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Open AccessCommunication

Microwave-Assisted Synthesis of 1-(5-Substituted-4-hydroxy-2-methyl-1H-pyrrol-3-yl)ethan-1-ones from 2-Amino Acid-Derived Enamine-Type Schiff Bases

by Diego Quiroga, Sergio Torres-Cortés and Ericsson Coy-Barrera

Molbank 2025, 2025(1), M1975; https://doi.org/10.3390/M1975 - 3 Mar 2025

Viewed by 2452

Abstract

Pyrrole-type compounds are widely known for their potential biological activity. However, methods for synthesizing 2,3,4,5-tetrasubstituted pyrroles remain limited. This study explores an intramolecular cyclocondensation of 2-amino acid-derived enamines to yield novel 1-(5-substituted-4-hydroxy-2-methyl-1H-pyrrol-3-yl)ethan-1-ones. Using ʟ-alanine, ʟ-tyrosine, ʟ-phenylalanine, and ʟ-tryptophan, the corresponding 2-amino [...] Read more.

Pyrrole-type compounds are widely known for their potential biological activity. However, methods for synthesizing 2,3,4,5-tetrasubstituted pyrroles remain limited. This study explores an intramolecular cyclocondensation of 2-amino acid-derived enamines to yield novel 1-(5-substituted-4-hydroxy-2-methyl-1H-pyrrol-3-yl)ethan-1-ones. Using ʟ-alanine, ʟ-tyrosine, ʟ-phenylalanine, and ʟ-tryptophan, the corresponding 2-amino esters were synthesized, converted into enamines, and cyclized under microwave irradiation (55–86% yield). The highest yield was obtained from methyl ʟ-phenylalaninate (R¹ = CH₂Ph, R⁴ = Me). Steric hindrance from bulkier groups reduced yields, while the electronic nature of R¹ influenced reactivity. Structural analysis (NMR, HR-ESI-MS) confirmed product identities, and a 5-exo-trig cyclization mechanism explained base-mediated deprotonation and steric effects. These findings highlight steric and electronic factors in this cyclocondensation, guiding reaction optimization for valuable heterocycles. Full article

(This article belongs to the Collection Heterocycle Reactions)

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12 pages, 1216 KB

Open AccessArticle

Copper-Catalyzed Trifluoromethylthiolaton and Radical Cyclization of N-Phenylpent-4-Enamides to Construct SCF₃-Substituted γ-Lactams

by Hanyang Zhang, Wen Liu, Jiale Hu, Qian Zhang, Zeguo Fang and Dong Li

Catalysts 2024, 14(11), 797; https://doi.org/10.3390/catal14110797 - 7 Nov 2024

Cited by 2 | Viewed by 1665

Abstract

An efficient method involving copper-catalyzed trifluoromethylthiolation and radical cyclization of N-phenylpent-4-enamides using readily available and stable AgSCF₃ as the trifluoromethylthiolating reagent is described. The method enables the synthesis of a series of potential medicinally valuable trifluoromethylthio-substituted γ-lactams and relative 2-oxazolidinone [...] Read more.

An efficient method involving copper-catalyzed trifluoromethylthiolation and radical cyclization of N-phenylpent-4-enamides using readily available and stable AgSCF₃ as the trifluoromethylthiolating reagent is described. The method enables the synthesis of a series of potential medicinally valuable trifluoromethylthio-substituted γ-lactams and relative 2-oxazolidinone derivatives with broad functional group compatibility. Mechanistic investigations indicated that this reaction involved amidyl radical-initiated cascade 5-exo-trig cyclization followed by trifluoromethylthiolation, resulting in the formation of new C-N and C-S bonds. Full article

(This article belongs to the Special Issue Recent Catalysts for Organic Synthesis)

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12 pages, 1403 KB

Open AccessArticle

Synthesis of Indenones via Persulfate Promoted Radical Alkylation/Cyclization of Biaryl Ynones with 1,4-Dihydropyridines

by Wanwan Wang and Lei Yu

Molecules 2024, 29(2), 458; https://doi.org/10.3390/molecules29020458 - 17 Jan 2024

Cited by 1 | Viewed by 1599

Abstract

The oxidative radical cascade cyclization of alkynes has emerged as a versatile strategy for the efficient construction of diverse structural units and complex molecules in organic chemistry. This work reports an alkyl radical initiated 5-exo-trig cyclization of biaryl ynones with 1,4-dihydropyridines [...] Read more.

