Palladium-catalyzed amidation–hydrolysis reaction of gem-dihaloolefins: efficient synthesis of homologated carboxamides from ketones

Ye, Wenchao; Mo, Jun; Zhao, Tiankun; Xu, Bin

doi:10.1039/b904991f

Cited by 44 publications

(15 citation statements)

References 53 publications

(7 reference statements)

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“…Carboxylic acids 1 and amines 2 (or their hydrochlorides) were provided by Enamine Ltd.; the gem-difluorinated representatives of the series can be also prepared according to the published procedures. [56][57][58][59] Amides 3.3-, [60] 3.5-, [61] and 3.6- [62] were obtained from the corresponding acyl chlorides and aniline according to the published procedures. All other starting materials were available from Enamine Ltd. or purchased from other commercial sources.…”

Section: Methodsmentioning

confidence: 99%

Effect of gem‐Difluorination on the Key Physicochemical Properties Relevant to Medicinal Chemistry: The Case of Functionalized Cycloalkanes

Holovach

Melnykov

Skreminskiy

et al. 2022

Chemistry A European J

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Physico‐chemical properties important to drug discovery (pKa, LogP, and aqueous solubility), as well as metabolic stability, were studied for a series of functionalized gem‐difluorinated cycloalkanes and compared to those of non‐fluorinated and acyclic counterparts to evaluate the impact of the fluorination. It was found that the influence of the CF2 moiety on the acidity/basicity of the corresponding carboxylic acids and amines was defined by inductive the effect of the fluorine atoms and was nearly the same for acyclic and cyclic aliphatic compounds. Lipophilicity and aqueous solubility followed more complex trends and were affected by the position of the fluorine atoms, ring size, and even the nature of the functional group present; also, significant differences were found for the acyclic and cyclic series. Also, gem‐difluorination either did not affect or slightly improved the metabolic stability of the corresponding model derivatives. The presented results can be used as a guide for rational drug design employing fluorine and establish the first chapter in a catalog of the key in vitro properties of fluorinated cycloalkanes.

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Section: Methodsmentioning

confidence: 99%

Effect of gem‐Difluorination on the Key Physicochemical Properties Relevant to Medicinal Chemistry: The Case of Functionalized Cycloalkanes

Holovach

Melnykov

Skreminskiy

et al. 2022

Chemistry A European J

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“…Other general procedures for amide synthesis include the Beckman rearrangement, [6] Staudinger ligations, [7] oxidative amidation of aldehydes, [8] coupling of aketoacids and hydroxylamines, [9] and amidation of ketones and thioacids with azides. [10] More recently, a number catalytic procedures have been developed including amidationhydrolysis of gem-dihaloolefins, [11] redox rearrangement of a-functionalized aldehydes, [12] and aminocarbonylation of aryl halides and terminal alkynes. [13] Abstract: The direct synthesis of amides from alcohols and amines is described with the simultaneous liberation of dihydrogen.…”

Section: Introductionmentioning

confidence: 99%

Amide Synthesis from Alcohols and Amines Catalyzed by Ruthenium N‐Heterocyclic Carbene Complexes

Dam

Osztrovszky

Nordstrøm

et al. 2010

Chemistry A European J

176

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The direct synthesis of amides from alcohols and amines is described with the simultaneous liberation of dihydrogen. The reaction does not require any stoichiometric additives or hydrogen acceptors and is catalyzed by ruthenium N-heterocyclic carbene complexes. Three different catalyst systems are presented that all employ 1,3-diisopropylimidazol-2-ylidene (IiPr) as the carbene ligand. In addition, potassium tert-butoxide and a tricycloalkylphosphine are required for the amidation to proceed. In the first system, the active catalyst is generated in situ from [RuCl(2)(cod)] (cod=1,5-cyclooctadiene), 1,3-diisopropylimidazolium chloride, tricyclopentylphosphonium tetrafluoroborate, and base. The second system uses the complex [RuCl(2)(IiPr)(p-cymene)] together with tricyclohexylphosphine and base, whereas the third system employs the Hoveyda-Grubbs 1st-generation metathesis catalyst together with 1,3-diisopropylimidazolium chloride and base. A range of different primary alcohols and amines have been coupled in the presence of the three catalyst systems to afford the corresponding amides in moderate to excellent yields. The best results are obtained with sterically unhindered alcohols and amines. The three catalyst systems do not show any significant differences in reactivity, which indicates that the same catalytically active species is operating. The reaction is believed to proceed by initial dehydrogenation of the primary alcohol to the aldehyde that stays coordinated to ruthenium and is not released into the reaction mixture. Addition of the amine forms the hemiaminal that undergoes dehydrogenation to the amide. A catalytic cycle is proposed with the {(IiPr)Ru(II)} species as the catalytically active components.

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“…The conversion of aldehydes and ketones into the corresponding gem ‐dihaloolefins is a valuable functional group transformation that delivers versatile intermediates for the synthesis of, inter alia , amides , ynamides , ketene N , N ‐acetals , 2‐bromo‐indoles , alkynyl methylidenes , 1‐alkenyl‐phosphonates or allylsilanes . gem ‐Dihaloolefins can also be used as starting materials in transition‐metal‐mediated CC cross‐coupling reactions .…”

Section: Introductionmentioning

confidence: 99%

Microwave‐Assisted Dibromoolefination of Aromatic and Heteroaromatic Aldehydes and Ketones

Nauroozi

Bruhn

Fürmeier

et al. 2015

Journal of Heterocyclic Chem

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Microwave (MW) irradiation was successfully employed to convert aromatic and heteroaromatic aldehydes and ketones efficiently to the corresponding dibromoolefins. Exemplified by the successful dibromoolefination of traditionally inert pyridyl‐flanked carbonyls, MW activation significantly broadens the scope of this valuable transformation, although some limitations especially with electron‐rich aromatic ketone derivatives remain.

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Palladium-catalyzed amidation–hydrolysis reaction of gem-dihaloolefins: efficient synthesis of homologated carboxamides from ketones

Abstract: A simple and efficient palladium-catalyzed amidation-hydrolysis reaction has been developed to afford N-aryl monosubstituted carboxamides in good to excellent yields from easily accessible ketone-derived gem-dihaloolefins and aryl amines.

Cited by 44 publications

References 53 publications

Effect of gem‐Difluorination on the Key Physicochemical Properties Relevant to Medicinal Chemistry: The Case of Functionalized Cycloalkanes

Effect of gem‐Difluorination on the Key Physicochemical Properties Relevant to Medicinal Chemistry: The Case of Functionalized Cycloalkanes

Amide Synthesis from Alcohols and Amines Catalyzed by Ruthenium N‐Heterocyclic Carbene Complexes

Microwave‐Assisted Dibromoolefination of Aromatic and Heteroaromatic Aldehydes and Ketones

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