Α-alkylation Of Ketones Research Articles

Copper-Catalyzed C(sp3)-H α-Acetylation: Generation of Quaternary Centers.

α-substituted ketones are important chemical targets as synthetic intermediates as well as functionalities in in natural products and pharmaceuticals. We report the α-acetylation of C(sp3)-H substrates R-H with arylmethyl ketones ArC(O)Me to provide α-alkylated ketones ArC(O)CH2R at RT withtBuOOtBu as oxidant via copper(I) β-diketiminato catalysts. Proceeding via alkyl radicals R•, this method enables α-substitution with bulky substituents without competing elimination that occurs in more traditional alkylation reactions between enolates and alkyl electrophiles. DFT studies suggest the intermediacy of copper(II) enolates [CuII](CH2C(O)Ar) that capture alkyl radicals R• to give R-CH2C(O)Ar under competing dimerization of the copper(II) enolate to give the 1,4-diketone ArC(O)CH2CH2C(O)Ar.

Novel Brønsted Acid Catalyzed C-C Bond Activation and α-Alkylation of Ketones.

A novel approach for the α-alkylation of ketones was developed using Brønsted acid-catalyzed C-C bond cleavage. Both aromatic and aliphatic ketones reacted smoothly with 2-substituted 1,3-diphenylpropane-1,3-diones to afford α-alkylation products with high yields and with excellent regioselectivity, in which the 1,3-dicarbonyl group acted as a leaving group in the presence of the catalyst TfOH. Mechanism experiments showed that the β-C-C bond cleavage of diketone and the shift of the equilibrium towards the enol formation from ketone are driving forces that induce the desired products.

Synthesis of a CCC-NHC pincer Mn complex: An earth abundant catalyst for synthesis of α-alkylated ketones, 2-oxindole derivatives via borrowing hydrogen and one-pot synthesis of quinolines

A CCC-NHC pincer Mn complex was prepared and was characterized by 1H and 13C NMR spectroscopy, mass spectroscopy, elemental analysis, and single crystal X-ray crystallography. Its catalytic activities were demonstrated through diverse chemical transformations including cross-coupling borrowing hydrogen reactions and dehydrogenative cyclization reactions, which resulted in the formation of both C–C and C–N bonds. These cascade reactions involved multiple processes, including dehydrogenation, condensation, and hydrogenation. Under optimized conditions, Mn catalyst affectively converted a broad substrate scope. The different reactions yielded saturated ketones (isolated yields, 42 %–92 %), 2-oxindole derivatives (isolated yields, 70 %–83 %), and quinoline derivatives (isolated yields, 70 %–89 %). These atom economical transformations produce only water molecules as by-products enhancing their environmental friendliness. The catalyst utilized earth-abundant Mn potentially reduce costs. Catalytic cycles were proposed for borrowing hydrogen and acceptorless dehydrogenative cyclization reactions based on control experiments. These included oxidation, aldol condensation, and hydrogenation reactions.

Synergistic Copper-Aminocatalysis for Direct Tertiary α-Alkylation of Ketones with Electron-Deficient Alkanes.

In this study, a novel approach for the tertiary α-alkylation of ketones using alkanes with electron-deficient C─H bonds is presented, employing a synergistic catalytic system combining inexpensive copper salts with aminocatalysis. This methodology addresses the limitations of traditional alkylation methods, such as the need for strong metallic bases, regioselectivity issues, and the risk of over alkylation, by providing a high reactivity and chemoselectivity without the necessity for pre-functionalized substrates. The dual catalytic strategy enables the direct functionalization of C(sp3)─H bonds, demonstrating remarkable selectivity in the presence of conventional C(sp3)─H bonds that are adjacent to heteroatoms or π systems, which are typically susceptible to single-electron transfer processes. The findings contribute to the advancement of alkylation techniques, offering a practical and efficient route for the construction of C(sp3)─C(sp3) bonds, and paving the way for further developments in the synthesis of complex organic molecules.

Continuous Enantioselective α-Alkylation of Ketones via Direct Photoexcitation.

