Electrophilic Acylation Research Articles

Nickel/Titanocene-Catalyzed Electrophilic Acylation Coupling of Styrene Oxides.

The cross-coupling of epoxides with acyl chlorides or anhydrides by a nickel/titanocene dual catalytic system is established. A variety of synthetically useful β-hydroxy ketones were obtained in good to high yields by using modified pyridine-oxazoline ligand. The reaction proceeds via the cooperation of titanocene-catalyzed ring-opening of epoxides and nickel-catalyzed acylation of the benzylic radical intermediate.

Direct C(sp3)-H Acylation by Mechanistically Controlled Ni/Ir Photoredox Catalysis.

ConspectusSynthetic chemists have consistently aimed to develop efficient methods for synthesizing ketones, which are essential building blocks in organic chemistry and play significant roles in bioactive molecules. Recent efforts have focused on using photoredox catalysis, which enables previously inaccessible activation modes, to synthesize ketones through the cross-coupling of an acyl electrophile and simple C(sp3)-H bonds. Over the past few years, we have worked on developing effective and versatile approaches for directly acylating activated hydrocarbons to forge ketones.Initially, thioesters were explored as the acyl source to achieve the direct acylation of ethers, but an unexpected thioesterification reaction was observed instead. To gain insights into this reactivity, we conducted the optimization of reaction conditions, substrate scope evaluation, and mechanistic studies. Drawing from our understanding of Ni/Ir photocatalysis obtained in this study, we subsequently developed a method for the direct acylation of simple hydrocarbons. The use of less-reactive amides as the acyl electrophiles was found to be critical for suppressing undesired pathways. This seemingly counterintuitive reactivity was carefully studied, revealing a substrate-assisted reaction mechanism in which the suppressed oxidative addition leads to early-stage nickel oxidation and C-H activation.To address the drawbacks of this method, which primarily arose from decarbonylative and transmetallative side pathways, we employed N-acyllutidiniums as the acyl electrophile. This prevented undesired decomposition pathways, enabling the use of α-chiral acyl substrates with the retention of their stereochemistry, particularly those derived from α-amino acids. The developed versatile methodology allowed us to access a diverse range of α-amino ketones and their homologues.Despite the elegant utility of Ni/photoredox catalysis in developing new synthetic methodologies, the precise behavior of nickel catalysts under redox conditions is incompletely understood. To gain insight into this behavior and develop new chemical reactions, we used a combination of experimental and computational methods. Our investigations revealed that devised adjustments to the reaction conditions in nickel/photoredox catalysis can result in significant differences in the reaction outcomes, providing chemists with opportunities to tailor reactions through carefully designed mechanistic strategies. We believe that continued efforts to study and apply nickel redox modulation will lead to the discovery of additional organic transformations.

A General Synthesis of Cross-Conjugated Enynones through Pd Catalyzed Sonogashira Coupling with Triazine Esters.

The palladium-catalyzed Sonogashira coupling of α, β-unsaturated acid derivatives offers a diversity-oriented synthetic strategy for cross-conjugated enynones. However, the susceptibility of the unsaturated C-C bonds adjacent to the carbonyl group toward Pd catalysts makes the direct conversion of α, β-unsaturated derivatives as acyl electrophiles to cross-conjugated ketones rare. This work presents a highly selective C-O activation approach to prepare cross-conjugated enynones using α, β-unsaturated triazine esters as acyl electrophiles. Under base and phosphine ligand-free conditions, NHC-Pd(II)-Allyl precatalyst alone catalyzed the cross-coupling of α, β-unsaturated triazine esters with terminal alkynes efficiently, yielding 31 cross-conjugated enynones with diverse functional groups. This method demonstrates the potential of triazine-mediated C-O activation for preparing highly functionalized ketones.

Formation of protein adducts with Hydroperoxy-PE electrophilic cleavage products during ferroptosis

Ferroptosis is an iron dependent form of cell death, that is triggered by the discoordination of iron, lipids, and thiols. Its unique signature that distinguishes it from other forms of cell death is the formation and accumulation of lipid hydroperoxides, particularly oxidized forms of polyunsaturated phosphatidylethanolamines (PEs), which drives cell death. These readily undergo iron-catalyzed secondary free radical reactions leading to truncated products which retain the signature PE headgroup and which can readily react with nucleophilic moieties in proteins via their truncated electrophilic acyl chains. Using a redox lipidomics approach, we have identified oxidatively-truncated PE species (trPEox) in enzymatic and non-enzymatic model systems. Further, using a model peptide we demonstrate adduct formation with Cys as the preferred nucleophilic residue and PE(26:2) +2 oxygens, as one of the most reactive truncated PE-electrophiles produced. In cells stimulated to undergo ferroptosis we identified PE-truncated species with sn-2 truncations ranging from 5 to 9 carbons. Taking advantage of the free PE headgroup, we have developed a new technology using the lantibiotic duramycin, to enrich and identify the PE-lipoxidated proteins. Our results indicate that several dozens of proteins for each cell type, are PE-lipoxidated in HT-22, MLE, and H9c2 cells and M2 macrophages after they were induced to undergo ferroptosis. Pretreatment of cells with the strong nucleophile, 2-mercaptoethanol, prevented the formation of PE-lipoxidated proteins and blocked ferroptotic death. Finally, our docking simulations showed that the truncated PE species bound at least as good to several of the lantibiotic-identified proteins, as compared to the non-truncated parent molecule, stearoyl-arachidonoyl PE (SAPE), indicating that these oxidatively-truncated species favor/promote the formation of PEox-protein adducts. The identification of PEox-protein adducts during ferroptosis suggests that they are participants in the ferroptotic process preventable by 2-mercaptoethanol and may contribute to a point of no return in the ferroptotic death process.

