A One-Pot Approach to Δ<sup>2</sup>-Isoxazolines from Ketones and Arylacetylenes

Schmidt, Elena Yu.; Tatarinova, Inna V.; Ivanova, Elena V.; Zorina, Nadezhda V.; Ushakov, Igor А.; Трофимов, Б. А.

doi:10.1021/ol303132u

Cited by 47 publications

(9 citation statements)

References 41 publications

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“…46 We have demonstrated a one-pot synthesis of 5-benzyl-Δ 2 -isoxazolines 41 via the superbase-mediated three-component reaction of arylace- tylenes, ketones, and hydroxylamine (Scheme 28). 47 The reaction involves ring closure of oximes 42, which subsequently isomerize to oximes 43 (Scheme 29).…”

Section: δ 2 -Isoxazolinesmentioning

confidence: 99%

Acetylenes in the Superbase-Promoted Assembly of Carbocycles and Heterocycles

Трофимов

Schmidt

2018

Acc. Chem. Res.

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In this Account, we briefly discuss the recently discovered and rapidly developing superbase-promoted self-organization reactions of several equivalents of acetylenes and ketones to afford complex compounds that represent promising synthetic building blocks common in natural products. Notably, acetylenes play a special role in these reactions because of their dual (acting as an electrophile and a nucleophile) and flexible reactivity. These unique properties of acetylenes are elegantly expressed in superbasic media, where acetylenes are more deprotonated and their electrophilicity increases as a result of complexation with alkali metal cations, with simultaneous enhancement of the nucleophilic reactants due to desolvation. Under these conditions, acetylenes behave as a driving and organizing force toward other reactants. Various combinations of nucleophilic addition to the triple bond and acetylene deprotonation in the presence of other reactants with dual reactivity (e.g., ketones) enables the self-organization of complex molecular architectures that are inaccessible by conventional reactions. Herein we analyze recent achievements in this area concerning the reactions of acetylenes with ketones in superbasic KOH/DMSO-type systems that selectively afford synthetically and pharmaceutically valuable carbo- and heterocycles. Most of the reactions are triggered by the nucleophilic addition of deprotonated ketones (enolate anions) to acetylenes (superbase-catalyzed C-vinylation of ketones with acetylenes, which was recently introduced by our group into a toolkit of organic chemistry). The β,γ-ethylenic ketones thus formed can then take part in cascade processes with ketones and acetylenes to afford either carbocycles (e.g., hexahydroazulenones, acyl terphenyls, functionalized and cyclopentenols) or heterocycles (e.g., furans, benzoxepines, dioxabicyclo[3.2.1]octanes, and dioxadispiro[5.1.5.2]pentadecanes), depending on the structure of the reactants and the reaction conditions. Most of these compounds are selectively built from several equivalents of ketones and acetylenes in different combinations, and despite the presence of two or more asymmetric carbons in the products, they are generated as single diastereomers. When other nucleophiles (hydroxylamine, hydrazines, guanidine, and oximes) and ketones are involved in these self-organization processes, the intermediate β,γ-ethylenic ketones allow the formation of diverse heterocyclic systems (pyrroles, isoxazolines, pyrazolines, aminopyrimidines, and azabicyclo[3.1.0]hexanes). The discovered unique chemical transformations do not require transition metal catalysts and proceed under mild and operationally simple conditions. Most of these syntheses involve cascade addition reactions and therefore represent pot-, atom-, step-, and energy-saving processes that meet the requirements of green chemistry. The significance of the approach discussed herein is that it represents a viable alternative to existing classic and modern transition-metal-based catalytic syntheses of some...

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Section: δ 2 -Isoxazolinesmentioning

confidence: 99%

Acetylenes in the Superbase-Promoted Assembly of Carbocycles and Heterocycles

Трофимов

Schmidt

2018

Acc. Chem. Res.

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“…Therefore, base-mediated hydroamination is in high demand. Base-assisted 6,7 C−N bond formation has been broadly classified as inorganic and organic base-catalyzed reactions. Among these, alkali base-promoted hydroamination reactions are the most popularly studied, as these bases can easily deprotonate the amines to provide more nucleophilic species, which can readily attack the unsaturated substrate.…”

