Nenitzescu Reaction Research Articles

Exploration of the Divergent Outcomes for the Nenitzescu Reaction of Piperazinone Enaminoesters

The Nenitzescu reaction is a condensation reaction between an enamine and a quinone, which can give rise to a wide variety of reaction products depending on the nature of the starting material and the reaction conditions. The most commonly observed products are 5-hydroxyindoles and 5-hydroxybenzofurans. Both classes are of interest since they are known to possess a variety of promising bioactivities. Despite the high chemodivergency for this reaction, it remains an interesting synthetic strategy thanks to the mild reaction conditions, easily accessible starting materials and simple reaction procedures. For these reasons, our research group investigated the Nenitzescu reaction of piperazinone enaminoesters, resulting in the unexpected formation of rearranged 2-imidazolidinone benzofurans. In this work, we aimed to develop reaction conditions that favor the formation of 5-hydroxyindoles via an extensive, multivariate optimization study. This led to valuable insights into the parameters that influence regio- and chemoselectivity. Furthermore, two novel products were obtained, a pyrrolo[2,3-f]indole and a benzofuranone, both of which are rarely reported in the literature.

Fluorescent Pyranoindole Congeners: Synthesis and Photophysical Properties of Pyrano[3,2-f], [2,3-g], [2,3-f], and [2,3-e]Indoles.

This paper reports the synthesis of four types of annulated pyranoindole congeners: pyrano[3,2-f]indole, pyrano[2,3-g]indole, pyrano[2,3-f]indole, and pyrano[2,3-e]indole and photophysical studies in this series. The synthesis of pyrano[3,2-f], [2,3-g], and [2,3-e]indoles involve a tandem of Bischler-Möhlau reaction of 3-aminophenol with benzoin to form 6-hydroxy- or 4-hydroxyindole followed by Pechmann condensation of these hydroxyindoles with β-ketoesters. Pyrano[2,3-f]indoles were synthesized through the Nenitzescu reaction of p-benzoquinone and ethyl aminocrotonates and subsequent Pechmann condensation of the obtained 5-hydroxyindole derivatives. Among the pyranoindoles studied, the most promising were pyrano[3,2-f] and [2,3-g]indoles. These compounds were characterized by moderate to high quantum yields (30-89%) and a large (9000-15,000 cm-1) Stokes shift. More detailed photophysical studies were carried out for a series of the most promising derivatives of pyrano[3,2-f] and [2,3-g]indoles to demonstrate their positive solvatochromism, and the data collected was analyzed using Lippert-Mataga equation. Quantum chemical calculations were performed to deepen the knowledge of the absorption and emission properties of pyrano[3,2-f] and [2,3-g]indoles as well as to explain their unusual geometries and electronic structures.

Interaction of arylbenzoquinones with enamines. Synthesis of 4-aryl-5a-morpholin-4-yl-5a,6,7,8,9,9a-hexahydro-dibenzo[b,d]furan-2-oles

An important way of forming the indole cycle is the Nenitsescu reaction. Convenient precursors for this reaction are readily available β-ketoesters or 1,3-diketones, which after conversion to enamines react with 1,4-quinones to form polysubstituted indoles. The regio- and chemoselectivity of the interaction depends on the conduction conditions, the structure of the quinone and enamine component, and the electronic effects of the substituents. Studies have shown that the condensation of quinones with enamines can take place in at least a few main directions. The most common are 5- or 6-hydroxyindoles, 5-hydroxybenzofurans and 5-hydroxyindazoles. However, the synthetic potential of the reaction is not limited to this, because it also allows to obtain other, more diverse structures that are difficult to access in other ways – benzocarbazoles, pyrido- [2,3- b ]indoles, furo[3,2- h ]indoles, furo[2,3- g ]indoles, imidazo[4,5- g ]indoles, dihydro-benzo[ g ]indoles, pyrrolo[2,3- h ]quinolines. However, interest in this reaction has not diminished to this day, as it is a convenient method of forming a base fragment for many biologically active substances. In this paper, we describe the results of studies obtained during the study of the reactivity of monoarylquinones to enamines derived from cyclic ketones and secondary amines. With the use of such enamines, it is impossible to obtain indoles by the Nenitsescu reaction, so the formation of benzofuran derivatives was expected, but the question of regioselectivity of the process remained open. It was found that the interaction of 1-morpholino-1-cyclohexene 6 with 2-aryl-1,4-benzoquinones 1 – 5 at room temperature in a dry benzene forms 4-aryl-5a-morpholin-4-yl-5a,6,7,8,9,9a-hexahydrodibenzo[ b , d ]furan-2-oles 7 – 11 . The reaction was found to be regioselective – of the three possible regioisomers, only 4-aryl-substituted dibenzofurans were formed, and no indole cyclization products were detected. The structures of the synthesized compounds were confirmed by the 1 H-, 13 C NMR spectroscopy and element analysis data. Keywords: 2-aryl-1,4-benzoquinones, 1-morpholino-1-cyclohexen, enamines, Nenitzescu reaction, dibenzo[ b , d ]furan-2-ones, heterocycles.