Motivated by the scarcity of enantioselective direct intermolecular α-alkylation reactions of ketones with simple alkyl halides, we report a photo-organocatalytic process to access diethyl 2-(2-oxocyclohexyl)malonate and derivatives in good yield and enantioselectivity. The reaction design is based on highly abundant and nature-derived 9-amino-9-deoxy-epi-cinchona alkaloids to activate ketones as transient secondary enamines, which exist unfavorably in equilibrium with imines. These condensed species can serve as powerful photoinitiators via direct photoexcitation. This concept provides access to both enantiomeric antipodes. In addition to introducing an uncomplicated batch-optimized procedure, we investigated the feasibility and limitations of implementing the reaction in continuous flow, thus enabling to obtain diethyl 2-(2-oxocyclohexyl)malonate with a productivity of 47 μmol/h and 84% enantioselectivity.

Catalytic utility of a bimetallic (pincer) PNN-based nickel complex in the synthesis of quinolines and α-alkylation of ketones

This paper describes the synthesis and characterization of a bipincer nickel complex containing bipyridine-based bisphosphine and its catalytic application in quinoline synthesis and α-alkylation of ketones.

α-Alkylation of ketones with primary alcohols by an active non-noble metal Cu/CuOx catalyst.

Development of convenient and effective heterogeneous non-noble metal catalysts for α-alkylation of ketones with alcohols is challenging in heterogeneous catalysis. Here, we report active non-noble metal Cu/CuOx catalysts for the construction of C-C bonds by the α-alkylation of ketones with alcohols through the borrowing hydrogen methodology. The optimal Cu/CuOx-250 catalyst exhibits good catalytic performance in the reactions to give the corresponding products in 50-96% yields. The Cu/CuOx catalysts are characterized by different analysis techniques such as XRD, TEM, XPS, H2-TPR, BET, and ICP. Moreover, the catalyst can be reused at least for five successive cycles without significant loss of activity. The present study provides meaningful insights into the development of non-noble metal heterogeneous catalysts for α-alkylation of ketones with alcohols.

Quinoline-derived NNP-manganese complex catalyzed α-alkylation of ketones with primary alcohols.

An air-stable quinoline-derived NNP ligand chelated Mn catalyst was developed for the efficient α-alkylation of ketones with primary alcohols via a hydrogen auto-transfer methodology. The sole by-product formed is water, rendering the protocol atom efficient. A wide range of ketone and alcohol substrates were employed, providing the α-alkylated ketones with isolated yields up to 94%. This system was also efficient for the green synthesis of quinoline derivatives while using (2-aminophenyl)methanol as an alkylating reagent.

Carbonate-assisted selectively deoxygenative cross-coupling reaction between aryl and aliphatic aldehydes: a straightforward route to access α-alkylated aryl ketones

A novel reductive cross-coupling reaction of two different aldehydes for rapidly assembling α-alkylated aryl ketones has been developed. The inexpensive carbonate served not only as a base but also as an efficient electron donor.

Ruthenium complexes of redox non-innocent aryl-azo-oximes for catalytic α-alkylation of ketones and synthesis of 2-substituted quinolines

In this work we demonstrated the synthesis, characterisation and catalytic applications of Ru(ii)–azooximato complexes. This is the first report where arylazooximato complexes of a transition metal are used in catalytic C–C bond formation reactions.

Blue-Light Induced Iron-Catalyzed Synthesis of γ,δ-Unsaturated Ketones.

A visible-light-induced iron-catalyzed α-alkylation of ketones with allylic and propargylic alcohols as pro-electrophiles is reported. The diaminocyclopentadienone iron tricarbonyl complex plays a dual role by harvesting light and facilitating dehydrogenation and reduction steps without the help of any exogenous photosensitizer. γ,δ-Unsaturated ketones can now be accessed through this borrowing hydrogen methodology at room temperature. Mechanistic investigations revealed that the steric hindrance on the δ-position of either the dienone or ene-ynone intermediate is the key feature to prevent or decrease the competitive 1,6-reduction (and consequently the formation of the saturated ketone) and to favor the synthesis of a set of non-conjugated enones and ynones.

Catalytic Asymmetric α-Alkylation of Ketones with Unactivated Alkyl Halides.

A catalytic, enantioselective method for direct α-alkylation of ketones with unactivated alkyl halides is realized by employing an α-enolizable ketone in a nickel-catalyzed C(sp3)-C(sp3) cross-coupling reaction. The key to the success is attributed to a unique bimetallic ligand. A variety of acyclic ketones and unactivated alkyl iodides can serve as suitable substrates under mild conditions to generate chiral ketones with α-quaternary carbon stereocenters in high yields with good enantioselectivities. A range of transformations based on the ketone moiety are also demonstrated to show the potential application of this method. Preliminary mechanistic studies support a dinickel-catalyzed cross-coupling mechanism.

