Saturated Ketones Research Articles

Iron-Catalyzed One-Pot Cascade Reactions of Oximes with Inactivated Saturated Ketones: Entry to Highly Substituted Pyridines.

An iron-catalyzed oxidative [3 + 3] annulation of oxime esters with inactivated saturated ketones is described. This cascade strategy allows one-step rapid synthesis of various structurally important pyridines through an oxidative dehydrogenation/annulation/oxidative aromatization sequence via direct α,β-dehydrogenation of simple saturated ketones followed by annulation with oximes. This method shows good functional group tolerance, readily accessible starting materials, a wide substrate scope, high chemoselectivity, and no need for extra stoichiometric oxidant and is also applicable to the late-stage functionalization of natural products.

Design and Understanding of Adaptive Hydrogenation Catalysts Triggered by the H2/CO2-Formic Acid Equilibrium.

An adaptive catalytic system for selective hydrogenation was developed exploiting the H2+CO2HCOOH equilibrium for reversible, rapid, and robust on/off switch of the ketone hydrogenation activity of ruthenium nanoparticles (Ru NPs). The catalyst design was based on mechanistic studies and DFT calculations demonstrating that adsorption of formic acid to Ru NPs on silica results in surface formate species that prevent C═O hydrogenation. Ru NPs were immobilized on readily accessible silica supports modified with guanidinium-based ionic liquid phases (Ru@SILPGB) to generate in situ sufficient amounts of HCOOH when CO2 was introduced into the H2 feed gas for switching off ketone hydrogenation while maintaining the activity for hydrogenation of olefinic and aromatic C═C bonds. Upon shutting down the CO2 supply, the C═O hydrogenation activity was restored in real time due to the rapid decarboxylation of the surface formate species without the need for any changes in the reaction conditions. Thus, the newly developed Ru@SILPGB catalysts allow controlled and alternating production of either saturated alcohols or ketones from unsaturated substrates depending on the use of H2 or H2/CO2 as feed gas. The major prerequisite for design of adaptive catalytic systems based on CO2 as trigger is the ability to shift the H2+CO2HCOOH equilibrium sufficiently to exploit competing adsorption of surface formate and targeted functional groups. Thus, the concept can be expected to be more generally applicable beyond ruthenium as the active metal, paving the way for next-generation adaptive catalytic systems in hydrogenation reactions more broadly.

Kinetic Study of OH Radical Reactions with Cyclopentenone Derivatives.

We investigated the reactions of the hydroxyl radical (OH) with cyclopentenone derivatives and cyclopentanone in a quasi-static reaction cell at 4 Torr across a 300-500 K temperature range. The OH radicals were generated using pulsed laser photolysis of hydrogen peroxide vapors, and the ketone reactants were introduced in excess. The relative concentrations of the radicals were monitored as a function of reaction time using laser-induced fluorescence. At room temperature, the reaction rate coefficients were measured to be 1.2(±0.1) × 10-11 cm3 s-1 for reaction with 2-cyclopenten-1-one (R1); 1.7(±0.2) × 10-11 cm3 s-1 for reaction with 2-methyl-2-cyclopenten-1-one (R2); and 4.4(±0. 7) × 10-12 cm3 s-1 for reaction with 3-methyl-2-cyclopenten-1-one (R3). Over the experimental temperature range, the rate coefficients can be fitted with the modified Arrhenius expressions k1(T) = 1.2 × 10-11 (T/300)0.26 exp (6.7 kJ mol-1/R {1/T - 1/300}) cm3 s-1, k2(T) = 1.7 × 10-11 (T/300)6.4 exp (27.6 kJ mol-1/R {1/T - 1/300}) cm3 s-1, k3(T) = 4.4 × 10-12 (T/300)17.8 exp (57.8 kJ mol-1/R {1/T - 1/300}) cm3 s-1. In the cases of 2-cyclopenten-1-one and 2-methyl-2-cyclopenten-1-one, the temperature dependence of the rate coefficients is similar to that calculated or measured for noncyclic conjugated ketones. We also found that the reaction with 3-methyl-2-cyclopenten-1-one was slower, with rate coefficients similar to those measured for the reaction with the saturated cyclic ketone cyclopentanone. To discuss the experimental data, we use potential energy surfaces (PES) calculated at the CCSD(T)/cc-pVTZ//M06-2X/6-311+G** level of theory. RRKM-based Master equation calculations were also performed to infer the most likely reaction products over a wide range of temperatures and pressures. We suggest that both abstraction and addition mechanisms contribute to the overall OH removal, forming radical products stabilized by resonance. We also discuss the relevance for combustion and atmospheric chemistry.