2-Imidazolidinone benzofurans as unexpected outcome of the Lewis acid mediated Nenitzescu reaction

Herein, a metal-free methodology towards 2-imidazolidinone benzofurans via piperazinone enaminoesters addition onto quinones and subsequent rearrangement has been disclosed.

Tandem Nenitzescu Reaction/Nucleophilic Aromatic Substitution to Form Novel Pyrido Fused Indole Frameworks

Abstract5‐Hydroxyindoles are privileged structures that form part of various bioactive compounds. The Nenitzescu reaction of quinones and enamines is one of the most powerful methods to obtain 5‐hydroxyindoles. In this work, we have applied the Nenitzescu reaction to 2‐(2‐chloropyrid‐3‐yl)benzoquinones. Mixtures of regioisomers were obtained that could be separated in the 4‐ and 6‐substituted analogues, and then cyclized separately in a metal‐free base‐catalyzed reaction, affording novel tetracyclic indole derivatives. These are indeed the first examples reported in the literature of the linear pyrido[3′,2′ : 4,5]furo[3,2‐b]indole and angular 1H‐pyrido[2′,3′ : 4,5]furo[2,3‐c]indole systems. The regioselectivity and the yield of the Nenitzescu reaction were found to be dependent on the N‐substituent at the enamine. Furthermore, we analyzed the UV‐Vis and PL spectra of the new systems, and this was supported by DFT calculations, allowing us to compare the properties of angular compared to linearly shaped compounds.

THE NENITZESCU REACTION IN THE SYNTHESIS OF NEW ABIETANE DITERPENE INDOLES

The new abietane diterpene indoles were synthesized by the Nenitzescu reaction of 1a,4a-dehydroquinopimaric acid and its methyl ester with methyl-3-aminocrotonate.

The Nenitzescu Reaction in the Synthesis of New Abietane Diterpene Indoles

The new abietane diterpene indoles were synthesized by the Nenitzescu reaction of 1a,4a-dehydroquinopimaric acid and its methyl ester with methyl-3-aminocrotonate.

Controlling the All-trans Stereochemistry in Liquid Crystalline 4,4′-Dialkyl-[1,1′-bicyclohexyl] Compounds

A good part of today’s liquid crystals (LCs) for display applications are derived from the Darzens–Nenitzescu reaction which, in a one-pot-process, yields 1,4-trans-acylphenylcyclohexanes from acid chlorides, benzene, and cyclohexene. A mechanism for this process is proposed based on quantum-chemical computations. The products of this reaction can be further elaborated to all-trans-4,4′-disubstituted-[1,1′-bicyclohexane] compounds, essential components in almost all fast switching LC-mixtures. An equilibration process involving carbo­cations is used to control the diastereomer distribution.

A short synthesis of Dronedarone

A modification of the Nenitzescu reaction was used to obtain Dronedarone from quinonimine 20 and 1,3-diketone 14 (R = CH2CH2CH2NBu2) in a two-stage process in almost 55% overall yield. Our results represent significant improvement over other state-of-the-art methods as no extra steps for the decoration of the benzofuran core are required.

