagents. Moreover, this methodology tolerates a wide range of functional groups. Radical scavenging experiments indicate that the acylation involves a benzoyl radical pathway.

Photoredox decarboxylative acylation of carboxylic acid by 4-acyl-1,2,3-triazoliums

Recent advancements in NHC-based radical coupling reactions have introduced NHC-derived ketyl radicals as innovative persistent radicals. However, current work involves NHC-based radical-radical coupling reactions that are limited to some stable alkyl radicals of the radical partners. This is mainly due to the high barriers among the transition state in the coupling process. Our study, supported by density functional theory (DFT) calculations, demonstrates that ketyl radicals derived from mesoionic carbenes (MICs) exhibit significantly lower barriers for radical-radical coupling. This facilitates rapid reactions with short-lived alkyl radicals. Herein, we disclose 4-acyl-1,2,3-triazoliums as versatile acylation reagents, which can be converted to MIC-derived ketyl radicals by photocatalyst. Photoredox decarboxylative acylation of primary, secondary, and tertiary carboxylic acids afford the corresponding ketones with broad substrate scope and excellent functional group tolerance.

Benzoyl cyanide, a general radical acylating reagent for photoredox-catalyzed benzylic site-selective acylation reactions

Benzoyl cyanide, a general radical acylating reagent for photoredox-catalyzed benzylic site-selective acylation reactions

Enamine Acylation Enabled Desymmetrization of Malonic Esters.

Asymmetric enamine alkylation represents a powerful tool for stereoselective C-C bond formation; in contrast, the development of enantioselective enamine acylation remains elusive. Here, we report that a chiral phosphoric acid can render an in-situ-formed enamine to undergo a stereoselective intramolecular α-carbon acylation, providing an alternative approach for the synthesis of useful pyrrolinones and indolinones bearing tetrasubstituted stereocenters. Utilizing an effective integration of the desymmetrization strategy and bifunctional organocatalysis, the first example of enantioselective enamine acylation is achieved by employing readily available aminomalonic esters and cyclic ketones. Instead of reactive and moisture-sensitive acyl chlorides, common esters with low electrophilicity were successfully used as efficient acylating reagents via hydrogen bonding interactions. The utility is demonstrated in the concise and enantioselective synthesis of (+)-LipidGreen I and II. Experimental studies and DFT calculations establish the reaction pathway and the origin of stereocontrol.

Acyl-1,4-Dihydropyridines: Universal Acylation Reagents for Organic Synthesis.

Acyl-1,4-dihydropyridines have recently emerged as universal acylation reagents. These easy-to-make and bench-stable NADH biomimetics play the dual role of single-electron reductants and sources of acyl radicals. This review article discusses applications of acyl-1,4-dihydropyridines in organic synthesis since their introduction in 2019. Acyl-1,4-dihydropyridines, activated by photochemical, thermal or electrochemical methods, have been successfully applied as radical sources in multiple diverse organic transformations such as acyl radical addition to olefins, alkynes, imines and other acceptors, as well as in the late-stage functionalisation of natural products and APIs. Release of acyl radicals and an electron can be performed under mild conditions-in green solvents, under air and sunlight, and without the use of photocatalysts, photosensitizers or external oxidants-which makes them ideal reagents for organic chemists.

Synthesis, infra red and nmr intensities of amphiphilic adamantane derivatives: Impact of hydroxylation, acetylation and chlorination

Novel chloro substituted adamantanamide was designed to have better supramolecular sites and accordingly synthesized via hydroxylation, acetylation and chlorination. Due to the specific electronic properties of chlorine atom it imparts better applications. Functionalization of highly unreactive adamantane was achieved with an overall yield of 80% under milder reaction conditions. Hydroxylation of adamantamine was carried out using urea as catalyst (10mol%) with an yield of 97%. Acetylation was optimized using acylating reagent (acetyl chloride, 1.1 equivalents) and DIPEA (1.5 equivalents) which resulted 97% yield. Finally, chlorination was carried out with thionyl chloride (2.0 equivalents) at 65 °C (84% yield). IR and NMR (including D2O exchanded) spectra were analyzed along with ESI-MS data of all the products. DFT studies were carried using B3LYP level {6–311++G (d, p) basis set}out for all the products to predict the stability, reactivity and other global descriptors.

Direct Synthesis of C4-Acyl Indoles via C-H Acylation.

