Aryl Ketones Research Articles

Transition‐Metal Catalyzed Coupling Reactions for the Synthesis of (Het)aryl Ketones: An Approach from their Synthesis to Biological Perspectives

AbstractSynthetic protocols capable of incorporating acyl based functional moieties have been proved fruitful to develop variety of carbonyl containing organic molecules. Substituted‐aromatic ketones are important motifs in different natural products and biologically active pharmaceuticals. Substituted aromatic ketones based compounds have been proved effective as antioxidant, antiallergic, antimicrobial, antimitotic, anticholinergic, antiinflammatory, anticonvulsant, antipsychotic age, anticancer, antimicrobial, antimalarial, and antiviral agents, Transition metals are necessary part of modern catalytic systems for carbonylative transformations. Carbonylative coupling reaction involves direct introduction of carbonyl fragment for synthesis of biaryls, aryl/alkyl ketones through transition metals based catalytic systems. In this review, we have reported the synthesis of biaryls, aryl/alkyl ketones by using different feed stocks in presence of various transition metal catalysts.

RuO2 supported on MOF-derived CeO2 as an efficient catalyst for selective C–H oxidation of alkylarenes in water at room temperature

Recently, MOFs as an important class of porous crystalline materials are widely utilized as carriers or catalysts in various catalytic systems. In this work, using Ce-BTC supported RuCl3 as a precursor, RuO2–CeO2 composites with high catalytic performance and excellent morphology were successfully synthesized by pyrolysis under ambient atmosphere. An efficient oxidation method for benzyl sp3 C–H bond using the synthesized composites as a heterogeneous catalyst was developed, which could effectively catalyze the selective oxidation of alkylarenes in water at room temperature, and successfully provide a variety of aryl ketone products in high yields with low catalyst dosage. The characterized results indicate that the existence of Ru (IV) is supported. The synthesized RuO2–CeO2 exhibits high activity for the gram-scale oxidation of indane with the lower ruthenium loading (3,837 h−1 TOF based on Ru). Furthermore, the heterogeneous catalyst could be utilized at least six cycles without significant loss of catalytic activity.

A Mechanistically Deceiving Formation of Aryl(1-indanyl)ketones via Acid-Catalyzed Cyclization of ortho-Alkynylarylmethanols.

The generation of reactive carbocation intermediates from ortho-alkynylarylmethanol substrates was utilized as a means for the synthesis of aryl(1-indanyl)ketones . Substrates with a tertiary carbon at the β-position to the arene generated a carbocation intermediate via dehydration/protonation, followed by cyclization and hydration to give indanylketone products. For substrates with a quaternary carbon at that position, a carbocation intermediate was generated by protonation/elimination of water, followed by a 1,2-shift and a subsequent cyclization/hydration to give highly substituted indanylketones.

Ketyl Radicals Generated from Magnesium(I) Compounds: Useful Reagents for C-C Bond Forming Reactions.

The aryl ketones, 9-fluorenone (fluor), 9-xanthenone (xanth) and 9,10-anthraquinone (anth), were reacted with β-diketiminato dimagnesium(I) compounds, [{(Ar Nacnac)Mg}2 ] (Ar Nacnac=[HC(MeCNAr)2 ]- , Ar=mesityl (Mes) or 2,6-diisopropylphenyl (Dip)). This gave stable magnesium ketyl complexes which are monomeric, [(Ar Nacnac)(DMAP)Mg(fluor⋅)] (Ar=Mes or Dip, DMAP=4-dimethylaminopyridine) and [(Mes Nacnac)Mg(xanth⋅)(xanth)]; dimeric, [{(Mes Nacnac)Mg(μ-fluor⋅)}2 ], or tetrameric, [{(Dip Nacnac)Mg(μ-anth⋅)}4 ]. In contrast, di-2-pyridylketone (OCPy2 ) is doubly reduced with [{(Xyl Nacnac)Mg}2 ] (Xyl=xylyl) to give a diamagnetic alkoxy/amido complex, [{(Xyl Nacnac)Mg}2 (μ-OCPy2 )]. These complexes have been characterized by X-ray crystallography, and in three cases, EPR spectroscopy. Regioselective C-C hetero-coupling reactions between magnesium ketyls and phenanthroline (phen) have yielded the alkoxy compounds, [(Mes Nacnac)Mg(OCR2 -2-phen)] (OCR2 =xanth, OCPh2 or OC(Ph)(2-Me-Ph)). In addition, homo- C-C couplings of the enones, chalcone (chalc) and dibenziylideneactetone (DBA), using magnesium(I) reducing agents, have afforded dimagnesium enolates, [{(Ar Nacnac)(THF)Mg}2 (μ-chalc2 )] (Ar=Mes or Xyl) and [{(Dip Nacnac)(THF)Mg}2 (μ-DBA2 )]. A pinacol coupling reaction between [{(Dip Nacnac)Mg}2 ] and 2-adamantanone (OAd) yielded [{(Dip Nacnac)(OAd)Mg}2 (μ-OAd2 )], presumably via a ketyl intermediate. This study further highlights the utility magnesium(I) compounds have as selective reducing agents in organic transformations.

