Synthesis Of Ketones Research Articles

Mo@PANI-catalyzed oxidative deoximation reaction

Deoximation is an important transformation in synthetic industry. It can be employed in protection, characterization and purification of the carbonyls, and in the synthesis of ketones from non-carbonyl molecules. In the field, oxidative deoximation reaction can utilize the driving force caused by the oxidation process so that the reaction can occur under relatively mild conditions. Recently, we designed and prepared polyaniline-supported molybdenum (Mo@PANI) just by immersing PANI into the EtOH/H2O solution of MoCl5. The material was successfully applied as the efficient catalyst for oxidative deoximation reactions, which were performed in ethanol using H2O2 as the clean oxidant. The substrate scope of the reaction was wide. It could be applied on heterocycle-containing substrates, making this protocol preferable for pharmaceutical intermediate synthesis. Since Mo is a necessary trace element for both animals and plants, this method is environment-friendly and is suitable for large-scale preparation. This work as the first example of Mo-catalyzed oxidative deoximation reaction may inspire novel ideas for both catalyst design and synthetic process development.

Pyridinium-Masked Enol as a Precursor for Constructing Alpha-Fluoromethyl Ketones.

We present herein a pyridinium-masked enol as a versatile platform to produce ketones bearing tri-, di-, and monofluoromethyl in the presence of [Ir(dF(Me)ppy)]2(dtbbpy)]PF6 under blue light (455 nm) irradiation. By simply changing the F-source, α-trifluoromethyl ketones, α-difluoromethyl ketones, and α-monofluoromethyl ketones could be easily prepared in moderate to excellent yields in one step, making it a practical tool for the synthesis of fluorine-containing ketones. In addition, the pyridinium-masked enol could also be extended to the synthesis of sulfonyl ketones. The findings of the present protocol contribute to the arsenal of fluorine chemistry and might have potential applications in the pharmaceutical and agrochemical industries.

Oxidative Deprotection of Benzyl Protecting Groups for Alcohols by an Electronically Tuned Nitroxyl-Radical Catalyst.

The oxidative deprotection of benzyl (Bn) groups using nitroxyl-radical catalyst 1 and co-oxidant phenyl iodonium bis(trifluoroacetate) (PIFA) is reported. This catalyst is highly active for the oxidation of benzylic ethers because of the electronic tuning on account of the electron-withdrawing ester groups next to the catalytically active center. This catalytic system promotes deprotections at ambient temperature and has a broad substrate scope, including substrates possessing hydrogenation-sensitive functional groups, while the deprotection hardly proceeds when using well-known nitroxyl-radical catalysts such as 2,2,6,6-tetramethylpiperidine N-oxyl (TEMPO). The 1/PIFA system also promotes the deprotection of several benzylic protecting groups, including 2-naphthylmethyl (NAP) and 4-methylbenzyl (MBn) groups. Catalyst 1 was also effective for the direct synthesis of ketones and aldehydes from Bn ethers via deprotected alcohols using an excess of the co-oxidant PIFA.

From Carboxylic Acid Derivatives to Ketones: Modular Ketone Synthesis via Catalytic Olefination

From Carboxylic Acid Derivatives to Ketones: Modular Ketone Synthesis via Catalytic Olefination

Ni/Al2O3: Catalyzed Carbonylative Homocoupling of Aryl Iodides for the Synthesis of Symmetrical Diaryl Ketone Using Co2(CO)8 as CO Surrogate

Ni/Al2O3: Catalyzed Carbonylative Homocoupling of Aryl Iodides for the Synthesis of Symmetrical Diaryl Ketone Using Co2(CO)8 as CO Surrogate

Access to Trifluoromethylketones from Alkyl Bromides and Trifluoroacetic Anhydride by Photocatalysis

AbstractAliphatic trifluoromethyl ketones are a type of unique fluorine‐containing subunit which play a significant role in altering the physical and biological properties of molecules. Catalytic methods to provide direct access to aliphatic trifluoromethyl ketones are highly desirable yet remain underdeveloped, partially owing to the high reactivity and instability of trifluoroacetyl radical. Herein, we report a photocatalytic synthesis of trifluoromethyl ketones from alkyl bromides with trifluoroacetic anhydride. The reaction features dual visible‐light and halogen‐atom‐transfer catalysis, followed by an enabling radical‐radical cross‐coupling of an alkyl radical with a stabilized trifluoromethyl radical. The reaction provides straightforward access to aliphatic trifluoromethyl ketones from readily available and cost‐effective alkyl halides and trifluoroacetic anhydride (TFAA).

Access to Trifluoromethylketones from Alkyl Bromides and Trifluoroacetic Anhydride by Photocatalysis.

