Transformations of Aryl Ketones via Ligand-Promoted C−C Bond Activation

The coupling of aromatic electrophiles (aryl halides, aryl ethers, aryl acids, aryl nitriles etc.) with nucleophiles is a core methodology for the synthesis of aryl compounds. Transformations of aryl ketones in an analogous manner via carbon–carbon bond activation could greatly expand the toolbox for the synthesis of aryl compounds due to the abundance of aryl ketones. An exploratory study of this approach is typically based on carbon–carbon cleavage triggered by ring-strain release and chelation assistance, and the products are also limited to a specific structural motif. Here we report a ligand-promoted β-carbon elimination strategy to activate the carbon–carbon bonds, which results in a range of transformations of aryl ketones, leading to useful aryl borates, and also to biaryls, aryl nitriles, and aryl alkenes. The use of a pyridine-oxazoline ligand is crucial for this catalytic transformation. A gram-scale borylation reaction of an aryl ketone via a simple one-pot operation is reported. The potential utility of this strategy is also demonstrated by the late-stage diversification of drug molecules probenecid, adapalene, and desoxyestrone, the fragrance tonalid as well as the natural product apocynin.     

Iron powder and tin/tin chloride as new reducing agents of Meerwein arylation reaction with unexpected recycling to anilines

Abstract

Simple and rapid route for Meerwein arylation reaction using iron powder or a mixture of tin/tin chloride has been developed. In the presence of iron powder, different aryl diazonium salts reacted with methyl vinyl ketone, acrylates, and isopropenyl acetate. Production of oximes was detected as the main product with acrylates or in a mixture with β-aryl methyl ketones in the case of methyl vinyl ketone. The in situ produced HNO₂ from an excess of NaNO₂/HCl was trapped by alkyl aryl radical to form oximes in the E configuration form. The presence of tin/tin chloride mixture in the reaction of the aryl diazonium salts with methyl vinyl ketone produced Michael products along with β-aryl methyl ketones. The predicted α-aryl methyl ketones from the reaction of isopropenyl acetate with the diazotized anilines were obtained using iron or tin/tin chloride mixture.     

Transformations of Aryl Ketones via Ligand‐Promoted C−C Bond Activation

The coupling of aromatic electrophiles (aryl halides, aryl ethers, aryl acids, aryl nitriles etc.) with nucleophiles is a core methodology for the synthesis of aryl compounds. Transformations of aryl ketones in an analogous manner via carbon–carbon bond activation could greatly expand the toolbox for the synthesis of aryl compounds due to the abundance of aryl ketones. An exploratory study of this approach is typically based on carbon–carbon cleavage triggered by ring‐strain release and chelation assistance, and the products are also limited to a specific structural motif. Here we report a ligand‐promoted β‐carbon elimination strategy to activate the carbon–carbon bonds, which results in a range of transformations of aryl ketones, leading to useful aryl borates, and also to biaryls, aryl nitriles, and aryl alkenes. The use of a pyridine‐oxazoline ligand is crucial for this catalytic transformation. A gram‐scale borylation reaction of an aryl ketone via a simple one‐pot operation is reported. The potential utility of this strategy is also demonstrated by the late‐stage diversification of drug molecules probenecid, adapalene, and desoxyestrone, the fragrance tonalid as well as the natural product apocynin.     

Highly efficient metal-free one-pot synthesis of α-aminophosphonates through reduction followed by Kabachnik–fields reaction using three-component system

One-pot synthesis of α-aminophosphonates directly from aryl nitro compounds, aldehydes/ketones, and diethyl phosphite using sodium dithionite through reduction and followed by Kabachnik–Fields reaction under metal-free conditions is reported. The major advantages are excellent yield, high chemoselectivity, neutral reaction medium, and simple experimental procedure. This methodology consists of the following steps: 1) amine formation from nitro compound, 2) imine formation from amine and aldehyde/ketone, 3) phosphate addition to imine.     

Copper‐Mediated Trifluoroacetylation of Arenediazonium Salts with Ethyl Trifluoropyruvate

A copper‐mediated trifluoroacetylation of various arenediazonium salts with ethyl trifluoropyruvate is reported. The reaction proceeded smoothly under mild conditions at room temperature giving trifluoromethyl aryl ketones in moderate to good yields. A variety of functional groups, including methoxy, hydroxy, ester, ketone, trifluoromethyl, and halide groups, were well tolerated. A possible reaction mechanism involving an aryl radical intermediate was proposed and supported by experimental evidence. This reaction provides a new route to trifluoromethyl aryl ketones, notable synthetic targets, from the corresponding anilines.     