Zinc-Catalyzed Asymmetric Cascade Michael/Acyl Transfer Reaction between α-Hydroxy Aryl Ketones and Enynones.

We described herein a neoteric enantioselective cascade Michael/acyl transfer reaction of enynones and α-hydroxy aryl ketones catalyzed by dinuclear zinc cooperative catalysis. A series of structurally diverse chiral 1,5-dicarbonyl compounds were synthesized in good yields with excellent stereoselectivities. This strategy features broad substrate scope, high atom economy, as well as enynones as efficient electrophilic acyl transfer reagents in asymmetric cascade reactions for the first time.

Halogen-free oxidation of aryl ketones and benzyl nitrile derivatives to corresponding carboxylic acids by using NaOH/ TBHP in aqueous medium

Using inexpensive NaOH as the base and aq. TBHP (70%) as the oxidant, we have developed an efficient oxidative methodology for converting aryl ketones and benzyl nitrile derivatives to their corresponding acids in good yields. Several industrially relevant carboxylic acids could be easily synthesized in gram scale using this protocol.

New Strategy for Effective Biosynthesis of Chiral Aryl Alcohols: Co-Cultivation Microbe with Natural Deep-Eutectic Solvent

In this study, a new strategy was developed for efficient synthesis of chiral aryl alcohols mediated by permeabilizing whole-cell catalyzed bioreduction. The permeabilized biocatalyst was prepared via co-cultivation microbial cells with natural deep-eutectic solvent (NADES) in their growth period, and the bioreductive efficiency was significantly enhanced due to the improvement of cell permeability for overcoming mass-transfer limitation in the reduction of prochiral ketones. This approach was successfully employed in the model reaction of 2-chloro-1-(3,4-difluorophenyl)ethanone to (S)-2-chloro-1-(3,4-difluorophenyl)ethanol [(S)-CFPL] with newly isolated Geotrichum candidum ZJPH1907 in a Tween 80-containing buffer system. Compared to the conventional NADES addition in reaction system as co-solvent, a much higher catalytic yield (98.7% vs 62.5%) was achieved with good enantioselectivity via a co-cultivation strategy, in which the permeabilizing biocatalyst was obtained by co-incubation G. candidum cells with 0.5% (w/v) choline chloride/lysine (ChCl/Lys) (molar ratio 1:2). The developed new strategy was concise, feasible, and eco-friendly through the analysis of green chemistry metric, and the catalytic efficiencies were also enhanced in the bioreduction of other aryl ketones. This work provides a new understanding of NADES in biocatalysis and broadens its application.

