Alkyl Aryl Ketones Research Articles

Synthesis of Isotopically Labelled Alkyl Aryl Ketones by Nickel-Catalyzed Carbonylative Cross-Coupling

Synthesis of Isotopically Labelled Alkyl Aryl Ketones by Nickel-Catalyzed Carbonylative Cross-Coupling

Water Participated Dual C(sp3)−C(sp3) Bond Cleavage of Cyclobutanones Catalyzed by Lewis Acid

AbstractLewis acid‐catalyzed ring‐opening reactions of cyclobutanones were mostly achieved through cleavage of a single C2−C3 bond to deliver cyclic products. Herein, an unprecedented Lewis acid catalyzed synergistic cleavage of both C2−C3 bonds in 3‐arylcyclobutanones was realized under participation of water, providing a series of aryl alkyl ketones in mild conditions. A broad scope of substrates decorated with various substituents were well accommodated. Mechanistic proposal including the function of water was unambiguously validated by experimental verification.

Construction of acenaphthylenes via C-H activation-based tandem penta- and hexaannulation reactions.

Acenaphthylene-containing polycyclic aromatic hydrocarbons (AN-PAHs) are noteworthy structural motifs for organic functional materials due to their non-alternant electronic structure, which increases electron affinity. However, the synthesis of AN-PAHs has traditionally required multiple sequential synthetic steps, limiting structural diversity. Herein, we present a tandem C-H penta- and hexaannulation reaction of aryl alkyl ketone with acetylenedicarboxylate. This integrated approach enhances overall efficiency and selectivity, marking a significant advancement in AN-PAH synthesis. Mechanistic studies unveil an orchestrated extension of five- and six-membered rings through C-H activation-annulation and Diels-Alder reaction. Additionally, the tandem annulation reaction can be performed stepwise, further validating the proposed mechanism and increasing the structural diversity of AN-PAHs.

Nickel Catalyzed Carbonylative Cross Coupling for Direct Access to Isotopically Labeled Alkyl Aryl Ketones.

Here we present an effective nickel-catalyzed carbonylative cross-coupling for direct access to alkyl aryl ketones from readily accessible redox-activated tetrachlorophthalimide esters and aryl boronic acids. The methodology, which is run employing only 2.5 equivalents of CO and simple Ni(II) salts as the metal source, exhibits a broad substrate scope under mild conditions. Furthermore, this carbonylation chemistry provides an easy switch between isotopologues for stable (13CO) and radioactive (14CO) isotope labeling, allowing its adaptation to the late-stage isotope labeling of pharmaceutically relevant compounds. Based on DFT calculations as well as experimental evidence, a catalytic cycle is proposed involving a carbon-centered radical formed via nickel(I)-induced outer-sphere decarboxylative fragmentation of the redox-active ester.

Nickel Catalyzed Carbonylative Cross Coupling for Direct Access to Isotopically Labeled Alkyl Aryl Ketones

Nickel Catalyzed Carbonylative Cross Coupling for Direct Access to Isotopically Labeled Alkyl Aryl Ketones

The Application of Flow Chemistry for the Synthesis of Alkyl Sodium Compounds and Their Transformations with Weinreb Amides and Carboxylic Acids.

Herein, we describe the application of a flow system for the generation of a soluble organo sodium compound and the transformation of this primary nucleophile with various Weinreb amides for the synthesis of alkyl-aryl ketones. Thereafter, the generation of secondary sodium intermediates, such as benzylic sodium nucleophiles or ortho-metalated sodium nucleophiles from various carbon pre-nucleophiles, is described. These transformations generated more complex ketones, and in this investigation the key aspect was to identify factors for the chemoselective and regioselective C-H deprotonation of concurring sites within the starting material. Finally, the direct synthesis of ketones from carboxylic acids and the organo sodium compound is described, revealing interesting aspects regarding the nucleophilicity and basicity of the alkyl sodium reagent.

Electrosynthesis of Quinoxalines via Intermolecular Cyclization/Dehydrogenation of Ketones with o-Phenylenediamines

AbstractIn this study, we proposed a novel electrochemical dehydrogenative synthetic method for preparing 2-substituted quinoxalines by intermolecular cyclization of aryl alkyl ketones and o-phenylenediamines. This method gave various quinoxalines in yields ranging from 35% to 71%. This novel protocol employs mild reaction conditions and offers moderate to excellent yields, a wide substrate scope, and broad functional-group compatibility. Furthermore, a late-stage functionalization and the wide substrate scope demonstrated the synthetic utility of this protocol.