Section: Introductionmentioning

confidence: 99%

Base-Mediated Hydroamination of Alkynes

2017

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Inter- or intramolecular hydroamination reactions are a paradigmatic example of modern sustainable organic chemistry, as they are a catalytic, 100% atom-economical, and waste-free process of fundamental simplicity in which an amine is added to an alkyne substrate. Many enamines are found in many natural and synthetic compounds possessing interesting physiological and biological activities. The development of synthetic protocols for such molecules and their transformation is a persistent research topic in pharmaceutical and organic chemistry. Hydroamination is conspicuously superior to the other accessible methods, such as the imination of ketones or the aminomercuration/demercuration of alkynes, that involve the stoichiometric use of toxic reagents. Additionally, the hydroamination of alkyne substrates has been successfully employed as a key step in synthesizing target molecules through total syntheses containing substituted indoles, pyrroles, imidazoles, and other heterocycles as core moieties. Many research groups have explored inter- or intramolecular hydroamination of alkynes for the synthesis of diversely substituted nitrogen heterocycles using expensive metal catalysts. However, in contrast to metal-catalyzed hydroamination, the base-mediated hydroamination of alkynes has not been extensively studied. Various inorganic (such as hydroxides, phosphates, and carbonates) and organic bases have been proven to be valuable reagents for achieving the hydroamination process. This method represents an attractive strategy for the construction of a broad range of nitrogen-containing compounds that prevents the formation of byproducts in the creation of a C-N linkage. The presence of a base is thought to facilitate the attack of nitrogen nucleophiles, such as indoles, pyrroles, and imidazoles, on unsaturated carbon substrates through the activation of the triple bond and thus transforming the electron-rich alkyne into an electrophile. In the past few years, we have been involved in the development of methods for the nucleophilic addition of N-heterocycles onto terminal and internal alkynes using alkali base catalysts to achieve new carbon-nitrogen bond-forming reactions. During our study, we discovered the regioselective preferential nucleophilic addition of N-heterocycles onto the haloarylalkyne over N-arylation of the aryl halide. In this Account, we summarize our latest achievements in regio-, stereo-, and chemoselective hydroamination chemistry of N-nucleophiles with alkynes using a superbasic medium to produce a broad range of highly functionalized vinyl and styryl enamines, which are valuable and versatile synthetic intermediates for the synthesis of bioactive compounds. Interestingly, the stereoselectivity of the addition products (kinetically stable Z and thermodynamically stable E isomers) was found to be dependent upon time. It is worthwhile to note that hydroaminated products formed by the addition reaction can further be utilized for the synthesis of indolo-/pyrrolo[2,1-a]isoquinolines, naphthyridines, and b...

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“…Nowadays, the recently discovered base-catalyzed addition of ketones to alkynes to afford β,γ-ethylenic ketones has been successfully employed as the intermediate step for an efficient one-pot synthesis of 2-isoxazolines, 2-pyrazolines and 1-formyl-2-pyrazolines, benzoxepines, 2,5-diaryl furans, , and acylated terphenyls …”

Section: Results and Discussionmentioning

confidence: 99%

A One-Pot Synthesis of 2-Aminopyrimidines from Ketones, Arylacetylenes, and Guanidine

et al. 2016

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The three-component reaction of ketones, arylacetylenes, and guanidine catalyzed by the KOBu/DMSO system leads to 2-aminopyrimidines in up to 80% yield. Depending on structure of the starting ketones, the aromatization of intermediate dihydropyrimidines occurs either with loss of hydrogen molecules or methylbenzenes. The latter process takes place in the ketones, in which one of the substituents is not a methyl group. The reaction conditions are tolerable for dialkyl-, aryl(hetaryl) alkyl-, and cycloalkyl ketones.

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A One-Pot Approach to Δ²-Isoxazolines from Ketones and Arylacetylenes

Abstract: The sequential reaction of ketones with arylacetylenes and hydroxylamine in the presence of KOBu(t)/DMSO followed by the treatment of the reaction mixture with H(2)O and KOH leads to Δ(2)-isoxazolines in up to 88% yield.

Cited by 47 publications

References 41 publications

Acetylenes in the Superbase-Promoted Assembly of Carbocycles and Heterocycles

Acetylenes in the Superbase-Promoted Assembly of Carbocycles and Heterocycles

Base-Mediated Hydroamination of Alkynes

A One-Pot Synthesis of 2-Aminopyrimidines from Ketones, Arylacetylenes, and Guanidine

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A One-Pot Approach to Δ2-Isoxazolines from Ketones and Arylacetylenes

Abstract: The sequential reaction of ketones with arylacetylenes and hydroxylamine in the presence of KOBu(t)/DMSO followed by the treatment of the reaction mixture with H(2)O and KOH leads to Δ(2)-isoxazolines in up to 88% yield.

Cited by 47 publications

References 41 publications

Acetylenes in the Superbase-Promoted Assembly of Carbocycles and Heterocycles

Acetylenes in the Superbase-Promoted Assembly of Carbocycles and Heterocycles

Base-Mediated Hydroamination of Alkynes

A One-Pot Synthesis of 2-Aminopyrimidines from Ketones, Arylacetylenes, and Guanidine

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Product

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A One-Pot Approach to Δ²-Isoxazolines from Ketones and Arylacetylenes