Α-alkylation Of Ketones Research Articles

Ruthenium-Catalyzed β-Alkylation of Secondary Alcohols and α-Alkylation of Ketones via Borrowing Hydrogen: Dramatic Influence of the Pendant N-Heterocycle

Three bidentate ruthenium(II) complexes with a pyridonate fragment were prepared and fully characterized. These complexes are structurally similar, but differ in their pendant substituents. Complex 1 contains a phenyl unit, whereas complexes 2 and 3 have uncoordinated thienyl and thiazolyl groups, respectively. These complexes were tested as catalysts for β-alkylation of secondary alcohols with primary alcohols, and 3 shows the highest activity, suggesting the thiazolyl ring participates in the catalytic process. Furthermore, 3 is an excellent catalyst for α-alkylation of ketones with primary alcohols. Various α-alkylated ketones were synthesized in high yields, by using 0.05 mol % 3 and 0.25 equiv of t-BuOK within 30 min.

α-Alkylation of Ketones and Alcohols with a Heterogeneous Zirconium Catalyst

α-Alkylation of Ketones and Alcohols with a Heterogeneous Zirconium Catalyst

The α-alkylation of ketones with alcohols in pure water catalyzed by a water-soluble Cp*Ir complex bearing a functional ligand

A water-soluble dinuclear Cp*Ir complex bearing 4,4′,6,6′-tetrahydroxy-2,2′-bipyrimidine as a bridging ligand was found to be a highly effective catalyst for the α-alkylation of ketones with alcohols in water.

Reaction condition controlled nickel(ii)-catalyzed C-C cross-coupling of alcohols.

The challenge in the C-C cross-coupling of secondary and primary alcohols using acceptorless dehydrogenation coupling (ADC) is the difficulty in accurately controlling product selectivities. Herein, we report a controlled approach to a diverse range of β-alkylated secondary alcohols, α-alkylated ketones and α,β-unsaturated ketones using the ADC methodology employing a Ni(ii) 4,6-dimethylpyrimidine-2-thiolate cluster catalyst under different reaction conditions. This catalyst could tolerate a wide range of substrates and exhibited a high activity for the annulation reaction of secondary alcohols with 2-aminobenzyl alcohols to yield quinolines. This work is an example of precise chemoselectivity control by careful choice of reaction conditions.

Graphene oxide catalyzed ketone α-alkylation with alkenes: enhancement of graphene oxide activity by hydrogen bonding.

Direct α-alkylation of carbonyl compounds represents a fundamental bond forming transformation in organic synthesis. We report the first ketone-alkylation using olefins and alcohols as simple alkylating agents catalyzed by graphene oxide. Extensive studies of the graphene surface suggest a pathway involving dual activation of both coupling partners. Notably, we show that polar functional groups have a stabilizing effect on the GO surface, which results in a net enhancement of the catalytic activity. The method represents the first alkylation of carbonyl compounds using graphenes, which opens the door for the development of an array of protocols for ketone functionalization employing common carbonyl building blocks and readily available graphenes.

Iron-Catalyzed Oxyalkylation of Terminal Alkynes with Alkyl Iodides

A general oxyalkylation of terminal alkynes enabled by iron catalysis has been developed. Primary and secondary alkyl iodides acted as the alkylating reagents and afforded a range of α-alkylated ketones under mild reaction conditions. Acetyl tert-butyl peroxide (TBPA) was used as the radical relay precursor, providing the initiated methyl radical to start the radical relay process. Preliminary mechanistic studies were conducted, and late-stage functionalizations of natural product derivatives were performed.

Transition-Metal-Catalyzed Ketone α-Alkylation and Alkenylation with Simple Alkenes and Alkynes through a Dual Activation Strategy