Zinc-Catalyzed Asymmetric Cascade Michael/Acyl Transfer Reaction between α-Hydroxy Aryl Ketones and Enynones.

We described herein a neoteric enantioselective cascade Michael/acyl transfer reaction of enynones and α-hydroxy aryl ketones catalyzed by dinuclear zinc cooperative catalysis. A series of structurally diverse chiral 1,5-dicarbonyl compounds were synthesized in good yields with excellent stereoselectivities. This strategy features broad substrate scope, high atom economy, as well as enynones as efficient electrophilic acyl transfer reagents in asymmetric cascade reactions for the first time.

Expedient assembly of densely functionalized indanonesvianickel-catalyzed alkene hydroacylation with methyl esters

A concise nickel-catalyzed intramolecular alkene hydroacylation with readily available but inert methyl esters as acyl electrophiles is disclosed, affording various antioxidant indanones and indazolones in good efficiency.

Photoinduced nickel-catalyzed reductive acyl cross-coupling: facile access to all carbon quaternary aliphatic ketones

A photochemical nickel-catalyzed reductive acyl coupling of unstrained tertiary acyl electrophiles with 1°, 2°, and 3°-alkyl radical precursors to synthesize sterically hindered α-tertiary dialkyl ketones is developed.

Tandem C/N-Difunctionalization of Nitroarenes: Reductive Amination and Annulation by a Ring Expansion/Contraction Sequence.

A synthetic method for the reductive transformation of nitroarenes into ortho-aminated and -annulated products is reported. The method operates via the exhaustive deoxygenation of nitroarenes by an organophosphorus catalyst and a mild terminal reductant to access aryl nitrenes, which after ring expansion, are trapped by amine nucleophiles to give dearomatized 2-amino-3H-azepines. Treatment of these ring-expanded intermediates with acyl electrophiles triggers 6π electrocyclization to extrude the nitrogen atom and restore aromaticity of the phenyl ring, which delivers via C-H functionalization 2-aminoanilide and benzimidazole products.

Ortho‐Acylation of Aryl Iodides Enabled with Imides via Palladium/Norbornene/CuI Catalysis

AbstractHerein, a three component Catellani‐type reaction catalyzed by the Palladium/Norbornene/CuI (Pd/NBE/CuI) cooperative system by using N‐acylph‐thalimides as acyl electrophiles is reported, which gives access to a series of aromatic ketones. The transformation is performable in the presence of water, albeit with decreased reaction yield. The additive CuI was crucial to facilitate the cleavage of C(O)−N bond of imide. This protocol showed broad substrate scope: both alkyl and aryl acyl groups could be installed at the ortho‐position of aryl iodides; alkenes and boronic acids can be used as termination reagents.magnified image

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.

Nickel-Catalyzed Three-Component Alkylacylation of Alkenes Enabled by a Photoactive Electron Donor-Acceptor Complex.

An electron donor-acceptor complex-enabled, nickel-catalyzed three-component net-reductive 1,2-alkylacylation of alkenes is developed. This conjunctive reductive acyl cross-coupling process obviates the use of an exogenous photocatalyst and a stoichiometric metal-based reductant, affording various synthetically useful 1,3-dicarbonyl compounds in good yields with a broad substrate scope and excellent functional group tolerance. Both alkyl and acyl electrophiles are derived from the highly abundant and readily accessible carboxylic acids, making the catalytic 1,2-dicarbofunctionalization more synthetically general and sustainable.

Buchwald-Hartwig amination of aryl esters and chlorides catalyzed by the dianisole-decorated Pd-NHC complex.

A modular and generic method for the Buchwald-Hartwig amination reactions of relatively unreactive aryl esters as acyl electrophiles and aryl chlorides as aryl electrophiles has been developed, leading to the efficient synthesis of amides/amines under air conditions and with low catalyst loadings. The success of this catalytic protocol is mainly attributed to the modification of the Pd-IPr skeleton with sterically hindered and electron-donating anisole groups. This method also features good functional group tolerance and excellent chemoselectivities. In summary, the results presented herein suggest the possibility of developing a versatile and general protocol for diverse electrophiles to undergo the Buchwald-Hartwig amination reactions, avoiding too much consideration of the reaction conditions for the substrate-dependent C-N bond formations.

From Esters to Ketones via a Photoredox-Assisted Reductive Acyl Cross-Coupling Strategy.