Cobalt catalyzed condensation interrupted selective transfer hydrogenation using methanol

Utilizing methanol transfer hydrogenation (TH) of nitroarene and α,β-unsaturated ketones has significant challenges as it mostly produced the corresponding N/C-methylated and over-hydrogenated products. Hence, selective synthesis of amines and saturated ketones from nitroarene and α,β-unsaturated ketones respectively employing methanol as hydrogen source is an exciting area of research. Additionally, development of air and moisture-stable reusable cobalt based catalytic system for the dehydrogenation of methanol is a fascinating area to investigate. In this prospect, we disclosed a single atom cobalt catalysed condensation interrupted selective TH of a library of various nitroarenes and α,β-unsaturated ketones using methanol as a hydrogen source. A series of pharmaceutically important drug molecules was synthesized to establish the synthetic applicability of this methodology. Several control experiments were carried out to understand the reaction mechanism. Notably, this catalyst was recycled up to six times without considerable loss of its catalytic activity.

One-Pot Sequential Synthesis of Alkenylated Dihydroquinolinones and Hexahydroacridinones in Deep Eutectic Solvent Medium.

The sequential synthesis of N-heterocycles from saturated ketones poses significant challenges and has rarely been reported. Herein, an efficient synthesis of alkenylated dihydroquinolinones 7 and hexahydroacridinones 8 is achieved from saturated ketones 1 or 2 via dehydrogenation, cyclization, oxidation, and α-alkenylation in choline chloride-based deep eutectic solvent (DES) medium. This strategy provides alkenylated dihydroquinolinones 7 and hexahydroacridinones 8 in excellent yield from low-cost, readily available starting materials under environmentally benign conditions. Furthermore, the synthesized compounds (4, 5, 7, and 8) were investigated for their photophysical properties through absorption and emission spectral studies.

Chemical Profile and Potential Applications of Sclerocarya birrea (A.Rich.) Hochst. subsp. caffra (Sond.) Kokwaro Kernel Oils: Analysis of Volatile Compounds and Fatty Acids.

Sclerocarya birrea kernel volatile compounds and fatty acid methyl esters (FAMEs) from the Bubi district in Matabeleland North province of Zimbabwe were characterised by GC-MS. The volatile compounds of the oil include 65 different compounds from 24 distinct classes, dominated by 13 alcohols and 14 aldehydes (42%). Other classes include carboxylic acids, phenols, sesquiterpenes, lactones, pyridines, saturated fatty acids, ketones, and various hydrocarbons. The kernel oils revealed essential fatty acids such as polyunsaturated (α-linolenic and linoleic acids) and monounsaturated fatty acids (palmitic, palmitoleic, and oleic acids). Notably, oleic acid is the predominant fatty acid at 521.61 mg/g, constituting approximately 73% of the total fatty acids. Linoleic acid makes up 8%, and saturated fatty acids make up about 7%, including significant amounts of stearic (42.45 mg/g) and arachidic (3.46 mg/g) acids. These results validate the use of marula oils in food, pharmaceutical, and health industries, as well as in the multibillion USD cosmetics industry. Therefore, the potential applications of S. berria kernel oils are extensive, necessitating further research and exploration to fully unlock their capabilities.