Aliphatic trifluoromethyl ketones are a type of unique fluorine-containing subunit which plays a significant role in altering the physical and biological properties of molecules. However, catalytic methods to provide direct access to aliphatic trifluoromethyl ketones is highly desirable yet remains underdeveloped, partially due to the high reactivity and instability of trifluoroacetyl radical. Herein, we report a photocatalytic synthesis of trifluoromethyl ketones from alkyl bromides with trifluoroacetic anhydride. The reaction features a dual catalysis of visible-light and XAT reaction, followed by an enabling radical-radical cross-coupling of alkyl radical with a stabilized trifluoromethyl radical. The reaction provides the first straightforward access to aliphatic trifluoromethyl ketones from easily-available and cost-effective alkyl halides and TFAA.

Rhodium-Catalyzed Alkylation of Aromatic Ketones with Allylic Alcohols and α,β-Unsaturated Ketones

The direct transition-metal-catalyzed addition of C–H bonds to unsaturated C=X (X=C, O, and N) bonds via C–H bond activation has been recognized as a powerful tool for the construction of C–C bonds (in terms of atom and step economy). Herein, the direct rhodium-catalyzed C–H bond addition of aromatic ketones to allylic alcohols and α,β-unsaturated ketones that affords β-aryl carbonyl compounds is described, in which a ketone carbonyl acts as a weakly coordinating directing group. It was found that the type of alkyl in aromatic ketones is crucial for the success of the reaction. This transformation provides a convenient and efficient methodology for the synthesis of 2-alkyl aromatic ketones in moderate-to-excellent yields.

Hijacking a P450 for ketone synthesis

Hijacking a P450 for ketone synthesis

Blue‐LED Synthesis of Pummerer's Ketones by Peroxidase‐Lignin‐Catalyzed Oxidative Coupling of Substituted Phenols

AbstractPummerer's ketones resembling the tricyclic scaffold of bioactive natural substances were synthesized by blue‐LED driven Horseradish Peroxidase oxidative coupling of substituted phenols in 2‐methyltetrahydrofuran by using meso‐tetraphenylporphyrin as photosensitizer and dioxygen as primary oxidant. The application of functionalized lignin nanoparticles as a renewable and efficient platform for the immobilization of the enzyme extended the effectiveness of the overall process to heterogeneous catalysis under buffer limiting conditions.

Unsymmetrical Ketone Synthesis via Selective Nickel-Catalyzed Reductive Carbonylation

Unsymmetrical Ketone Synthesis via Selective Nickel-Catalyzed Reductive Carbonylation

Nickel-Catalyzed Directed Cross-Electrophile Coupling of Phenolic Esters with Arylmethyl Trimethylammonium Triflates.

In this context, we successfully utilize polycyclic aryl-activated alkyl ammonium triflates as the electrophilic aryl-activated alkylating agent in the nickel-catalyzed hydroxyl- or sulfonamide-directed cross-electrophile coupling reaction with an array of phenyl benzoates, allowing for the synthesis of various aryl ketones under mild conditions.

Ketones from aldehydes via alkyl C(sp3)−H functionalization under photoredox cooperative NHC/palladium catalysis

Direct synthesis of ketones from aldehydes features high atom- and step-economy. Yet, the coupling of aldehydes with unactivated alkyl C(sp3)-H remains challenging. Herein, we develop the synthesis of ketones from aldehydes via alkyl C(sp3)-H functionalization under photoredox cooperative NHC/Pd catalysis. The two-component reaction of iodomethylsilyl alkyl ether with aldehydes gave a variety of β-, γ- and δ-silyloxylketones via 1,n-HAT (n = 5, 6, 7) of silylmethyl radicals to generate secondary or tertiary alkyl radicals and following coupling with ketyl radicals from aldehydes under photoredox NHC catalysis. The three-component reaction with the addition of styrenes gave the corresponding ε-hydroxylketones via the generation of benzylic radicals by the addition of alkyl radicals to styrenes and following coupling with ketyl radicals. This work demonstrates the generation of ketyl radical and alkyl radical under the photoredox cooperative NHC/Pd catalysis, and provides two and three component reactions for the synthesis of ketones from aldehydes with alkyl C(sp3)-H functionalization. The synthetic potential of this protocol was also further illustrated by the late-stage functionalization of natural products.

Rhodium(I)-Catalyzed Enantioselective Ring-Opening and Isomerization of Cyclobutanols through a (Z)-Unsaturated Ketone Intermediate.