Understanding the hydration of arylacetylenes to synthesize the carbonyl compounds via electroreduction of bromide intermediates

A deeper understanding of the electrochemical hydration of the alkynes may promote the development of such reactions. By using 4-tert-butylphenylacetylene as the model substrate, the mechanism of the electro-hydration of acetylenes is investigated through the designed experiments and theoretical calculations. It is suggested that the reaction may follow two possible radical processes simultaneously. The major is a cascade pathway including an oxidative halogenation followed by an electrochemical stepwise-dehalogenation, and the minor is the direct hydration of the substrate on the electrode surface. The inference is further confirmed by the corresponding thermodynamic calculations. This mechanistic study provides a theoretical basis for the future design and synthesis of various functionalized aryl ketones from the arylacetylenes by the electrochemistry strategy.

Preparation of Vinylphosphonates from Ketones Promoted by Tf2O.

An efficient triflic anhydride promoted phosphorylation of ketone was disclosed, and vinylphosphorus compounds were prepared under solvent- and metal-free conditions. Both aryl and alkyl ketones could perform smoothly to give vinyl phosphonates in high to excellent yields. In addition, the reaction was easy to carry out and easy to scale up. Mechanistic studies suggested that this transformation might involve nucleophilic vinylic substitution or a nucleophilic addition-elimination mechanism.

Iridium-Catalyzed Asymmetric Hydrogenation of Simple Ketones with Tridentate PNN Ligands Bearing Unsymmetrical Vicinal Diamines

An iridium catalytic system with a ferrocene-based phosphine ligand bearing a modular and tunable unsymmetrical vicinal diamine scaffold was developed for the asymmetric hydrogenation of aryl ketones. This approach provided a powerful tool for the enantioselective synthesis of diverse chiral alcohols with excellent reactivity and enantioselectivity (up to 99% yield, up to 99% ee, and up to 50,000 turnover number). The substituents and chirality of unsymmetrical diamines in ligands played an important role in the satisfactory results.

Catalytic, Interrupted Carbonyl-Olefin Metathesis for the Formation of Functionalized Cyclopentadienes

Cyclopentadienes are scaffolds in organometallic chemistry, synthetic organic chemistry, and catalysis. We herein describe a regioselective Lewis-acid-catalyzed method for the synthesis of highly functionalized cyclopentadienes incorporating electronically and sterically diverse subunits. Our experimental and theoretical investigations support a mechanism that is related to catalytic carbonyl-olefin metathesis reactions wherein Lewis-acid-catalyzed cycloadditions between carbonyl and alkene functionalities afford reactive oxetane intermediates. However, in lieu of a [2+2]-cycloreversion, stepwise oxetane fragmentation to intermediate carbocations results in the formation of functionalized cyclopentadienes via interrupted carbonyl-olefin metathesis. This work provides insights into the design of catalytic carbonyl-olefin metathesis reactions of aliphatic ketone substrates as stepwise oxetane fragmentation was previously only reported as a competing reaction pathway for aryl ketones.

Asymmetric Hydrogenation of Tetrasubstituted α,β-Unsaturated Ketones: Access to Chiral 2-Substituted Cyclopentyl Aryl Ketones

Asymmetric hydrogenation of tetrasubstituted alkenes is an important but challenging research topic. Herein, we report an efficient iridium-catalyzed asymmetric hydrogenation of tetrasubstituted α,β-unsaturated ketones for the synthesis of chiral 2-substituted cyclopentyl aryl ketones, an important chiral structural motif for the preparation of chiral pharmaceuticals and bioactive molecules. The reaction proceeded very well with good functional group compatibility and delivered the hydrogenated products in high yields and stereoselectivities (up to 99% yield, >20:1 dr and 99% ee). In addition, the reaction could be carried out on a gram-scale, and all four stereoisomers of the hydrogenated products bearing two contiguous stereocenters were obtained. Furthermore, the hydrogenated product can be transformed into the ERβ agonist Erteberel, and the reaction pathway was also studied via deuterium-labelling experiments.

Oxidative Cleavage of Csp3–Csp2 and Csp3–H Bonds with KOtBu: Highly Robust and Practical Synthesis of Diaryl/(het-Ar) Ketones

Herein, we report an efficient and practical approach for synthesizing diaryl(het) ketones from R-CO-CHR-Ar through a simultaneous oxidative cleavage of C-C and C-H bonds using KOtBu. This method enables synthesizing a variety of unsymmetrical and symmetrical (hetero)aryl ketones in excellent yields, which are otherwise difficult to make. Besides, we synthesized natural products using this method.