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.

Bimetallic Ru(II) Complex Catalysed β‐Alkylation of Secondary Alcohols and α‐Alkylation of Ketones: Selective Formation of Saturated Ketones

AbstractRu(II) bimetallic [(p‐cymene)2(RuCl)2L1]2X (X=BF4 (Cat2); X=PF6 (Cat3)) and monometallic [(p‐cymene)(RuCl)L2]BF4 (Cat4) (where L1=N,N’‐(3,3’,5,5’‐tetraisopropyl‐[1,1’‐biphenyl]‐4,4’‐diyl)bis(1‐(pyridin‐2‐yl)methanimine); L2=N‐(2,6‐diisopropyl‐phenyl)‐1‐(pyridin‐2‐yl)‐methanimine) catalyse selective synthesis of saturated ketones using β‐alkylation of secondary alcohol or α‐alkylation of ketones with primary alcohol. Notably, a single catalyst facilitates the oxidation of both secondary and primary alcohols followed by condensation and hydrogenation yielding α‐alkylated saturated ketones. Remarkably, this system allows catalyst loading as low as 0.01 mol% for β‐alkylation of secondary alcohols and 0.005 mol% for the α‐alkylation of ketone, delivering access to a wide array of α‐alkylated ketones derivatives with yields of ~97 %. Complex Cat2, in particular, orchestrates one‐pot alkylation reactions with a high turnover frequency (TOF) of 5.6 105 h−1 using as low as low catalyst loading of 0.0001 mol%. A comparative study between bimetallic and monometallic complexes reveals that complex Cat2 exhibits better selectivity for the formation of saturated ketones presumably owing to a cooperative effect between the metal centres. The scale‐up synthesis highlights the practical applicability of the catalytic approach. To delve into the plausible mechanisms, we conducted initial investigations through meticulously controlled experiments and spectroscopic analysis.

Dehydrogenation and Transfer Hydrogenation of Alkenones to Phenols and Ketones on Carbon-Supported Noble Metals.

The catalytic dehydrogenation of substituted alkenones on noble metal catalysts supported on carbon (Pt/C, Pd/C, Rh/C, and Ru/C) was investigated in an organic phase under inert conditions. The dehydrogenation and semihydrogenation of the enone starting materials resulted in aromatic compounds (primary products), saturated cyclic ketones (secondary products), and cyclic alcohols (minor products). Pd/C exhibits the highest catalytic activity, followed by Pt/C and Rh/C. Aromatic compounds remain the primary products, even in the presence of hydrogen donors. Joint experimental and theoretical analyses showed that the four catalytic materials stabilize a common dienol intermediate on the metal surfaces, formed by keto-enol tautomerization. This intermediate subsequently forms aromatic products upon dehydrogenation. The binding orientation of the enone reactants on the catalytic surface is strongly metal-dependent, as the M-O bond distance changes substantially according to the metal. The longer M-O bonds (Pt: 2.84 Å > Pd: 2.23 Å > Rh: 2.17 Å > Ru: 2.07 Å) correlate with faster reaction rates and more favorable keto-enol tautomerization, as shorter distances correspond to a more stabilized starting material. Tautomerization is shown to occur via a stepwise surface-assisted pathway. Overall, each of the studied metals exhibits a distinct balance of enthalpy and entropy of activation (ΔH°‡, ΔS°‡), offering unique possibilities in the realm of enone dehydrogenation reactions that can be achieved by suitable selection of catalytic materials.

Nickel-Catalyzed Chemodivergent Coupling of Alcohols: Efficient Routes to Access α,α-Disubstituted Ketones and α-Substituted Chalcones.