Synthesis of fused polyhalogeno-7a-hydroxy-[1,2-a]indol-5-one derivatives

A series of novel fused polyhalogeno-7a-hydroxy-[1,2-a]indol-5-one derivatives has been synthesized with good yields based on the Nenitzescu reaction of heterocyclic ketene aminals (HKAs) with halogenated quinones without catalyst in acetone under room temperature. The highly efficient, catalyst-free and one pot synthesis serves as a nice addition to group-assisted-purification (GAP) chemistry, and the pure products were obtained simply by washing the crude products with 95% ethanol.

ChemInform Abstract: A Novel and Facile Synthesis of N‐Substituted 8‐Hydroxybenzo[g]chromeno[4,3‐b]indol‐6(13H)‐ones by a Nenitzescu Reaction.

ChemInformVolume 45, Issue 32 Heterocyclic Compounds ChemInform Abstract: A Novel and Facile Synthesis of N-Substituted 8-Hydroxybenzo[g]chromeno[4,3-b]indol-6(13H)-ones by a Nenitzescu Reaction. Zhiwei Chen, Zhiwei Chen Key Lab. Green Pharm. Technol., Zhejiang Univ. Technol., Hangzhou 310014, Peop. Rep. ChinaSearch for more papers by this authorXiaodong Wang, Xiaodong Wang Key Lab. Green Pharm. Technol., Zhejiang Univ. Technol., Hangzhou 310014, Peop. Rep. ChinaSearch for more papers by this authorWeike Su, Weike Su Key Lab. Green Pharm. Technol., Zhejiang Univ. Technol., Hangzhou 310014, Peop. Rep. ChinaSearch for more papers by this author Zhiwei Chen, Zhiwei Chen Key Lab. Green Pharm. Technol., Zhejiang Univ. Technol., Hangzhou 310014, Peop. Rep. ChinaSearch for more papers by this authorXiaodong Wang, Xiaodong Wang Key Lab. Green Pharm. Technol., Zhejiang Univ. Technol., Hangzhou 310014, Peop. Rep. ChinaSearch for more papers by this authorWeike Su, Weike Su Key Lab. Green Pharm. Technol., Zhejiang Univ. Technol., Hangzhou 310014, Peop. Rep. ChinaSearch for more papers by this author First published: 24 July 2014 https://doi.org/10.1002/chin.201432162Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat No abstract is available for this article. Volume45, Issue32August 12, 2014 RelatedInformation

ChemInform Abstract: Montmorillonite Clay Catalyzed Three Component, One‐Pot Synthesis of 5‐Hydroxyindole Derivatives.

AbstractThe synthesis of a variety of 5‐hydroxyindole derivatives is achieved via the Nenitzescu reaction using montmorillonite clay as simple, cost‐effective and recyclable catalyst.

A Novel and Facile Synthesis of N-Substituted 8-hydroxybenzo[g] chromeno[4, 3-b]indol-6(13H)-ones by a Nenitzescu Reaction

N-Substituted 8-hydroxybenzo[g]chromeno[4,3-b]indol-6(13H)-ones have been efficiently synthesized via a Nenitzescu reaction of naphthoquinone (or benzoquinone) and N-substituted 4-aminocoumarins in the presence of a catalytic amount of KHSO4 with a [bmim][BF4]/toluene system. Keywords: Coumarins, Nenitzescu reaction, quinones, ionic liquid.

The Construction of Polysubstituted Aromatic Core Derivatives via a Cycloaddition/Oxidative Aromatization Sequence from Quinone and β‐Enamino Esters

AbstractAn unexpected strategy has been discovered for the construction of polysubstituted aromatic core derivatives from the reaction of quinones or N‐substituted maleimides with β‐enamino esters by a cycloaddition/oxidative aromatization sequence that provides products contrary to those delivered by the Nenitzescu reaction. The current method provides a highly favorable synthetic strategy for the efficient construction of important therapeutic agents containing polysubstituted aromatic core structures.magnified image

A new CAN-catalyzed domino process related to the Nenitzescu reaction: very concise access to fused ortho-indolequinones from simple precursors

The CAN-catalyzed three-component reaction between primary amines, β-ketoesters and naphthoquinone in ethanol at room temperature afforded as the main products the corresponding Michael adducts, oxidized to the quinone stage. When these compounds were refluxed in ethanol in the presence of CAN, they afforded tricyclic ortho-quinones derived from the benzo[g]indole-4,5-dione framework via a domino mechanism comprising a sequence of 5-exo-trig cyclization, elimination, Michael addition, oxo–enol tautomerism and hydroquinone oxidation individual steps.