I2 Catalyzed and TBHP/Ammonium-Promoted Conversion of Arylethanone to Nitriles via β-Scission of Iminyl Radicals.

Herein, we report a general I2-catalyzed and TBHP/ammonium-promoted conversion of arylethanone to aromatic nitriles under air. This procedure proceeded with the β-scission of iminyl radical, which was facilitated via quenching the released alkyl radical by tert-butyl peroxyl radical leading to peroxide followed with Kornblum-DeLaMare rearrangement. A series of aryl methyl ketone and alkyl aryl ketone worked well with good functional group tolerance in high yields. As such, this metal-free procedure represents a facile, safe, green, and practical procedure in conversion of arylethanone to aromatic nitriles.

1,2]-Retro-Brook rearrangement induced by electrochemical reduction of silyl enolates

Abstract Electrochemical reduction of the trimethylsilyl enolates of alkyl aryl ketones induces retro-Brook rearrangement to provide 1-aryl-1-trimethylsilylalkan-1-ols. The transformation proceeds through a sequence of 1) single-electron reduction of the silyl enolate, 2) protonation with a phenol, 3) another single-electron reduction to form a siloxy-substituted benzylic anion, and 4) the pivotal retro-Brook rearrangement.

Regioselective Hydroxylation of Unsymmetrical Ketones Using Cu, H2O2, and Imine Directing Groups via Formation of an Electrophilic Cupric Hydroperoxide Core.

Herein, we describe the regioselective functionalization of unsymmetrical ketones using imine directing groups, Cu, and H2O2. The C-H hydroxylation of the substrate-ligands derived from 2-substituted benzophenones occurred exclusively at the γ-position of the unsubstituted ring due to the formation of only one imine stereoisomer. Conversely, the imines derived from 4-substituted benzophenones produced E/Z mixtures that upon reacting with Cu and H2O2 led to two γ-C-H hydroxylation products. Contrary to our initial hypothesis, the ratio of the hydroxylation products did not depend on the ratio of the E/Z isomers but on the electrophilicity of the reactive [LCuOOH]1+. A detailed mechanistic analysis suggests a fast isomerization of the imine substrate-ligand binding the CuOOH core before the rate-determining electrophilic aromatic hydroxylation. Varying the benzophenone substituents and/or introducing electron-donating and electron-withdrawing groups on the 4-position of pyridine of the directing group allowed for fine-tuning of the electrophilicity of the mononuclear [LCuOOH]1+ to reach remarkable regioselectivities (up to 91:9 favoring the hydroxylation of the electron-rich arene ring). Lastly, we performed the C-H hydroxylation of alkyl aryl ketones, and like in the unsymmetrical benzophenones, the regioselectivity of the transformations (sp3 vs sp2) could be controlled by varying the electronics of the substrate and/or the directing group.

Mild Access to Aryl–Alkyl Ketones Enabled by Photoinduced Nickel Catalysis

Mild Access to Aryl–Alkyl Ketones Enabled by Photoinduced Nickel Catalysis

Intermolecular C-C/C-N σ-bond metathesis enabled by visible light.

Transition-metal-catalyzed double/triple bond metathesis reactions have been well-established due to the ability of transition-metal catalysts to readily interact with π bonds, facilitating the progression of the entire reaction. However, activating σ-bonds to induce σ-bond metathesis is more challenging due to the absence of π bonds and the high bond energy of σ bonds. In this study, we present a novel photo-induced approach that does not rely on transition metals or photosensitizers to drive C-C and C-N σ-bond metathesis reactions. This method enables the cross-coupling of tertiary amines with α-diketones via C-C and C-N single bonds cleavage and recombination. Notably, our protocol exhibits good compatibility with various functional groups in the absence of transition metals and external photosensitizers, resulting in the formation of aryl alkyl ketones and aromatic amides in good to high yields. To gain insights into the mechanism of this pathway, we conducted controlled experiments, intermediate trapping experiments, and DFT (Density Functional Theory) calculations. This comprehensive approach allowed us to elucidate the detailed mechanism underlying this transformative reaction.

