Α-arylation Of Ketones Research Articles

Visible-Light-Induced α-Arylation of Ketones with (Hetero)aryl Halides.

An enamine-mediated photoredox catalyzed C(sp2)-C(sp3) cross-coupling of dual radical precursors for the arylation of ketone is presented in this Letter. These reactions led to the formation of an enamine by using pyrrolidine to functionalize the C(sp3)-H bond in ketone substrates, which could be smoothly converted to α-arylated ketones with inert aryl bromides and even aryl chlorides in moderate to good yields under mild reaction conditions. The photocatalytically induced C(sp2)-C(sp3) cross-coupling between unactivated noncyclic ketones and aryl halides was achieved, and multiple carbonyl α-arylated backbones containing various natural products and drug molecules were successfully constructed.

Dual-Catalytic Structural Isomerisation as a Route to α-Arylated Ketones.

Isomerisation reactions provide streamlined routes to organic compounds which are otherwise hard to directly synthesise. The most common forms are positional, geometrical or stereochemical isomerisations which involve the relocation of a double bond or a change in relative location of groups in space. In contrast, far fewer examples of structural (or constitutional) isomerisation exist where the connectivity between atoms is altered. The development of platforms capable of such rearrangement poses a unique set of challenges because chemical bonds must be selectively cleaved, and new ones formed without overall addition or removal of atoms. Here, we show that a dual catalytic system can enable the structural isomerisation of readily available allylic alcohols into more challenging-to-synthesise α-arylated ketones via a H-atom transfer initiated semi-pinacol rearrangement. Key to our strategy is the combination of a cobalt catalyst and photocatalyst under reductive, protic conditions which allows intermediates to propagate catalytic turnover. By providing an unusual disconnection to structural motifs which are difficult to access through direct arylation, we anticipate inspiring other advanced catalytic isomerisation strategies that will further retrosynthetic logic for complex molecule synthesis.

Enantioselective Synthesis of α-Aryl Ketones by a Cobalt-Catalyzed Semipinacol Rearrangement.

A highly enantioselective cobalt-catalyzed semipinacol rearrangement of symmetric α,α-diarylallylic alcohols is disclosed. A chiral cobalt-salen catalyst generates a highly electrophilic carbocation surrogate following hydrogen atom transfer and radical-polar crossover steps. This methodology provides access to enantioenriched α-aryl ketones through invertive displacement of a cobalt(IV) complex during 1,2-aryl migration. A combination of readily available reagents, silane and N-fluoropyridinium oxidant, are used to confer this type of reactivity. An exploration into the effect of aryl substitution revealed the reaction tolerates para- and meta-halogenated, mildly electron-rich and electron-poor aromatic rings with excellent enantioselectivities and yields. The yield of the rearrangement diminished with highly electron-rich aryl rings whereas very electron-deficient and ortho-substituted arenes led to poor enantiocontrol. A Hammett analysis demonstrated the migratory preference for electron-rich aromatic rings, which is consistent with the intermediacy of a phenonium cation.

Divergent Transformations of Aromatic Esters: Decarbonylative Coupling, Ester Dance, Aryl Exchange, and Deoxygenative Coupling.

ConspectusAromatic esters are cost-effective, versatile, and commonly used scaffolds that are readily synthesized or encountered as synthetic intermediates. While most conventional reactions involving these esters are nucleophilic acyl substitutions or 1,2-nucleophilic additions─where a nucleophile attacks the carbonyl group, decarbonylative transformations offer an alternative pathway by using the carbonyl group as a leaving group. This transition-metal-catalyzed process typically begins with oxidative addition of the C(acyl)-O bond to the metal. Subsequently, the reaction involves the migration of CO to the metal center, the reaction with a nucleophile, and reductive elimination to yield the final product. Pioneering work by Yamamoto on nickel complexes and the development of decarbonylative reactions (such as Mizoroki-Heck-type olefination) using aromatic carboxylic anhydrides catalyzed by palladium were conducted by de Vries and Stephan. Furthermore, reports have surfaced of decarbonylative hydrogenation of pyridyl methyl esters by Murai using ruthenium catalysts as well as Mizoroki-Heck-type reactions of nitro phenyl esters by Gooßen under palladium catalysis. Our group has been at the forefront of developing decarbonylative C-H arylations of phenyl esters with 1,3-azoles and aryl boronic acids using nickel catalysts. The key to this reaction is the use of phenyl esters, which are easy to synthesize, stabilize, and handle, allowing oxidative addition of the C(acyl)-O bond; nickel, which facilitates oxidative addition of the C(acyl)-O bond; and suitable bidentate phosphine ligands that can stabilize the intermediate. By modification of the nucleophiles, esters have been effectively utilized as electrophiles in cross-coupling reactions, encouraging the development of these nucleophiles among researchers. This Account summarizes our advancements in nucleophile development for decarbonylative coupling reactions, particularly highlighting the utilization of aromatic esters in diverse reactions such as alkenylation, intramolecular etherification, α-arylation of ketones, C-H arylation, methylation, and intramolecular C-H arylation for dibenzofuran synthesis, along with cyanation and reductive coupling. We also delve into reaction types that are distinct from typical decarbonylative reactions, including ester dance reactions, aromatic ring exchanges, and deoxygenative transformations, by focusing on the oxidative addition of the C(acyl)-O bond of the aromatic esters to the metal complex. For example, the ester dance reaction is hypothesized to undergo 1,2-translocation starting with oxidative addition to a palladium complex, leading to a sequence of ortho-deprotonation/decarbonylation, followed by protonation, carbonylation, and reductive elimination. The aromatic exchange reaction likely involves oxidative addition of complexes of different aryl electrophiles with a nickel complex. In deoxygenative coupling, an oxidative addition complex with palladium engages with a nucleophile, forming an acyl intermediate that undergoes reductive elimination in the presence of an appropriate reducing agent. These methodologies are poised to captivate the interest of synthetic chemists by offering unconventional and emerging approaches for transforming aromatic esters. Moreover, we demonstrated the potential to transform readily available basic chemicals into new compounds through organic synthesis.