Transition metal salt-catalyzed direct three-component mannich reactions of aldehydes, ketones, and carbamates: efficient synthesis of N-protected beta-aryl-beta-amino ketone compounds

The transition metal salt-catalyzed direct three-component Mannich reactions of aryl aldehydes, aryl ketones, and carbamates are described. The RuCl(3).xH(2)O-, AuCl(3)-PPh(3)-, and AuCl(3)-catalyzed direct Mannich reactions led to the synthesis of N-protected beta-aryl-beta-amino ketones, and the results create new possibilities for exploiting the transition metal salt-catalyzed direct Mannich reaction and facile synthesis of beta-amino ketone libraries.     

Transition metal-catalyzed conversion of aldehydes to ketones

Ketones are one of the most important classes of organic compounds, and widely present in various pharmacological compounds, biologically active molecules and functional materials. Over the past few decades, transition metal-catalyzed conversion of aldehydes has been found to be a powerful method. With the continuous development in recent years, it has become an efficient and uncomplicated strategy for constructing ketones. There are four major mechanisms for transition metal-catalyzed ketone synthesis from aldehyde: (1) carbonyl-Heck reaction, that is 1,2-insertion of organometal species to aldehydic C=O double bond, (2) direct insertion of transition metal catalysts to aldehydic C-H bond, (3) aldehyde as acyl radical, (4) aldehyde as carbon radical acceptor. This article summarizes related reports on the transformations of aldehydes to generate corresponding ketones under different reaction conditions.     

Dual-activation protocol for tandem cross-aldol condensation: An easy and highly efficient synthesis of α,α′-bis(aryl/alkylmethylidene)ketones

Commercially available lithium hydroxide monohydrate (LiOH·H₂O) was found to be a novel ‘dual activation’ catalyst for tandem cross-aldol condensation between cyclic/acyclic ketones and aromatic/heteroaromatic/styryl/alkyl aldehydes leading to an efficient and easy synthesis of α,α′-bis(aryl/alkylmethylidene)ketones at r.t. in short times. The reaction of aryl, heteroaryl, styryl and alkyl aldehydes with acyclic and five/six-membered cyclic ketones afforded excellent yields after 2 min to 1.25 h. The reaction conditions were compatible with various electron withdrawing and electron donating substituents, e.g. Cl, F, NO₂, OMe and NMe₂. The rate of the cross-aldol condensation was influenced by the nature of the ketone and electronic and steric factors associated with the aldehyde. The reaction took place at a faster rate for acyclic ketone (e.g., acetone) than that for cyclic ketone (e.g., cyclohexanone). In case of cycloalkanones, the rate of the reaction was dependent on the size of the ring of the cycloalkanone. The cross-aldol condensation of cyclopentanone was faster than that of cyclohexanone for a common aldehyde. In case of reactions involving aliphatic aldehyde having α-hydrogen atom no self-aldol condensation of the aldehyde took place.     

3+2] cycloadditions of aryl cyclopropyl ketones by visible light photocatalysis

We report a new method for the formal [3+2] reaction of aryl cyclopropyl ketones with olefins to generate highly substituted cyclopentane ring systems. The key initiation step in this process is the one-electron reduction of the ketone to the corresponding radical anion, which is accomplished using a photocatalytic system comprising Ru(bpy)(3)(2+), La(OTf)(3), and TMEDA.     

钒取代的杂多酸催化一锅四组分Dakin-West反应合成β-乙酰氨基酮(英文)

The multicomponent condensation of an aryl aldehyde,acetyl chloride,acetonitrile,and enolizable ketone as one-pot synthesis of β-acetamido ketones in high yields was investigated using commercial,non-corrosive,and environmentally benign Keggin and Wells-Dawson heteropolyacid catalysts.The best catalyst was H5PW10V2O40.The methodology used simple experimental conditions,and the short reaction times and high yields indicate it is a useful strategy for the large scale synthesis of β-acetamido ketones.     