A Catalytic Method for the Enantioselective Synthesis of α-Quaternary Ketones, α-Ketoesters and Aldehydes.

A practical method for the efficient and enantioselective preparation of versatile ketones and aldehydes that contain an α-quaternary stereocenter is described. Reactions utilize simple carboxylic acid or ester starting materials, a monodentate chiral phosphine, and afford a variety of aryl, alkenyl, alkynyl, and alkyl-substituted ketone and aldehyde products in 25-94 % yield and 90 : 10 to >99 : 1 enantiomeric ratio. Reactions proceed by acyl substitution with in situ formed chiral allylic nucleophiles, and display selectivity and conversion dependence on a protic additive. The utility of the approach is demonstrated through several product transformations.

Highly Efficient Asymmetric Hydrogenation Catalyzed by Iridium Complexes with Tridentate Chiral Spiro Aminophosphine Ligands

ConspectusCatalytic asymmetric hydrogenation is one of the most reliable, powerful, and environmentally benign methods for the synthesis of chiral molecules with high atom economy and has been successfully applied in the industrial production of pharmaceuticals, agrochemicals, and fragrances. The key to achieving highly efficient and highly enantioselective hydrogenation reactions is the design and synthesis of chiral catalysts.Our recent studies involving iridium complexes of bidentate chiral spiro aminophosphine ligands (Ir-SpiroAP) have revealed that adding another coordinating group on the nitrogen atom to form a tridentate ligand can provide catalysts with markedly higher stability, enantioselectivity, and efficiency. Specifically, chiral Ir-SpiroAP catalysts bearing an added pyridine group (designated Ir-SpiroPAP) exhibit high activity and excellent enantioselectivity in the asymmetric hydrogenation of a wide range of carbonyl compounds, including aryl ketones, β- and δ-ketoesters, α,β-unsaturated ketones and esters, and racemic α-substituted lactones, as well as highly electron-deficient alkenes such as α,β-unsaturated malonates and analogues. The efficiency of the Ir-SpiroPAP catalysts is extremely high: in the hydrogenation of aryl ketones, turnover numbers reach 4.5 million, which is the highest value reported to date for a molecular catalyst. Moreover, when a thioether or a bulky triarylphosphine group is added to afford tridentate ligands designated SpiroSAP and SpiroPNP, respectively, the resulting iridium catalysts show high efficiency and enantioselectivity for asymmetric hydrogenation of β-alkyl-β-ketoesters and dialkyl ketones, which are challenging substrates. Furthermore, chiral spiro catalysts containing an added oxazoline moiety (Ir-SpiroOAP) show high enantioselectivity for asymmetric hydrogenation of α-keto amides and racemic α-aryloxy lactones. The above-described catalysts have been used for enantioselective synthesis of chiral pharmaceuticals and other bioactive compounds.We have shown that chiral spiro ligands that combine a rigid skeleton with tridentate coordination stabilize iridium catalysts. The careful tailoring of the substituents on the ligand creates a chiral environment around the active metal center of the catalyst that can precisely discriminate between the two faces of a substrate carbonyl group. These factors are key for controlling the activity, enantioselectivity, and turnover numbers of asymmetric hydrogenation catalysts. We expect that catalysts based on iridium, and other transition metals, coordinated by tridentate chiral ligands with a rigid skeleton will find more applications in asymmetric hydrogenation and other asymmetric transformations.