Chemodivergent (de)hydrogenative coupling of primary and secondary alcohols is achieved utilizing an inexpensive nickel catalyst, (6-OH-bpy)NiCl2 . This protocol demonstrates the synthesis of branched carbonyl compounds, α,α-disubstituted ketones, and α-substituted chalcones via borrowing hydrogen strategy and acceptorless dehydrogenative coupling, respectively. A wide range of aryl-based secondary alcohols are coupled with various primary alcohols in this tandem dehydrogenation/hydrogenation reaction. The nickel catalyst, along with KOt Bu or K2 CO3 , governed the selectivity for the formation of branched saturated ketones or chalcones. A preliminary mechanistic investigation confirms the reversible dehydrogenation of alcohols to carbonyls via metal-ligand cooperation (MLC) and the involvement of radical intermediates during the reaction.

Synthesis of polysubstituted pyridazines via Cu-mediated C(sp3)-C(sp3) coupling/annulation of saturated ketones with acylhydrazones.

Pyridazine is a significant skeleton that widely exists in drugs and bioactive molecules. We herein describe expeditious approaches to access polysubstituted pyridazines from readily accessible unactivated ketones and acylhydrazones via Cu-promoted C(sp3)-C(sp3) coupling/cyclization sequences in a single-step fashion. Notably, the disparate 3,4,6-trisubstituted pyridazines and 3,5-disubstituted pyridazines could be obtained by tailoring the ketone's structure and reaction conditions. These transformations feature good functional group compatibility, excellent step-economy, and chemoselectivity. The potential synthetic utility of these conversions is illustrated by scale-up reactions and late-stage derivatizations of the as-prepared pyridazine products.

Multigram synthesis of β-fluorinated saturated heterocyclic methanamines

An efficient multigram synthesis of β-fluorinated saturated heterocyclic methanamines - promising building blocks for drug discovery, starting from the corresponding saturated heterocyclic ketones is described. The method includes Wittig olefination, bromofluorination, nucleophilic substitution with azide, and Staudinger reaction and works well for four- to seven-membered nitrogen- and oxygen-containing heterocyclic derivatives

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.

Gem‐Difluoro‐3‐azabicyclo[3.n.1]alkanes and Their Derivatives – Bicyclic Fluorinated Piperidine Isosteres for Drug Discovery

AbstractAn approach to gem‐difluoro‐3‐azabicyclo[3.n.1]alkane‐ derived building blocks through double‐Mannich addition– deoxofluorination sequence is described. The scope of the method was demonstrated for a series of saturated (hetero)cyclic ketones or ketoesters (including five‐ to seven‐membered cycloalkane derivatives and N‐, O‐, S‐containing saturated heterocycles). Further transformations of functional groups produced various bifunctionalized difluorinated building blocks, namely, N‐protected aminoacids, mono‐N‐Boc‐protected diamines, and unprotected aminoalcohols in good to excellent overall yields. For the azabicyclo[3.3.1]alkane series, a potential for isosteric replacements is demonstrated by evaluation of the key physicochemical properties (i. e., pKa(H) and LogP).

Synthesis of thiophene-substituted ketones via Manganese-Catalyzed Dehydrogenative Coupling Reaction.

This study reports an efficient and green one-step method for synthesizing thiophene-substituted ketones from 2-thiophenemethanoland ketonesvia dehydrogenative coupling using manganese complexes as catalysts.The manganese complex demonstrated a broad applicability under mild conditions and extended the range of usable substrates. Utilizing this strategy, we carried out an efficient and diverse reaction of ketones with 2-thiophenemethanol, and successfully synthesized a series of thiophene-substituted saturated ketonesand α,β-unsaturated ketones in good isolated yields.

Synthesis of β-Enaminones via Palladium-catalyzed Dehydrogenative β-Amination of Saturated Ketones

Abstract A palladium-catalyzed method was developed for the synthesis of β-enaminones from saturated ketones using allyl acetate. In this reaction, allyl acetate acts as a hydrogen scavenger to α,β-dehydrogenate saturated ketones in the presence of a palladium catalyst and diamine ligand. This reaction achieved internal β-carbon–nitrogen bond formation for the first time via the dehydrogenation/conjugate addition protocol, eliminating the need to isolate unstable α,β-unsaturated ketones generated in the reaction.