The oxidative radical cascade cyclization of alkynes has emerged as a versatile strategy for the efficient construction of diverse structural units and complex molecules in organic chemistry. This work reports an alkyl radical initiated 5-exo-trig cyclization of biaryl ynones with 1,4-dihydropyridines to selectively synthesize indenones. Full article

(This article belongs to the Section Organic Chemistry)

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12 pages, 1120 KB

Open AccessArticle

Iodine-Mediated Alkoxyselenylation of Alkenes and Dienes with Elemental Selenium

by Evgeny O. Kurkutov and Bagrat A. Shainyan

Molecules 2022, 27(19), 6169; https://doi.org/10.3390/molecules27196169 - 20 Sep 2022

Cited by 5 | Viewed by 2884

Abstract

A one-pot synthesis of linear and cyclic β-alkoxyselenides is developed through the iodine-mediated three-component reaction of elemental selenium with alkenes (dienes) and alcohols. Selenylation of 1,5-hexadiene gives 2,5-di(methoxymethyl)tetrahydroselenophene and 2-methoxy-6-(methoxymethyl)tetrahydro-2H-selenopyran via the 5-exo-trig and 6-endo-trig cyclization. 1,7-Octadiene affords only [...] Read more.

A one-pot synthesis of linear and cyclic β-alkoxyselenides is developed through the iodine-mediated three-component reaction of elemental selenium with alkenes (dienes) and alcohols. Selenylation of 1,5-hexadiene gives 2,5-di(methoxymethyl)tetrahydroselenophene and 2-methoxy-6-(methoxymethyl)tetrahydro-2H-selenopyran via the 5-exo-trig and 6-endo-trig cyclization. 1,7-Octadiene affords only linear 1:2 adduct with two terminal double bonds. 1,5-Cyclooctadiene results in one diastereomer of 2,6-dialkoxy-9-selenabicyclo [3.3.1]nonanes via 6-exo-trig cyclization. With 1,3-diethenyl-1,1,3,3-tetramethyldisiloxane, the first ring-substituted representative of a very rare class of heterocycles, 1,4,2,6-oxaselenadisilinanes, was obtained at a high yield. Full article

(This article belongs to the Special Issue Feature Papers in Organic Chemistry)

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11 pages, 1883 KB

Open AccessArticle

Metal-Free α-C(sp³)–H Functionalized Oxidative Cyclization of Tertiary N,N-Diaryl Amino Alcohols: Theoretical Approach for Mechanistic Pathway

by Zakir Ullah and Mihyun Kim

Molecules 2017, 22(4), 547; https://doi.org/10.3390/molecules22040547 - 29 Mar 2017

Cited by 10 | Viewed by 7634

Abstract

The mechanistic pathway of TEMPO/I₂-mediated oxidative cyclization of N,N-diaryl amino alcohols 1 was investigated. Based on direct empirical experiments, three key intermediates (aminium radical cation 3, α-aminoalkyl radical 4, and iminium 5), four types of reactive species [...] Read more.

The mechanistic pathway of TEMPO/I₂-mediated oxidative cyclization of N,N-diaryl amino alcohols 1 was investigated. Based on direct empirical experiments, three key intermediates (aminium radical cation 3, α-aminoalkyl radical 4, and iminium 5), four types of reactive species (radical TEMPO, cationic TEMPO, TEMPO-I, and iodo radical), and three types of pathways ((1) SET/PCET mechanism; (2) HAT/1,6-H transfer mechanism; (3) ionic mechanism) were assumed. Under the assumption, nine free energy diagrams were acquired through density functional theory calculations. From the comparison of solution-phase free energy, some possible mechanisms were excluded, and then the chosen plausible mechanisms were concretized using the more stable intermediate 7. Full article

(This article belongs to the Special Issue Reactions of Hydrocarbons and other C‒H Compounds)

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9 pages, 815 KB

Open AccessArticle

Photochemical Aryl Radical Cyclizations to Give (E)-3-Ylideneoxindoles

by Michael Gurry, Ingrid Allart-Simon, Patrick McArdle, Stéphane Gérard, Janos Sapi and Fawaz Aldabbagh

Molecules 2014, 19(10), 15891-15899; https://doi.org/10.3390/molecules191015891 - 30 Sep 2014