A rhodium(I)-catalyzed highly enantioselective ring-opening and isomerization of cyclobutanols has been developed. The reaction provides a mild, atom-economical, and redox-neutral approach for the synthesis of chiral acyclic ketones bearing a β-tertiary stereocenter. Excellent enantioselectivities and high yields can be achieved using cyclobutanols with alkoxy substituents at the C3 position. Mechanistic studies reveal that cyclobutanol only undergoes intramolecular hydrogen migration, and the formation of a (Z)-unsaturated ketone intermediate is crucial for achieving high enantioselectivity.

Engineered cytochrome P450 for direct arylalkene-to-ketone oxidation via highly reactive carbocation intermediates

Ketones are crucial intermediates in synthesis and frequent moieties in many products. The direct regioselective synthesis of ketones from internal alkenes could simplify synthetic routes and solve a long-standing challenge in catalysis. Here we report the laboratory evolution of a cytochrome P450 enzyme for the direct oxidation of internal arylalkenes to ketones with several thousand turnovers. This evolved ketone synthase benefits from 15 crucial mutations, most of them distal to the active site. Computational analysis revealed that all these mutations collaborate to generate and tame a highly reactive carbocation intermediate. This is achieved through a confined, rigid, and geometrically and electrostatically preorganized active site. The engineered enzyme exploits a metal–oxo species for ketone synthesis and enables various challenging alkene functionalization reactions. This includes the catalytic, enantioselective oxidation of internal alkenes to ketones and formal asymmetric hydrofunctionalizations of internal alkenes in combination with other biocatalysts.

Photoinduced Electron Transfer from Xanthates to Acyl Azoliums: Divergent Ketone Synthesis via N-Heterocyclic Carbene Catalysis.

Considering the prevalence of alcohols and carboxylic acids, their fragment cross-coupling reactions could hold significant implications in organic synthesis. Herein, we report a versatile method for synthesizing a diverse range of ketones from alcohols and carboxylic acid derivatives via N-heterocyclic carbene (NHC) catalysis. Mechanistic investigations revealed that photoexcited xanthates and acyl azoliums undergo single electron transfer (SET) under photocatalyst-free conditions, generating NHC-derived ketyl radicals and alkyl radicals. These open-shell intermediates subsequently undergo the radical-radical cross-coupling reaction, yielding valuable ketones. Furthermore, this approach can be employed in three-component reactions involving alkenes and enynes, resulting in structurally diverse cross-coupled ketones. The unified strategy offers a unique opportunity for the fragment coupling of a diverse range of alcohols and carboxylic acid derivatives, accommodating diverse functional groups even in complex settings.

Photoinduced Electron Transfer from Xanthates to Acyl Azoliums: Divergent Ketone Synthesis via N‐Heterocyclic Carbene Catalysis

AbstractConsidering the prevalence of alcohols and carboxylic acids, their fragment cross‐coupling reactions could hold significant implications in organic synthesis. Herein, we report a versatile method for synthesizing a diverse range of ketones from alcohols and carboxylic acid derivatives via N‐heterocyclic carbene (NHC) catalysis. Mechanistic investigations revealed that photoexcited xanthates and acyl azoliums undergo single electron transfer (SET) under photocatalyst‐free conditions, generating NHC‐derived ketyl radicals and alkyl radicals. These open‐shell intermediates subsequently undergo the radical‐radical cross‐coupling reaction, yielding valuable ketones. Furthermore, this approach can be employed in three‐component reactions involving alkenes and enynes, resulting in structurally diverse cross‐coupled ketones. The unified strategy offers a unique opportunity for the fragment coupling of a diverse range of alcohols and carboxylic acid derivatives, accommodating diverse functional groups even in complex settings.

Ti-Catalyzed Modular Ketone Synthesis from Carboxylic Derivatives and gem-Dihaloalkanes.

Ketones are ubiquitous in organic synthesis. However, the general method to convert widely available carboxylic acids, unactivated esters, and amides into ketones remains elusive. Herein, we describe the Ti-catalyzed modular ketone synthesis from carboxylic derivatives and easily accessed gem-dihaloalkanes. Notably, this protocol could achieve the direct catalytic olefination of carboxylic acids. This method features a sequence of olefination and electrophilic transformation and good functional group compatibility and allows rapid access to various functionalized ketones. Preliminary mechanistic studies provide insights into the reaction pathway and support the intermediacy of plausible alkylidene titanocene and gem-bimetallic complexes.

N-Difluoromethylthiophthalimide Reagents for Modular Synthesis of Diversified α-Difluoromethylthiolated Ketones.