Selective Transfer Hydrogenation of C=O and Conjugated C=C Bonds Using An NHC-Based Pincer (CNC)MnI Complex in Methanol.

Base metal catalyzed transfer hydrogenation reactions using methanol is highly challenging. Employing a single N-heterocyclic carbene (NHC)-based pincer (CNC)MnI complex, chemoselective single and double transfer hydrogenation of α, β-unsaturated ketones to saturated ketones or alcohols by utilizing methanol as the hydrogen source is disclosed. The protocol was tolerant towards the selective transfer hydrogenation of C=C or C=O bonds in the presence of several other reducible functional groups and led to the synthesis of several biologically relevant molecules and natural products. Notably, this is the first report of a Mn-catalyzed transfer hydrogenation of carbonyl groups with methanol. Several control experiments, kinetic studies, Hammett studies, and density functional theory (DFT) calculations were carried out to understand the mechanistic details of this catalytic process.

Chemoselective Reduction of α,β-Unsaturated Carbonyl Compounds via a CS2/t-BuOK System: Dimethyl Sulfoxide as a Hydrogen Source.

A novel and practical approach to access saturated ketones from unsaturated ketone derivatives via a CS2/t-BuOK system in dimethyl sulfoxide (DMSO) is reported. The in situ generation of xanthate salt through the reaction of carbon disulfide and potassium tert-butoxide is essential to this transformation. Deuterium-labeling experiments demonstrated that DMSO can act as a hydrogen donor.

Manganese(I)-Catalyzed Chemoselective Transfer Hydrogenation of the C=C Bond in Conjugated Ketones at Room Temperature.

Chemoselective transfer hydrogenation of C=C bond in α,β-unsaturated ketones is demonstrated at room temperature employing a manganese(I) catalyst and half an equivalent of ammonia-borane (H3 N-BH3 ). A series of mixed-donor pincer-ligated Mn(II) complexes, (tBu2 PN3 NPyz )MnX2 [κP ,κN ,κN -(N-(di-tert-butylphosphaneyl)-6-(1H-pyrazol-1-yl)pyridin-2-amine)MnX2 ] {X=Cl (Mn2), X=Br (Mn3), X=I (Mn4)} were synthesized and characterized. Amongst the Mn(II) complexes, (Mn2, Mn3, Mn4) and Mn(I) complex, (tBu2 PN3 NPyz )Mn(CO)2 Br (Mn1) screened; the Mn1 acts as an efficient catalyst for the chemoselective C=C bond reduction in α,β-unsaturated ketones. Various synthetically important functionalities like halides, methoxy, trifluoromethyl, benzyloxy, nitro, amine, and unconjugated alkene and alkyne groups, including heteroarenes, were compatible and provided saturated ketones in excellent yields (up to 97 %). A preliminary mechanistic study highlighted the crucial role of metal-ligand (M-L) cooperation through the dearomatization-aromatization process in catalyst Mn1 for the chemoselective C=C bond transfer hydrogenation.

Examining the Scope of Deriving β-Aryl Enones from Enol Silanes as Ketone Equivalents via Pd(II)-Mediated Sequential Dehydrosilylation and Arylation.

Silyl enol ethers were examined as a masked source of saturated ketones to derive β-aryl enones and their derivatives by dehydrosilylation to generate enones in situ and subsequent oxidative arylation with arylboronic acids as transmetallation coupling partners using relayed Pd(II) catalysis in one pot under base-free conditions. Oxygen was found to be an efficient and green oxidant to enable both dehydrosilylation of enol silanes and arylation. Additionally, arylation conditions can be custom-designed to take advantage of aryl halides as an alternative source of arylating agents. The preparative scope was investigated with 35 examples (up to 95% yield), and mechanistic studies implied a cationic Pd(II)-based catalytic system.