Synthesis of Chiral α-Aryl Ketones by Photoredox/Nickel-Catalyzed Enantioconvergent Acyl Cross-Coupling with Organotrifluoroborate.

Photoredox/nickel-catalyzed enantioconvergent acyl cross-coupling of carboxylic derivatives with racemic secondary organotrifluoroborate was developed for the synthesis of an enolizable chiral α-aryl ketone under mild neutral conditions. Moderate to high yields and good enantioselectivities were achieved.

Cross-Coupling of Benzylic and Aldehydic C-H Bonds via Photocatalytic Tandem Radical-Radical Coupling and Acceptorless Alcohol Dehydrogenation.

The construction of a C-C bond by cross-coupling of two different C-H bonds with the release of hydrogen gas represents an ideal yet challenging bond formation strategy. Herein, we report a photocatalytic metal-free cross-coupling of benzylic and aldehydic C-H bonds by synergistic catalysis of organophotocatalyst 4CzIPN and a thiol, which affords the corresponding α-aryl ketones in acceptable yields along with hydrogen evolution. The mechanistic investigation indicates a radical-radical coupling to give an intermediary alcohol, followed by an acceptorless alcohol dehydrogenation.

Asymmetric Retro-Claisen Reaction Catalyzed by Chiral Aza-Bisoxazoline–Zn(II) Complex: Enantioselective Synthesis of α-Arylated Ketones

An asymmetric retro-Claisen reaction of α-monosubstituted β-diketones and quinones (or quinone imine) has been developed under the catalysis of a chiral aza-bisoxazoline-Zn(II) complex. The reaction proceeds via a sequence of conjugate addition, arylation, hemiketal anion-initiated C-C bond cleavage, and enantioselective protonation of enolate to provide various functionalized α-arylated ketones bearing a tertiary stereogenic center with high enantioselectivities. Notably, biologically important benzofuran and γ-butyrolactone derivatives could be synthesized by application of the developed protocol.

Ligand Relay Catalysis Enables Asymmetric Migratory Reductive Acylation of Olefins or Alkyl Halides

Design of ligands in transition-metal catalyzed reactions is challenging, especially in asymmetric transformations. With each step in the catalytic cycle promoted by its privileged ligand and different steps well-connected by dynamic ligand exchange, synergistic combination of multiple ligands could potentially enhance the catalytic efficiency and selectivity. Now, this concept has been applied to the NiH-catalyzed asymmetric remote hydroacylation of olefins and migratory acylation of alkyl halides with excellent regio- and enantioselectivity, utilizing two simple ligands, one for chain-walking and the other for asymmetric acylation. Starting from abundant alkenes/alkyl halides and carboxylic acids, a wide range of enantioenriched chiral α-aryl ketones can be efficiently accessed under mild conditions.

Asymmetric Intermolecular Iodinative Difunctionalization of Allylic Sulfonamides Enabled by Organosulfide Catalysis: Modular Entry to Iodinated Chiral Molecules

Electrophilic halogenation of alkenes is a powerful transformation offering a convenient route for the construction of valuable functionalized molecules. However, as a highly important reaction in this field, catalytic asymmetric intermolecular iodinative difunctionalization remains a formidable challenge. Herein, we report that an efficient Lewis basic chiral sulfide-catalyzed approach enables this reaction. By this approach, challenging substrates such as γ,γ-disubstituted allylic sulfonamides and 1,1-disubstituted alkenes with an allylic sulfonamide unit undergo electrophilic iodinative difunctionalization to give a variety of iodine-functionalized chiral molecules in good yields with excellent enantio- and diastereoselectivities. A series of free phenols as nucleophiles are successfully incorporated into the substrates. Aside from phenols, primary and secondary alcohols, fluoride, and azide also serve as efficient nucleophiles. The obtained iodinated products are a good platform molecule, which can be easily transformed into various chiral compounds such as α-aryl ketones, chiral secondary amines, and aziridines via rearrangement or substitution. Mechanistic studies revealed that the chiral sulfide catalyst displays a superior effect on control of the reactivity of electrophilic iodine and the enantioselective construction of the chiral iodiranium ion intermediate and catalyst aggregates might be formed as a resting state in the reactions.