The direct synthesis of C4-acyl indoles deprived of C2 and C3 substituents has proven to be challenging, with scarce efficient synthetic routes being reported. Herein, we disclose a highly site-selective palladium-catalyzed C-H acylation for the construction of C4-acyl indoles via a Catellani-Lautens cyclization strategy. In addition, we systematically studied the ortho C-H acylation mechanism of iodoaniline through density functional theory (DFT) calculations and combined experimental results to elucidate the principle of high chemoselectivity brought by triazine benzoate as an acylation reagent.

Deselenylative Acylation and Nitration of Monoselenides.

A deselenylative protocol that enables the construction of the C-C and C-N bonds has been disclosed. By using acyl chloride/AgOTf as an efficient acylation reagent, diarylselenides smoothly undergo deselenylative acylation to produce a series of aroyl compounds. In addition, deselenylative nitration can be enabled by a mild nitration reagent consisting of TsCl and AgNO3, furnishing a diverse array of nitroaromatic compounds.

Gold‐Zinc Co‐Catalyzed Alkynoate Hydrocarboxylation with N‐Protected Amino Acids for Preparation of Storable Acylating Reagents and Racemization‐Free Peptide Synthesis

AbstractHydrocarboxylation of methyl 2‐octynoate, a chemical commercially available at a low cost, with N‐protected amino acids was developed with a gold‐zinc cooperative catalyst constructed with a 5‐[(2,2′‐bipyridin)‐5‐yl]imidazo[1,5‐a]pyridin‐3‐ylidene to prepare α‐methoxycarbonyl enol esters as acylating reagents. The α‐methoxycarbonyl enol esters were isolable through silica‐gel column chromatography and storable without precautions regarding moisture. Acylation of free amines with the α‐methoxycarbonyl enol esters proceeded without epimerization of the stereogenic center derived from the enol esters, affording analytically pure dipeptide compounds through filtration and hexane‐washing.

C-C Bond Cleavage-Induced C- to N-Acyl Transfer for Synthesis of Amides.

A new approach for the preparation of amides was developed using C-C bond cleavage that initiates C- to N-acyl transfer, employing activated ketones as acylation reagents and amine nucleophiles. The reaction was operational under the coupling reagent system that is commonly utilized for peptide bond formations. The method enables practical preparation of amides using linear and cyclic ketone substrates under mild conditions.

Catalytic N-Acylation for Access to N–N Atropisomeric N-Aminoindoles: Choice of Acylation Reagents and Mechanistic Insights

Catalytic N-Acylation for Access to N–N Atropisomeric N-Aminoindoles: Choice of Acylation Reagents and Mechanistic Insights

Synthesis of Amides Using Triazine Esters as Stable Acylation Reagents

Synthesis of Amides Using Triazine Esters as Stable Acylation Reagents

Highly Practical Aqueous Phase Acylation of Phenols, Amines and Alcohols Employing New Green Acylation Reagents Derived From DBU

AbstractTwo new Lewis base adducts (LBAs) of DBU were prepared, isolated in grams scale and are employed as Green reagents for base free benzoylation and pivaloylation in water. The structures of these reagents are unambiguously confirmed and the practicality of these LBAs (transient species) in organic synthesis as operationally simple protecting reagents of various phenols, amines, and alcohols in water at ambient temperature is explored. The products are furnished in very good yields (up to 95 %) and are purified just by filtration followed by recrystallization thus avoiding column chromatography. The Lewis base, DBU is recycled and reused for the preparation of LBAs. The methodology is an environmentally benign due to aqueous phase, base free reaction, chromatography free purificatios, ambient temperature reactions and recycling DBU.

Photoredox-Catalyzed Hydroacylation of Azobenzenes with Carboxylic Acids.

Acyl hydrazides are widely found in bioactive compounds and have important applications as versatile synthetic intermediates. In the current report, a photoredox-catalyzed hydroacylation of azobenzenes was disclosed with carboxylic acids as the acylation reagent, affording a variety of N,N'-disubstituted hydrazides. The process possesses the advantages of mild reaction conditions, broad substrate scope, and high efficiency. Preliminary mechanistic investigation indicated that the addition of an acyl radical to the azo compound should be involved.

Efficient post-synthesis incorporation and conjugation of reactive ketones in RNA via 2'-acylation.

Despite the broad utility of ketones in bioconjugation, few methods exist to introduce them into RNA. Here we develop highly reactive 2'-OH acylating reagents containing strained-ring ketones, and employ them as versatile labeling handles for RNA.

Eco-Conscious Approach to Thermoresponsive Star-Comb and Mikto-Arm Polymers via Enzymatically Assisted Atom Transfer Radical Polymerization Followed by Ring-Opening Polymerization.