INDAZOLEQUINONES IN THE NENITZESCU REACTION. SYNTHESIS OF PYRROLO[2,3- e ] AND FURO[2,3- e ]INDAZOLES

A heterocyclic quinone was used in the Nenitzescu reaction for the first time. New tricyclic compounds – pyrrolo[3,2- e ]- and furo[3,2- e ]indazoles – were synthesized by the condensation of 1,3-diphenyl-4,7-dioxoindazole with various enamines. Authors: V. M. Lyubchanskaya, L. M. Alekseeva, S. A. Savina, and V. G. Granik. English Translation in Chemistry of Heterocyclic Compounds , 2000, 36 (11), pp 1276-1283 http://link.springer.com/article/10.1023/A%3A1017515300244

A scalable Nenitzescu synthesis of 2‐methyl‐4‐(trifluoromethyl)‐1H‐indole‐5‐carbonitrile

Abstract2‐Methyl‐4‐(trifluoromethyl)‐1H‐indole‐5‐carbonitrile is a key intermediate in the synthesis of selective androgen receptor modulators discovered in these laboratories. A practical and convergent synthesis of the title compound starting from 4‐nitro‐3‐(trifluoromethyl)phenol and tert‐butyl acetoacetate was developed, including a telescoped procedure for synthesis (without isolation) and Nenitzescu reaction of 2‐trifluoromethyl‐1,4‐benzoquinone. Conversion of the known Nenitzescu indole product to a novel triflate intermediate followed by palladium‐catalyzed cyanation afforded a penultimate carbonitrile. Removal of the C‐3 tert‐butyl ester group on the indole through a decarboxylative pathway completed the synthesis of the title compound in six steps (27% overall yield) from 4‐nitro‐3‐(trifluoromethyl)phenol (five steps, 37% overall yield from tert‐butyl acetoacetate). J. Heterocyclic Chem., (2011).

A novel application of DDQ as electrophile in the Nenitzescu reaction

Reaction of 2,3-dichloro-5,6-dicyano-benzoquinone (DDQ) with secondary enaminones yields surprisingly 2-aza-spiro[4,5]decatrienes. The reaction occurs via cyclisation of the primary Michael-adduct with the nitrile group. Reaction of DDQ with tertiary and also certain secondary enamines leads to 3-amino-benzo[ b]furan derivatives. This is formed not by Michael-addition, but via geminate radical ion pair formation with subsequent generation of an oxygen–carbon bond to yield benzofurans. The new products are investigated with regards to inhibition of purified human proteinkinase CK2 and their general cytostatic activity. It turned out, that the most active compound is the 3-amino-5-hydroxy-benzofuran derivative 11s with an IC 50 value of 0,2 μM for CK2.

ChemInform Abstract: Lewis Acid Catalyzed Rapid Synthesis of 5‐Hydroxy‐benzo[g]indole Scaffolds by a Modified Nenitzescu Reaction.

AbstractThe preparation of the pharmacologically important title compounds (III) (12 examples) involves a Michael addition of acetophenone derivatives to naphthoquinone followed by aza cyclization using urea as source of ammonia.

Tandem Blaise–Nenitzescu reaction: one-pot synthesis of 5-hydroxy-α-(aminomethylene)benzofuran-2(3H)-ones from nitriles

In contrast to the reaction of benzoquinones with β-enaminoesters providing indoles (Nenitzescu reaction), the tandem one-pot reaction of the Blaise reaction intermediate, zinc bromide complex of β-enaminoesters, with benzoquinone affords 5-hydroxy-α-(aminomethylene)benzofuran-2(3H)-ones in good to excellent yields (tandem Blaise-Nenitzescu reaction).