A method was developed for ketone synthesis via a photoredox-assisted reductive acyl cross-coupling (PARAC) using a nickel/photoredox dual-catalyzed cross-electrophile coupling of two different carboxylic acid esters. A variety of aryl, 1°, 2°, 3°-alkyl 2-pyridyl esters can act as acyl electrophiles while N-(acyloxy)phthalimides (NHPI esters) act as 1°, 2°, 3°-radical precursors. Our PARAC strategy provides an alternative and reliable way to synthesize various sterically congested 3°-3°, 3°-2°, and aryl-3° ketones under mild and highly unified conditions, which have been otherwise difficult to access. The combined experimental and computational studies identified a Ni0 /NiI /NiIII pathway for ketone formation.

From Esters to Ketones via a Photoredox‐Assisted Reductive Acyl Cross‐Coupling Strategy

AbstractA method was developed for ketone synthesis via a photoredox‐assisted reductive acyl cross‐coupling (PARAC) using a nickel/photoredox dual‐catalyzed cross‐electrophile coupling of two different carboxylic acid esters. A variety of aryl, 1°, 2°, 3°‐alkyl 2‐pyridyl esters can act as acyl electrophiles while N‐(acyloxy)phthalimides (NHPI esters) act as 1°, 2°, 3°‐radical precursors. Our PARAC strategy provides an alternative and reliable way to synthesize various sterically congested 3°‐3°, 3°‐2°, and aryl‐3° ketones under mild and highly unified conditions, which have been otherwise difficult to access. The combined experimental and computational studies identified a Ni0/NiI/NiIII pathway for ketone formation.

Pd-Catalyzed Asymmetric Acyl-Carbamoylation of an Alkene to Construct an α-Quaternary Chiral Cycloketone.

Herein, we report the palladium-catalyzed asymmetric acyl-carbamoylation of an alkene by employing thioesters as the acyl electrophiles and t-BuNC as the carbamoyl reagent, affording an α-quaternary chiral cycloketone in synthetically useful yields with excellent enantioselectivity. The reaction proceeded via asymmetric 1,2-migratory insertions of acyl-Pd into alkenes and subsequent migratory insertion of isocyanides into C(sp3)-PdII. The product could be diversified to some valuable skeletons with retention of enantiopurity, demonstrating the synthetic utility of this protocol.

Nickel-Catalyzed Reductive Asymmetric Aryl-Acylation and Aryl-Carbamoylation of Unactivated Alkenes

Nickel-Catalyzed Reductive Asymmetric Aryl-Acylation and Aryl-Carbamoylation of Unactivated Alkenes

Palladium-Catalyzed Intermolecular Acylative Heck Reactions with Imides as Acyl Electrophiles.

We disclose palladium-catalyzed, intermolecular, acylative Heck reactions that use imides as acyl electrophiles. The catalyst generated from [Pd(allyl)Cl]2 and DPEphos promotes the reaction between N-benzoylglutarimides and norbornene in the presence of silver phosphate. The acylative Heck reaction encompasses an array of N-benzoylglutarimide electrophiles that contain electron-donating, halogenated, and electron-withdrawing substituents to generate α,β-unsaturated ketones in moderate to high yields (25-82%). The bicylic α,β-unsaturated ketones are readily transformed into polycyclic architectures via thermal hetero-Diels-Alder reactions that occur by the dimerization of the α,β-unsaturated ketones.

Palladium-Catalyzed Intermolecular Alkene Carboacylation via Ester C-O Bond Activation.

We report palladium-catalyzed intermolecular carboacylation of alkenes with ester electrophiles and tetraarylborate nucleophiles. Bicyclic alkenes react with a variety of pentafluorophenyl benzoate and alkanoate esters and sodium tetraarylborates to form ketone products in ≤99% yields. These reactions occur in the absence of a directing group and demonstrate esters are competent acyl electrophiles for intermolecular alkene carboacylation reactions.

Synthesis of Pyrrolo[1,2-a][1,6]- and [1,8]naphthyridines by Alkyne-Carbonyl Metathesis

AbstractA concise and modular synthesis of pyrrolo[1,2-a][1,6]- and [1,8]naphthyridines by a one-pot two-step reaction consisting of electrophilic acylation followed by an alkyne-carbonyl-metathesis reaction as the final cyclization step is reported. This developed synthetic methodology allows the facile synthesis of these heterocyclic core structures in mainly high overall yields under metal-free conditions. Reaction conditions are carefully optimized and display a novel supplement to access these tricyclic heterocyclic compounds.

Nickel-Catalyzed Directed Cross-Electrophile Coupling of Phenolic Esters with Alkyl Bromides.

Herein, we demonstrate the successful use of robust phenolic esters as an electrophilic acyl source in the reaction with diverse primary and secondary unactivated alkyl bromides. The cleavage of the relatively inert C-O bond is facilitated by the neighboring coordinating hydroxyl or sulfonamide moiety. By circumventing the use of pregenerated organometallics, this method allows efficient preparation of a variety of o-hydroxyl and tosyl-protected o-amino aryl ketones with high compatibility with a wide range of functionalities.