The compounds featuring α-difluorothiomethylated ketone skeleton derivatives are of particular interest in pharmaceuticals and agrochemicals. Herein, we designed novel electrophilic N-difluoromethylthiophthalimide reagents that can be easily prepared with commercially available and economical chemicals. These reagents could smoothly react with various nucleophiles, such as Grignard reagents, boronic acids, β-keto esters, and anilines, which affords structurally diverse α-difluoromethylthiolated ketones in good to excellent yields. The formal synthesis of active antifungal compounds positively confirmed the practicability of these reagents.

#3665 DCR2 PROMOTES TUBULAR MALADAPTIVE REPAIR BY INHIBITING KETONE BODY–INDUCED FOXO3 SIGNALING AFTER ACUTE KIDNEY INJURY

Abstract Background and Aims The proximal tubule has a capacity for repair after acute kidney injury (AKI), but this capacity is limited, especially in severe AKI. Tubular maladaptive repair after AKI leads to chronic kidney disease (CKD), even to end-stage renal disease (ESRD). However, the mechanism of maladaptive repair is not fully clarified, and there is a lack of effective treatment for AKI in clinic. Our previous study found that decoy receptor 2 (DcR2), a trans-membrane receptor of tumor necrosis factor-related apoptosis inducing ligand (TRAIL), was specifically expressed renal tubules and did not have the ability of proliferation in AKI, suggesting DcR2 may be associated with maladaptive repair of tubular cells. This study aims to investigate the role and mechanism of DcR2-positive tubular cells in the repair of AKI. Method The DcR2-GFP lineage trace mice,KSP-creDcR2f/f mice (Distal tubular DcR2 Conditional Knockout CKO) mice and GGT1-creDcR2f/f (proximal tubular DcR2 Conditional Knockout CKO) mice were constructed, and three AKI mouse models (moderate and severe ischemia-reperfusion injury and cisplatin-induced AKI) were conducted. Light microscopic examination of paraffin-embedded sections stained with haematoxylin and eosin, periodic acid–Schiff stain and Masson stain. Confocal analysis the co-expression of DcR2-GFP and proximal tubular markers(AQP1, Villin), distal markers (AQP2), failed repair markers (Vcam1, Dcdc2), proliferative markers (Ki-67, Edu, PCNA), Kim1, differentiated markers (pax2, sox9, six2), senescent markers (P16, P21, SA-β-gal), senescent phenotype (IL-6, TGF-β1) and fibrotic markers (a-SMA, collagen I, Fibronectin). And wild type (WT) mice and DcR2 CKO mice were used to compare the degree of kidney injury, renal function and tubular repair after AKI. Furthermore, quantitative proteomics and bioinformatics analyzed the downstream molecules of DcR2 in renal tissues from WT-AKI and CKO-AKI, and validated studied were done. Results In this study, we found decoy receptor DcR2 was highly expressed in renal tubules and associated with kidney damage in AKI patients and mouse models. DcR2-GFP transgenic mice verified that DcR2 was specifically expressed in proximal tubular epithelial cells (PTECs) after AKI. The levels of Scr, BUN and urinary DcR2 and renal acute and chronic injury scores were significantly lower inGGT1-creDcR2f/f -AKI than that of WT-AKI. Meanwhile, the proliferative markers, senescent markers and area of renal fibrosis and fibrotic markers expression was decreased inGGT1-creDcR2f/f mice compared with WT. However, the above effects were not obviously improved in KSP-creDcR2f/f mice after AKI. These results suggested that proximal tubular DcR2 knockout alleviated kidney injury and promote tubular repair after AKI. Consistent with findings in vivo, DcR2 promoted cell senescence and inhibited cell proliferation in hypoxia-reoxygenation and cisplatin-treated primary PTECs. Further quantitative proteomics and validated studies showed Hmgcs2, a key enzyme for ketone synthesis, was increased in GGT1-creDcR2f/f mice compared with WT. And the levels of urinary and renal β-hydroxybutyrate (β-OHB) were higher inGGT1-creDcR2f/f mice, suggesting DcR2 affects the synthesis of β-hydroxybutyrate through regulating the expression of Hmgcs2. Inhibition or deletion of Hmgcs2 aggravated kidney damage and repressed renal repair, but administration with β-OHB rescued these phenomena. Subsequently, PTEC-specific DcR2/Hmgcs2 double deletion decreased β-OHB levels, which inhibited FOXO3 signaling by regulating histone acetylation, thereby boosting tubular maladaptive repair after AKI. Conclusion DcR2 promotes maladaptive repair of tubular cells by regulating Hmgcs2-induced β-OHB production, and β-OHB affects FOXO3 signaling by regulating histone acetylation. The findings suggests that DcR2/Hmgcs2/ketogenesis/FOXO3 signaling mediates tubular maladaptive repair, and DcR2 could serve as a promising target for improving renal repair and AKI prognosis.