Reactivities of dianions of pyridyl phenyl ketones

Substituted pyridylphenylcarbinols are formed in the reaction of the dianions of isomeric pyridyl phenyl ketones with alkyl halides, aldehydes, and benzonitrile. The reaction of the dianion of 3-pyridyl phenyl ketone with benzophenone, in contrast to the analogous reaction of the dianion of 2-pyridyl phenyl ketone, gives 5-benzoyl-2-diphenylhydroxymethyl-1,2-dihydropyridine. It is assumed that the observed reaction includes one-electron transfer and the formation of two anion radicals. Recombination of the anion radical of 3-pyridyl phenyl ketone leads to 5,5′-dibenzoyl-2,2′-di(1,2-dihydropyridyl).     

Gold‐Catalyzed Oxidation/C−H Functionalization of Ynones: Efficient and Rapid Access to Functionalized Polycyclic Salicyl Ketones

An efficient strategy to construct salicyl ketones through gold‐catalyzed oxidation/C?H functionalization of ynones is reported. A variety of functionalized salicyl ketones are readily accessed by utilizing this non‐diazo approach, thus providing a viable alternative to synthetically useful salicyl ketones with a yield up to 98 %. The α‐oxo gold carbenes generated in situ through gold‐catalyzed oxidation of ynones can be trapped effectively by internal aryl and heteroaromatic groups. Electronic and steric effects were also investigated in this reaction. The anticancer activity of one salicyl ketone analogue was investigated and its cytotoxicity assays against the PC‐3 prostate cancer cell line and SKOV‐3 human ovarian carcinoma cell line yield IC₅₀ were 0.81±0.05 and 0.87±0.15 μm , respectively, demonstrating that salicyl ketone analogues showed good anticancer activity.     

Palladium-catalyzed oxidative coupling of trialkylamines with aryl iodides leading to alkyl aryl ketones

A new, simple method for selectively synthesizing alkyl aryl ketones has been developed by palladium-catalyzed oxidative coupling of trialkylamines with aryl iodides. In the presence of PdCl(2)(MeCN)(2), TBAB, and ZnO, a variety of aryl iodides underwent an oxidative coupling reaction with tertiary amines and water to afford the corresponding alkyl aryl ketones in moderate to excellent yields. It is noteworthy that this method is the first example of using trialkylamines as the carbonyl sources for constructing alkyl aryl ketone skeletons.     

Well-defined,air-stable (NHC)Pd(Allyl)Cl (NHC = N-heterocyclic carbene) catalysts for the arylation of ketones

A number of palladium-N-heterocyclic carbene (NHC) complexes were found to be active catalysts for the arylation of ketones. A large number of substrates, both aryl halides and ketones, are compatible with the reaction conditions. The ketone arylation reactions are achieved with low catalyst loading in short reaction times using aryl chlorides and triflates as reactive partners. [reaction: see text]     

A novel and efficient direct aldol condensation from ketones and aromatic aldehydes catalyzed by proline-TEA through a new pathway

A novel and efficient direct aldol condensation from various ketones and a wide range of aldehydes was catalyzed by l-proline-TEA (triethylamine) in MeOH at room temperature, affording the corresponding (E)-α,β-unsaturated ketones in excellent yields. By using the method, some complicated (E)-α,β-unsaturated ketone C-glycosides were obtained from unmodified ketone C-glycosides and aldehydes. This reaction proceeds through a new pathway, in which the specific intermediate was captured and identified.     

Fe(OTf)3‐Catalyzed α‐Benzylation of Aryl Methyl Ketones with Electrophilic Secondary and Aryl Alcohols

Acid‐catalyzed Friedel–Crafts alkylation of 1,3‐dicarbonyl compounds with electrophilic alcohols, is known to be an effective C? C bond forming reaction. However, until now, this reaction has not been amenable for α‐alkylation of aryl methyl ketones because of the notoriously low nucleophilicities of these compounds. Therefore, α‐alkylation of aryl methyl ketone relies on precious metal catalysts and also, the use of primary alcohols is mandatory. In this study, we found that a system composed of a Fe(OTf)₃ catalyst and chlorobenzene solvent is sufficient to promote the title Friedel–Crafts reaction by using benzhydrols as electrophiles. 3,4‐Dihydro‐9‐(2‐hydroxy‐4,4‐dimethyl‐6‐oxo‐1‐cyclohexen‐1‐yl)‐3,3‐dimethyl‐xanthen‐1(2 H)‐one was also applicable as an electrophile in this type of benzylation reaction. On the basis of this result, a three‐component reaction of salicylaldehyde, dimedone, and aryl methyl ketone was also developed, and this provided an efficient way for the synthesis of densely substituted 4H‐chromene derivatives.     