In this personal account, we summarize our investigations on the α-alkylation and α-alkenylation reactions of ketones with nonactivated alkenes and alkynes, respectively. The serendipitous discovery of C–H alkylation/alkenylation of cyclic 1,2-diketones provided a proof of concept for a dual activation strategy. Extension to the α-alkylation and α-alkenylation of regular ketones was achieved by using 7-azaindoline as a bifunctional ligand. Subsequently, intramolecular coupling ­between ketones and olefins was achieved with Rh- and Ru-based systems, respectively. Finally, branched-selective α-alkylation was achieved through an Ir-catalyzed enamide-mediated C–H alkylation.1 Introduction2 Serendipitous Discovery of α-Alkylation and α-Alkenylation of 1,2-Diketones through Enamine-Mediated C–H Activation3 Intermolecular Ketone α-Alkylation of Regular Ketones with Nonactivated Olefins4 Intermolecular Ketone α-Alkenylation of Regular Ketones with Nonactivated Alkynes5 Intramolecular Ketone α-Alkylation of Regular Ketones with Nonactivated Olefins6 Branched-Selective α-Alkylation of Regular Ketones with Non­activated Olefins7 Conclusions and Outlook

Nickel-Catalyzed α-Alkylation of Ketones with Alcohols

Nickel-Catalyzed α-Alkylation of Ketones with Alcohols

Manganese-Catalyzed α-Alkylation of Ketones, Esters, and Amides Using Alcohols.

Herein we report the manganese-catalyzed C–C bond-forming reactions via α-alkylation of ketones, amides, and esters, using primary alcohols. β-Alkylation of secondary alcohols by primary alcohols to obtain α-alkylated ketones is also reported. The reactions are catalyzed by a (iPr-PNP)Mn(H)(CO)2 pincer complex under mild conditions in the presence of (catalytic) base liberating water (and H2 in the case of secondary alcohol alkylation) as the sole byproduct.

In Water and under Mild Conditions: α-Alkylation of Ketones with Alcohols by Phase-Transfer-Assisted Borrowing Hydrogen Catalysis.

Borrowing hydrogen is a powerful and green technique that allows readily available alcohols to be used as alkylating agents and produces water as the only by-product. Nevertheless, harsh conditions such as high temperatures and organic solvents are usually required. Herein, we present a strategy to perform the α-alkylation of ketones in aqueous media at mild temperatures by combining borrowing hydrogen with phase-transfer catalysis. A broad scope of methyl ketones was functionalized with alkyl and benzyl alcohols in moderate to good yields at 40 °C. The protocol was also highly effective at large scale and room temperature.

Nickel-Catalyzed Hydrogen-Borrowing Strategy for α-Alkylation of Ketones with Alcohols: A New Route to Branched gem-Bis(alkyl) Ketones.

The α-alkylation of ketones using an earth-abundant and nonprecious NiBr2/L1 system is reported. This nickel-catalyzed reaction could be performed in gram scale and successfully applied in the synthesis of donepezil (Alzheimer's drug) and functionalization of steroid hormones and fatty acid derivatives. Synthesis of N-heterocycles, methylation of ketones, and one-pot double alkylation to bis-hetero aryl ketones using two different alcohols with a single catalyst broadens the scope of the catalytic protocol. Preliminary mechanistic studies using defined Ni-H species and deuterium-labeling experiments established the participation of the borrowing-hydrogen strategy.

Formation, Alkylation, and Hydrolysis of Chiral Nonracemic N-Amino Cyclic Carbamate Hydrazones: An Approach to the Enantioselective α-Alkylation of Ketones.

The α-alkylation of ketones is a fundamental synthetic transformation. The development of asymmetric variants of this reaction is important given that numerous natural products, drugs, and related compounds exist as α-functionalized ketones or derivatives thereof. We previously reported our preliminary studies on the development of a new enantioselective ketone α-alkylation procedure using N-amino cyclic carbamate (ACC) auxiliaries. In comparison to other auxiliary-based methods, ACC alkylation offers a number of advantages and is both highly enantioselective and high yielding. Herein, we provide a full account of our studies on the enantioselective ACC ketone α-alkylation method.

Silver/NBS-Catalyzed Synthesis of α-Alkylated Aryl Ketones from Internal Alkynes and Benzyl Alcohols via Ether Intermediates.

The silver hexafluoroantimonate/ N-bromosuccinimide (NBS)-catalyzed synthesis of α-alkylated aryl ketones with a tertiary carbon center from internal alkynes and benzyl alcohols is reported. This reaction proceeds via the etherification of benzyl alcohols with an in situ generated benzyl bromide, formed by the reaction of benzyl alcohol with a catalytic amount of NBS and AgSbF6. Ag-catalyzed C-O cleavage of the ether leads to a tolyl radical, which undergoes addition to the alkyne, ultimately leading to the α-alkylated aryl ketone products.