Exploration of Oxidative Ritter-Type Reaction of α-Arylketones and Its Application for the Collective Total Syntheses of Erythrina Alkaloids

Exploration of Oxidative Ritter-Type Reaction of α-Arylketones and Its Application for the Collective Total Syntheses of <i>Erythrina</i> Alkaloids

Palladium-Catalyzed α-Arylation of Ketones in Water

Palladium-Catalyzed α-Arylation of Ketones in Water

Nickel-Catalyzed Multicomponent Coupling: Synthesis of α-Chiral Ketones by Reductive Hydrocarbonylation of Alkenes.

A nickel-catalyzed, multicomponent regio- and enantioselective coupling via sequential hydroformylation and carbonylation from readily available starting materials has been developed. This modular multicomponent hydrofunctionalization strategy enables the straightforward reductive hydrocarbonylation of a broad range of unactivated alkenes to produce a wide variety of unsymmetrical dialkyl ketones bearing a functionalized α-stereocenter, including enantioenriched chiral α-aryl ketones and α-amino ketones. It uses chiral bisoxazoline as a ligand, silane as a reductant, chloroformate as a safe CO source, and a racemic secondary benzyl chloride or an N-hydroxyphthalimide (NHP) ester of a protected α-amino acid as the alkylation reagent. The benign nature of this process renders this method suitable for late-stage functionalization of complex molecules.

α-Arylation of Ketones with Nitroarenes

Key words palladium catalysis - nitroarenes - α-arylation - ketones

Enantioselective α-Arylation of Ketones via a Novel Cu(I)-Bis(phosphine) Dioxide Catalytic System.

A novel catalytic system based on copper(I) and chiral bis(phosphine) dioxides is described. This allows the arylation of silyl enol ethers to access enolizable α-arylated ketones in good yields and enantiomeric excess up to 95%. Noncyclic ketones are amenable substrates with this method, which complements other approaches based on palladium catalysis. Optimization of the ligand structure is accomplished via rational design driven by correlation analysis. Preliminary mechanistic hypotheses are also evaluated in order to identify the role of chiral bis(phosphine) dioxides.

Manganese/Copper Co-catalyzed Electrochemical Wacker-Tsuji-Type Oxidation of Aryl-Substituted Alkenes.

A manganese/copper co-catalyzed electrochemical Wacker-Tsuji-type oxidation of aryl-substituted alkenes has been developed. The process involves the use of 5 mol % MnBr2 and 7.5 mol % CuCl2, in 4:1 acetonitrile/water in an undivided cell at 60 °C, with 2.8 V constant applied potential. α-Aryl ketones are formed in moderate to excellent yields, with the advantages of avoidance of palladium as a catalyst and any external chemical oxidant in an easily operated, cost-effective procedure.

Direct Synthesis of Mono-α-arylated Ketones from Alcohols and Olefins via Ni-Catalyzed Oxidative Cross-Coupling.

Controlled synthesis of α-monoarylated ketones is significant yet challenging due to the site-selectivity issues and nonproductive overarylation reactions. Herein, we reported the direct synthesis of α-arylated ketones enabled by Ni-catalyzed dehydrogenative cross-coupling reaction cascade between alcohols and olefins. The use of readily available and cost-effective alcohols and olefins provides a straightforward access to monoarylated ketones in good yields with exclusive selectivity without using any advanced synthetic intermediates.

Dehydrogenative Coupling of Benzylic and Aldehydic C-H Bonds.

A photoinduced dehydrogenative coupling reaction between benzylic and aldehydic C-H bonds is reported. When a solution of an alkylbenzene and an aldehyde in ethyl acetate is irradiated with visible light in the presence of iridium and nickel catalysts, a coupled α-aryl ketone is formed with evolution of dihydrogen. An analogous C-C bond forming reaction occurs between a C-H bond next to the nitrogen of an N-methylamide and an aldehydic C-H bond to produce an α-amino ketone. These reactions provide a straightforward pathway from readily available materials leading to valued structural motifs of pharmacological relevance.

Transition metal-free synthesis of α-aryl ketones via oxyallyl cation capture with arylboronic acids

α-Arylated ketones were accessed via oxyallyl cation capture with arylboronic acids in good yields with broad substrate tolerance.

Iridium-catalyzed arylation of sulfoxonium ylides and arylboronic acids: a straightforward preparation of α-aryl ketones

A highly efficient iridium(iii)-catalyzed arylation coupling of sulfoxonium ylides with arylboronic acids to generate α-aryl ketones has been established for the first time.

Atroposelective Arene Formation by Carbene-Catalyzed Formal [4+2] Cycloaddition.

Atroposelective arene formation is an efficient method to build axially chiral molecules with multi-substituted arenes. Reported here is an organocatalyzed atroposelective arene formation reaction by an N-heterocyclic carbene (NHC) catalyzed formal [4+2] cycloaddition of conjugated dienals and α-aryl ketones. This study expands the synthetic potential of NHC organocatalysis and provides a competitive pathway for the synthesis of axially chiral ligands, catalysts, and other functional molecules.