Synthesis, characterization, and DFT study of the s-triazine analogues of medicinal interest incorporated with five- and six-membered bioactive heterocyclic scaffolds

The present paper reports the synthesis, NMR study, and detailed computational investigation of various novel s-triazine analogues 9–12 of medicinal interest embellished with bioactive heterocyclic scaffolds such as isoxazole, pyrazole, and pyrimidine, linked to triazine backbone through an oxyphenyl spacer. The synthesis of 9–12 was performed by exploiting the synthetic potential of the chalcone 4 which resulted from the reaction of benzaldehyde and s-triazine bound aryl ketone derivative 3. The later was in turn obtained by the reaction of p-hydroxyacetophenone with 6‑chloro-2,4-dicyclopropylamino-1,3,5-triazine(2). This strategy allowed the s-triazine to act as a three-pronged stencil to embrace three bioactive motifs jointly in the same molecular framework in 9–12.Detailed density function theory (DFT) study corroborated the experimental findings. It was shown that the molecules of the synthesized compounds would be quite uncrowded and therefore would be packed quite loosely in the crystalline phase. The molecular orbital (MOs) analysis showed that all the synthesized compounds should have quite pronounced thermodynamic stability and thatthe modification of the substituting group would allow to finely tune the reactivity of the s-triazine derivatives. Also, possible formation of various noncovalent interactions between the molecules of the studied compounds within their crystals or between the molecules of these compounds with various polar solvents and biologically important molecules was suggested. Moreover, potential reactivity of these compounds towards various electrophiles and nucleophiles suggesting possibility of their successful employment for medical purposes was proposed. Further, the global reactivity parameters (GRP) analysis suggested that the compound studied would be quite stable in redox processes, with the pyridine derivatives showing higher stability.

Exceptionally Long Lifetimes of Strongly Entangled Acyl–Trityl Radical Pairs Photochemically Generated in Crystalline Trityl Ketones

Triplet acyl-alkyl radical pairs generated by pulsed laser excitation within the constraints of their nanocrystalline ketone precursors were recently introduced as a potential platform for the robust and repeated instantiation of spin qubit pairs for applications in quantum information science. Here, we report the transient spectroscopy of a series of nanocrystalline trityl-alkyl and trityl-aryl ketones capable of generating correlated triplet radical pairs with persistent triphenylmethyl radicals forced to remain within bonding distances of highly reactive acyl radicals. Whereas triplet trityl-acyl radical pairs decay by competing product-forming decarbonylation and intersystem crossing, triplet trityl-benzoyl radical pairs have lifetimes of up to ca. 4 ms and exclusively regenerate the starting ketone. We propose that these long lifetimes are the result of the short inter-radical distances and the colinear orientation of the two singly occupied orbitals, which are expected to result in large singlet-triplet energy gaps, large zero-field splitting parameters, and a poor geometry for spin-obit coupling. Ketones generating trityl-benzoyl radical pairs demonstrate promising performance along multiple dimensions that are crucial for quantum information science.

Visible light-mediated hydrogen atom transfer and proton transfer for the conversion of (2-vinylaryl)methanol derivatives to aryl aldehydes or aryl ketones

A visible-light-mediated strategy for the efficient conversion of (2-vinylaryl)methanol derivatives to aryl aldehydes or aryl ketones has been developed. The plausible reaction mechanism has been verified by a series of mechanistic studies.

Exploiting the reactivities ofortho-alkynyl aryl ketones: opportunities in designing catalytic annulation reactions

We provide a comprehensive overview of recent progress in this rapidly growing field by summarizing catalytic annulation reactions ofortho-alkynyl aryl ketones which involve carbo- andoxo-cyclization patterns with consideration of their mechanisms and applications.

Solvent-promoted photochemical carbonylation of benzylic C-H bonds under iron catalysis.

This paper describes the iron-catalyzed photochemical carbonylation of benzylic C-H bonds resulting in the synthesis of various aryl ketones. Using 5 W blue LED irradiation, the reactions proceed smoothly in the presence of 2 mol% of FeBr3 in MeOH at 35 °C. The catalytic system could be extended for the oxidation of silane, thioether, and phosphine into silenol, sulphoxide, and phosphoxide, respectively. A mechanistic study suggests that a hydrogen bond-stabilized iron-hydroperoxo species is the reactive intermediate. It is shown that the reaction proceeds via a four-electron-transfer pathway, and a benzylic cation seems to be the crucial reactive species. The method is applied for the synthesis of pomalyst, haloperidol, melperone, and lenperone.