NNN Pincer Ru(II)-Complex-Catalyzed α-Alkylation of Ketones with Alcohols.

A series of novel ruthenium(II) complexes supported by a symmetrical NNN ligand were prepared and fully characterized. These complexes exhibited good performance in transfer hydrogenation to form new C-C bonds using alcohols as the alkylating agents, generating water as the only byproduct. A broad range of substrates, including (hetero)aryl- or alkyl-ketones and alcohols, were well tolerated under the optimized conditions. Notably, α-substituted methylene ketones were also investigated, which afforded α-branched steric hindrance products. A potential application of α-alkylation of methylene acetone to synthesize donepezil was demonstrated, which provided the desired product in 83% yield. Finally, this catalytic system could be applied to a one-pot double alkylation procedure with sequential addition of two different alcohols. The current protocol is featured with several characteristics, including a broad substrate scope, low catalyst (0.50 mol %) loadings, and environmental benignity.

Iridium(I)-Catalyzed Alkylation Reactions To Form α-Alkylated Ketones.

A highly effective and green procedure for the formation of α-alkylated ketones has been disclosed via the reaction of primary alcohols with secondary alcohols and ketones by using [IrCl(COD)(NHC)] complexes as a catalyst. Various α-alkylated ketones were obtained in high yields from the alkylation of alcohol with alcohol and ketone with alcohol through a borrowing hydrogen reaction by using 0.05-0.5 mol % iridium(I) and a catalytic amount of KOH (5-10 mol %) as the base under air atmosphere and within very short reaction times.

Ligand-Controlled Copper(I)-Catalyzed Cross-Coupling of Secondary and Primary Alcohols to α-Alkylated Ketones, Pyridines, and Quinolines.

One hexanuclear Cu(I) cluster of 4,6-dimethylpyrimidine-2-thiolate efficiently catalyzes the dehydrogenative cross-coupling of secondary and primary alcohols to α-alkylated ketones with high selectivity. This transformation proceeds through a one-pot sequence of dehydrogenation of alcohols, condensation of aldehydes and ketones, hydrogenation of the resulting α,β-unsaturated ketones, and dehydrogenation of the α-alkylated alcohols to generate α-alkylated ketones. This catalytic system also displays high activity for the annulation reaction of secondary alcohols with γ-amino- and 2-aminobenzyl alcohols to yield pyridines and quinolines, respectively.

Stereoselective synthesis of α-methyl and α-alkyl ketones from esters and alkenes via cyclopropanol intermediates.

Alkenes bearing a stereocenter in the allylic position were found to undergo Kulinkovich hydroxycyclopropanation with good diastereoselectivity. For the isomerization of the resulting cyclopropanols to diastereomerically enriched α-methyl ketones, a new mild regioselective method has been developed. A sequence of stereoselective cyclopropanation and cyclopropanol ring opening was successfully employed for the construction of the C20 stereocenter in steroids.

Solvent-free direct α-alkylation of ketones by alcohols catalyzed by nickel supported on silica–alumina

The α-alkylation of acetophenone with benzyl alcohol through borrowing hydrogen has been studied using nickel catalysis.

Mechanism, selectivity, and reactivity of iridium- and rhodium-catalyzed intermolecular ketone α-alkylation with unactivated olefinsviaan enamide directing strategy

DFT calculations were performed to investigate the title reaction, focusing on detailed reaction mechanism and origins of selectivity and reactivity.

Reactivity of Lithium β-Ketocarboxylates: The Role of Lithium Salts.

Lithium β-ketocarboxylates 1(COOLi), prepared by the reaction of lithium enolates 2(Li+) with carbon dioxide, readily undergo decarboxylative disproportionation in THF solution unless in the presence of lithium salts, in which case they are indefinitely stable at room temperature in inert atmosphere. The availability of stable THF solutions of lithium β-ketocarboxylates 1(COOLi) in the absence of carbon dioxide allowed reactions to take place with nitrogen bases and alkyl halides 3 to give α-alkyl ketones 1(R) after acidic hydrolysis. The sequence thus represents the use of carbon dioxide as a removable directing group for the selective monoalkylation of lithium enolates 2(Li+). The roles of lithium salts in preventing the disproportionation of lithium β-ketocarboxylates 1(COOLi) and in determining the course of the reaction with bases and alkyl halides 3 are discussed.