Sulfur nitride in organic chemistry. 9. The reaction of tetrasulfur tetranitride with benzyl ketones. Preparation of 3,4-disubstituted-1,2,5-thiadiazoles

The reaction of tetrasulfur tetranitride ( 1 ) with various aryl and alkyl benzyl ketones ( 2a-o ), oxindole ( 11 ), benzyl α-pyridyl ketone ( 12 ) and α-phenacylpyridine ( 13 ) afforded the corresponding 1,2,5-thiadiazoles ( 3a-n, 11 and 14 ). The scope and limitations of the above reaction were investigated and the evidences suggesting the radical anion mechanism are presented.     

Development of new synthetic methods with aryl 1-chlorovinyl sulfoxides

Aryl 1-chlorovinyl sulfoxides were easily synthesized from ketones and aldehydes with aryl chloromethyl sulfoxide in three-steps with high overall yields. Low-temperature treatment of the aryl 1-chlorovinyl sulfoxides with alkyllithium or a Grignard reagent gave alkylidene carbenoids via a sulfoxide-metal exchange reaction. From the alkylidene carbenoids, acetylenic compounds, tetra-substituted olefins, and allenes were synthesized. Enolization of alpha-chloro alpha-sulfinyl ketones, which were synthesized from methyl esters and chloromethyl phenyl sulfoxide, is another method for the generation of aryl 1-chloroalkyl sulfoxides. Treatment of 1-chlorovinyl phenyl sulfoxides so generated with t-BuLi followed by some nucleophiles having an acidic hydrogen gave one-carbon elongated carboxylic acids and their derivatives. Conjugate addition of some carbanions with 1-chlorovinyl p-tolyl sulfoxides was found to have taken place. For example, reaction of 1-chlorovinyl p-tolyl sulfoxides with cyanomethyllithium gave high yields of cyclic enaminonitriles. Acidic treatment of the enaminonitriles afforded good yields of 4,4-disubstituted 2-cyclopentenones. By using unsymmetrical ketones and optically pure chloromethyl p-tolyl sulfoxide, this procedure suggests a good method for an asymmetric synthesis of optically pure 4,4-disubstituted 2-cyclopentenones. This method achieved an asymmetric total synthesis of (+)-alpha-cuparenone starting from methyl 4-methylphenyl ketone and (R)-(-)-chloromethyl p-tolyl sulfoxide. A novel synthesis of 2,4,4-trisubstituted 2-cyclopentenones is also successful using cyanomethyllithium and its homologues. Conjugate addition of the lithium enolate of tert-butyl acetate and its homologues gave high yields of the adduct, 3,3-disubstituted esters. Synthesis of various kinds of carboxylic acids and their derivatives and lactones was realized from the adducts.     

Direct asymmetric aldol reaction of aryl ketones with aryl aldehydes catalyzed by chiral BINOL-derived zincate catalyst

Direct asymmetric aldol reaction of aryl ketones with aryl aldehydes catalyzed by chiral metal complex is reported for the first time herein. Two novel semicrown chiral ligands 1a and 1b were synthesized from (S)- and (R)-BINOL, respectively, and then employed to catalyze the direct asymmetric aldol addition of aryl ketones to aryl aldehydes. Introduced with 2.0 equiv of diethylzinc, 1b had higher enantioselectivity than 1a. Up to 97% yield and up to 80% enantioselectivity were achieved.     

Synthesis and some reactions of aryl 4,5-dichloroisothiazol-3-yl ketones

By acylation of benzene, toluene, and p-xylene with 4,5-dichloroisothiazole-3-carbonyl chloride the corresponding aryl 4,5-dichloroisothiazol-3-yl ketones were obtained. By reaction of 4,5-dichloroisothiasol-3-yl 4-methylphenyl ketone with piperidine, alkyl(aryl) thiolates, sodium alcoholates, and 2,4-dinitrophenylhydrazine were synthesized 4-methylphenyl 5-piperidyl-4-chloroisothiazol-3-yl ketone, 5-alkyl(aryl)sulfanyl-4-chloroisothiazol-3-yl 4-methylphenyl ketones, 5-alkoxy-4-chloroisothiazol-3-yl 4-methylphenyl ketones, and 2,4-dinitrophenylhydrazone of the initial ketone respectively.