Pd-catalyzed relay Heck arylation of alkenyl alcohols with arylsulfonium salts

The Pd-catalyzed relay Heck arylation of alkenyl alcohols with arylsulfonium salts is first reported for synthesizing arylalkyl ketones or aldehydes.

Selenium dioxide as a selenylating reagent: An overview and its Sanguine future

AbstractSelenylation of heterocyclic and carbocyclic compounds using selenium dioxide as a selenylating reagent has emerged as a novel research area. Selenium dioxide is a cheap, easily available and odorless selenium source with wide functional group tolerance. Selenium dioxide is much known for α‐oxidation reactions but this review will elaborate its role as oxidizing as well as selenylating agents. In this review, we have summarized the selenylation of different molecules like anilines, phenylhydrazines, aryl alkyl ketones, phenols, indoles, active methylene compounds, imidazole heterocycles, 1,3‐diones, boronic acids, pyrazoles, 2‐hydroxy acetophenones, alkyl halides and different electron rich arenes along with detailed mechanism. Triselenium dicyanide is a yellow colored addition product that has now been emerged as a well‐known reagent of selenocyanation and many research groups extensively working on it. Selenium containing compounds possess biological as well as pharmacological activity. The immense potential of selenium dioxide as a selenylating reagent attracted the interest of researchers working on selenylation.

Mechanistic Study of B(C6F5)3-Catalyzed Transfer Hydrogenation of Aldehydes/Ketones with PhSiH3 and Stoichiometric Water.

A DFT study was performed on the mechanisms of B(C6F5)3-catalyzed transfer hydrogenation of aldehydes/ketones, using PhSiH3 and stoichiometric water. Path B2 includes a stepwise Piers SN2-Si process, H- transfer, and hydrolysis desilylation of siloxane, in which the hydrolysis desilylation step is rate-determining. Path C1 is first determined, involving a B(C6F5)3-catalyzed concerted addition step of 2H2O to carbonyl generating R1R2C(OH)2, a subsequent SN2-Si dehydroxylation step of R1R2C(OH)2 giving R1R2C=OH+ and (C6F5)3B-H-, and final H- transfer producing the respective alcohol R1R2CHOH. A B(C6F5)3-catalyzed H2 generation process (Path H0) is determined. Path B2 is the only mechanism for the stepwise method. Using a one-time one-pot feeding method, alkyl/aryl aldehydes, dialkyl ketones, and alkyl aryl ketones (1a-g) can be reduced into alcohols chemoselectively and effectively at room temperature. More than 1 equiv of water over substrates is necessary. Herein, Path C1 is the dominant transfer hydrogenation pathway, and the H2 generation is efficiently inhibited, by the competitive advantage of Path C1 and initial dominant existence of the complexes IM0 and IM1-x. The diaryl ketones (1h,1i) cannot be efficiently reduced into the respective alcohols using the one-time feeding one-pot method. The barriers of C-TS1-h/i are obviously higher than those of C-TS1-a-g, attributed to the electron-donating and space effects of the two aryls on carbonyl C. The possible Paths B2 and C1 of transfer hydrogenation have no competitive advantage with Path H0. The DFT results are consistent with the experiments.

Introduction of Carbonyl Groups into Antibodies

Antibodies and their derivatives (scFv, Fabs, etc.) represent a unique class of biomolecules that combine selectivity with the ability to target drug delivery. Currently, one of the most promising endeavors in this field is the development of molecular diagnostic tools and antibody-based therapeutic agents, including antibody–drug conjugates (ADCs). To meet this challenge, it is imperative to advance methods for modifying antibodies. A particularly promising strategy involves the introduction of carbonyl groups into the antibody that are amenable to further modification by biorthogonal reactions, namely aliphatic, aromatic, and α-oxo aldehydes, as well as aliphatic and aryl–alkyl ketones. In this review, we summarize the preparation methods and applications of site-specific antibody conjugates that are synthesized using this approach.

Reaction of 4-Bpin-o-Carborane with Ketones: Sequential Carbon Vertex Alkylation and B-B Bond Activation.