Ketone α-alkylation at the more-hindered site

Control of the regioselectivity of α-alkylation of carbonyl compounds is a longstanding topic of research in organic chemistry. By using stoichiometric bulky strong bases and carefully adjusting the reaction conditions, selective alkylation of unsymmetrical ketones at less-hindered α-sites has been achieved. In contrast, selective alkylation of such ketones at more-hindered α-sites remains a persistent challenge. Here we report a nickel-catalysed alkylation of unsymmetrical ketones at the more-hindered α-sites with allylic alcohols. Our results indicate that the space-constrained nickel catalyst bearing a bulky biphenyl diphosphine ligand enables the preferential alkylation of the more-substituted enolate over the less-substituted enolate and reverses the conventional regioselectivity of ketone α-alkylation. The reactions proceed under neutral conditions in the absence of additives, and water is the only byproduct. The method has a broad substrate scope and permits late-stage modification of ketone-containing natural products and bioactive compounds.

Borrowing hydrogen and dehydrogenative/oxidative cyclization reactions catalyzed by a CCC-NHC pincer Re complex: An air stable catalyst for the synthesis of α-alkylated ketones and quinolines

Successful catalytic activity of the CCC-NHC pincer Re(I) complex was achieved for the borrowing hydrogen coupling reaction between primary and secondary benzylic alcohols. An expansive scope of 17 aromatic and 2 aliphatic substrates were investigated and isolated yields from 40% to 91% were collected. The aliphatic substrates yielded complex aldol self-condensation by-products. The catalytic activity of the CCC-NHC pincer Re(I) complex was also evaluated for the formation of quinolines via the dehydrogenative/oxidative cyclization of 2-aminobenzyl alcohols with benzylic ketones or secondary benzylic alcohols. Isolated yields from 68% to 87% were obtained for 12 examples. All products and by-products were fully characterized by 1H &13C NMR and mass spectroscopies. Control studies such as dehydrogenative and hydrogen transfer reaction were carried out, and the results from these experiments supported a proposed mechanism of a borrowing hydrogen coupling reaction catalyzed by the CCC-NHC pincer Re(I) complex.

Synthesis of α-Alkylated Ketones via Nickel-Catalyzed Dehydrogenative Coupling of Alcohols

Synthesis of α-Alkylated Ketones via Nickel-Catalyzed Dehydrogenative Coupling of Alcohols

Erratum - Nickel-Catalyzed Sustainable and Selective Alkylation of Alcohols to α-Alkylated Ketones via Borrowing Hydrogen Approach

Correction to: Nickel-Catalyzed Sustainable and Selective Alkylation of Alcohols to α-Alkylated Ketones via Borrowing Hydrogen ApproachSynlett 2023; 34(06): 635-644DOI: 10.1055/a-1934-1056

The α-alkylation of ketones in flow

A continuous flow methodology is described which gives α-alkylated ketones in good yields, avoids cryogenic temperatures, excessive exposure to alkyllithiums/alkylhalides, and can be easily and continuously scaled-out (to >3 g in 45 min).

Visible light-enabled alkylation of enol acetates with alkylboronic acids for the synthesis of α-alkyl ketones

Visible light-catalyzed alkylation of enol acetates with alkylboronic acids has been successfully developed to synthesize α-alkyl ketones. A variety of asymmetric ketones with various structural skeletons were obtained under mild conditions.

Palladium single-atom catalyst supported on ceria for α-alkylation of ketones with primary alcohols

A highly active and dispersed palladium single-atom supported on cubic CeO2catalyst was developed for α-alkylation of ketones with primary alcohols under low catalyst and base usage.

Reductive α-alkylation of ketones with aldehydes at atmospheric pressure of carbon monoxide: the effect of fluoride activation in ruthenium catalysis

Fluoride additive to [(p-cymene)RuCl2]2, a readily available ruthenium catalyst, allows one to achieve milder conditions for the reductive alkylation of aldehydes with ketones using carbon monoxide as a reducing agent. The procedure is suitable for the broad substrate scope, and a probable explanation for the fluoride role was provided.