This study explores the synthesis, characterization, and application of a heterofunctional initiator derived from 2-hydroxypropyl cyclodextrin (HP-β-CD), having eight bromoester groups and thirteen hydroxyl groups allowing the synthesis of mikto-arm star-shaped polymers. The bromoesterification of HP-β-CD was achieved using α-bromoisobutyryl bromide as the acylation reagent, modifying the cyclodextrin (CD) molecule as confirmed by electrospray ionization mass spectrometry (ESI-MS), nuclear magnetic resonance (NMR), attenuated total reflection-Fourier transform infrared (ATR-FTIR) spectroscopy analysis, and differential scanning calorimetry (DSC) thermograms. The initiator's effectiveness was further demonstrated by obtaining star-comb and mikto-arm polymers via an enzymatically assisted atom transfer radical polymerization (ATRP) method and subsequent ring-opening polymerization (ROP). The ATR polymerization quality and control depended on the type of monomer and was optimized by the way of introducing the initiator into the reaction mixture. In the case of ATRP, high conversion rates for poly(ethylene oxide) methyl ether methacrylate (OEOMA), with molecular weights (Mn) of 500 g/mol and 300 g/mol, were achieved. The molecular weight distribution of the obtained polymers remained in the range of 1.23-1.75. The obtained star-comb polymers were characterized by different arm lengths. Unreacted hydroxyl groups in the core of exemplary star-comb polymers were utilized in the ROP of ε-caprolactone (CL) to obtain a hydrophilic mikto-arm polymer. Cloud point temperature (TCP) values of the synthesized polymers increased with arm length, indicating the polymers' reduced hydrophobicity and enhanced solvation by water. Atomic force microscopy (AFM) analysis revealed the ability of the star-comb polymers to create fractals. The study elucidates advancements in the synthesis and utilization of hydrophilic sugar-based initiators for enzymatically assisted ATRP in an aqueous solution for obtaining complex star-comb polymers in a controlled manner.

Proof-of-Concept of ketene chemistry: Experimental and theoretical calculations on the synthesis of p-methoxyacetophenone from ethenone with anisole

Ketene compounds with the specific structure (>C=C=O) have been widely used for over 110 years and already become a research hotspot. This study proposes a reaction route to produce aromatic ketone by using ethenone as a new acylation reagent, and offers a novel catalytic direction in the field of Ketene Chemistry: acylation of ketenes. The results show that ethenone can react with anisole to form acylation compounds, where the formation of acylium ion from ethenone is the key step. The easy activation of ethenone provides a new insight and breakthrough direction for the application of ketene compounds in acylation reactions.

RNA-Polymer Hybrids via Direct and Site-Selective Acylation with the ATRP Initiator and Photoinduced Polymerization.

Combining synthetic polymers with RNA paves the way for creating RNA-based materials with non-canonical functions. We have developed an acylation reagent that allows for direct incorporation of the atom transfer radical polymerization (ATRP) initiator into both short synthetic oligoribonucleotides and natural biomass RNA extracted from torula yeast. The acylation was performed in a quantitative yield. The resulting initiator-functionalized RNAs were used for grafting polymer chains from the RNA by photoinduced ATRP, resulting in RNA-polymer hybrids with narrow molecular weight distributions. The RNA initiator was used for the polymerization of oligo(ethylene oxide) methyl ether methacrylate, poly(ethylene glycol) dimethacrylate, and N-isopropylacrylamide monomers, resulting in RNA bottlebrushes, hydrogels, and stimuli-responsive materials. This approach, readily applicable to both post-synthetic and nature-derived RNA, can be used to engineer the properties of a variety of RNA-based macromolecular hybrids and assemblies providing access to a wide variety of RNA-polymer hybrids.

Regiodivergent C-H Acylation of Arenes by Switching from Ionic to Radical Type Chemistry Using NHC-Catalysis.

The Friedel-Crafts acylation which belongs to the class of electrophilic aromatic substitutions is a highly valuable and versatile reaction in synthesis. Regioselectivity is well predictable and determined by electronic as well as steric factors of the (hetero)arene substrate. In this communication, a radical approach for the acylation of arenes and heteroarenes is presented. C-H Acylation is achieved through mild cooperative photoredox/NHC radical catalysis with the cross coupling of an arene radical cation with an NHC-bound ketyl radical as a key step. As compared to the classical Friedel-Crafts acylation, a regiodivergent outcome is observed upon switching from the ionic to the radical mode. In these divergent reactions, aroyl fluorides act as the acylation reagents in both the ionic as well as the radical process.