Diboron compounds are important reagents in a series of transition metal catalyzed or metal-free borylation reactions. We describe herein a unique reactivity of 4-Bpin-o-carborane with ketones under basic conditions, leading to sequential cage carbon alkylation, B-B bond activation and unexpected O-migration. The reaction was compatible with a good substrate scope including dialkyl or alkyl aryl ketones. The reaction mechanism is also proposed, involving cage CH deprotonation, nucleophilic attack of ketone, and O-migration along with B-B bond cleavage.

Nickel-Catalyzed Highly Selective Reductive Carbonylation Using Oxalyl Chloride as the Carbonyl Source

Nickel-catalyzed carbonylative cross-electrophile coupling which emerges as a powerful, efficient, and low-cost method for constructing challenging carbonyl derivatives has attracted increasing attention of organic chemists. To avoid the generation of a poisonous, volatile, and inert nickel carbonyl complex, it is critical to develop an efficient, cheap, and easily available CO surrogate. Oxalyl chloride, a cheap commercially available chemical, is one of the most versatile organic reagents used in chemical reactions. In this work, high chemoselectivity can be achieved with a 1:1:1 ratio of Ar–I to alkyl-I to oxalyl chloride. A wide range of alkyl aryl ketones which present an important class of molecules in synthetic and medicinal chemistry are accessed from alkyl halides, aryl iodides, under mild conditions. Primary and secondary alkyl iodides were suitable substrates. Various functional groups were well tolerated, affording up to 90% yields. This protocol was also used in the derivatization of natural products and drug molecules. Mechanistic investigation indicates that the reaction of Zn and oxalyl chloride under mild reaction conditions could release CO slowly. This knowledge should be useful for the further development of multicomponent carbonylative cross-coupling reactions.

Preparation of Vinylic Lithium Reagents from Silyl Enolates of Alkyl Aryl Ketones Using Lithium Arenide

AbstractThe preparation of vinylic lithium reagents from vinylic halides is a common practice in organic synthesis. However, the preparation of vinylic halides is not always straightforward. In this study, we propose the use of silyl enolates of alkyl aryl ketones as a readily available and efficient alternative for generating vinylic lithium species. Treatment of triisopropylsilyl enolates of alkyl aryl ketones with lithium naphthalenide or lithium 4,4’‐di‐t‐butylbiphenylide affords the corresponding vinylic lithium species. This preparation represents a reductive transformation of electron‐rich silyl enolates, which had remained unexplored. This process provides an alternative to the Shapiro reaction and has great potential for various applications in organic synthesis.

Synthesis of Chiral Primary Amines via Enantioselective Reductive Amination: From Academia to Industry

AbstractChiral primary amines widely exist in drugs and are exceptionally important subunits or synthons in the syntheses of chiral secondary and tertiary amines of medicinal interest. Metal-catalyzed enantioselective reductive amination (ERA) of ketones with ammonium salts or ammonia provides a direct method for their synthesis. Although very useful, progress in this field has been very slow and important advances have only been achieved in the last few years. Several major challenges exist in this reaction, including (1) the reversible formation of unstable NH-imine intermediates; (2) the strong coordination property of N-containing reagents toward metal species; and (3) the lack of efficient catalytic systems that enable high enantiocontrol. Generally, the efficiency and enantiocontrol of this reaction is dependent on the substrate type, for instance, the use of α-keto esters/amides or aryl alkyl ketones is well established and they have even been used in the industrial production of chiral amine drugs. However, highly enantioselective control in dialkyl ketones, cyclic ketones, and α-keto acids remains unsolved. Herein, the historical development of ERA reactions with ammonium salts or ammonia gas is summarized, and novel synthetic applications toward useful synthons or drugs are presented. In addition, the factors restricting the growth of this method are also discussed.1 Introduction2 Enantioselective Reductive Amination via Hydrogenation2.1 Enantioselective Reductive Amination of β-Keto Esters/Amides2.2 Enantioselective Reductive Amination of Simple Ketones2.3 Enantioselective Reductive Amination of α-Functionalized Ketones2.4 Enantioselective Reductive Amination/Cyclization Cascade Reactions2.5 Others3 Enantioselective Reductive Amination via Transfer Hydrogenation4 Synthetic Applications5 Conclusions and Outlook