Cited by 3 | Viewed by 8371

Abstract

(E)-3-Ylideneoxindoles are prepared in methanol in reasonable to good yields, as adducts of photochemical 5-exo-trig of aryl radicals, in contrast to previously reported analogous radical cyclizations initiated by tris(trimethylsilyl)silane and azo-initiators that gave reduced oxindole adducts. Full article

(This article belongs to the Special Issue Free Radicals and Radical Ions)

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10 pages, 198 KB

Open AccessArticle

A Novel Strategy Towards the Asymmetric Synthesis of Orthogonally Funtionalised 2-N-Benzyl-N-α-methylbenzylamino- 5-carboxymethyl-cyclopentane-1-carboxylic acid.

by Narciso M. Garrido, Mohamed M. El Hammoumi, David Díez, Mercedes García and Julio G. Urones

Molecules 2004, 9(5), 373-382; https://doi.org/10.3390/90500373 - 30 Apr 2004

Cited by 8 | Viewed by 11358

Abstract

The asymmetric synthesis of the orthogonally funtionalised compounds tert-butyl 2-N-benzyl-N-α-methylbenzylamino-5-methoxycarbonylmethylcyclopentane- 1-carboxylate and methyl 2-N-benzyl-N-α-methylbenzylamino-5–carboxymethylcyclo- pentane-1-carboxylate by a domino reaction of tert-butyl methyl (E,E)-octa-2,6- diendioate with lithium N-α-methylbenzyl-N-benzylamide initiated by a Michael addition, subsequent 5-exo-trig intramolecular cyclisation and posterior selective hydrolysis with trifluoroacetic acid [...] Read more.

The asymmetric synthesis of the orthogonally funtionalised compounds tert-butyl 2-N-benzyl-N-α-methylbenzylamino-5-methoxycarbonylmethylcyclopentane- 1-carboxylate and methyl 2-N-benzyl-N-α-methylbenzylamino-5–carboxymethylcyclo- pentane-1-carboxylate by a domino reaction of tert-butyl methyl (E,E)-octa-2,6- diendioate with lithium N-α-methylbenzyl-N-benzylamide initiated by a Michael addition, subsequent 5-exo-trig intramolecular cyclisation and posterior selective hydrolysis with trifluoroacetic acid is reported. Full article

(This article belongs to the Special Issue Carbanion chemistry from Carboxylic acids in honor of Prof. Ramón Mestres on his 65th anniversary)

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9 pages, 223 KB

Open AccessArticle

Unexpected Syntheses of seco-Cyclopropyltetrahydroquinolines >From a Radical 5-Exo-Trig Cyclization Reaction: Analogs of CC-1065 and the Duocarmycins

by Hari Pati, Lori Forrest, Heather Townes, Brian Lingerfelt, LuAnne McNulty and Moses Lee

Molecules 2004, 9(3), 125-133; https://doi.org/10.3390/90300125 - 28 Feb 2004

Cited by 8 | Viewed by 10688

Abstract

Analogs of the seco-cyclopyrroloindoline (seco-CPI), the DNA alkylation pharmacophore of CC-1065 and the duocarmycins, can be prepared through a 5-exo-trig radical cyclization of a free radical and a 3-chloro-2-allylic moiety. This manuscript reports an unexpected discovery that, depending on the structure and stability [...] Read more.

Analogs of the seco-cyclopyrroloindoline (seco-CPI), the DNA alkylation pharmacophore of CC-1065 and the duocarmycins, can be prepared through a 5-exo-trig radical cyclization of a free radical and a 3-chloro-2-allylic moiety. This manuscript reports an unexpected discovery that, depending on the structure and stability of the free radical, the cyclization process leads to the production of an appreciable amount of seco- cyclopropyltetrahydroquinolines 7a-d along with the seco-cyclopropoyltetra- hydroindoline products (6a-e). For instance, free radical reaction of the bromoallylic chloride 5a produced an equal amount of 6-benzyloxy-N-t-butoxycarbonyl-3- (chloromethyl)furano[e]indoline (6a), and 7-benzyloxy-N-t-butoxycarbonyl-3-chloro- 1,2,3,4-tetrahydrofurano[f]quinoline (7a). Three other examples that produced mixtures of indoline and quinoline products are provided. In only one of the examples reported in this manuscript, the 6-benzyloxy-N-t-butoxycarbonyl-3-(chloromethyl)benzo[e]indoline, was a seco-CBI precursor 6e formed exclusively, consistent with literature precedents. Full article

(This article belongs to the Special Issue Biologically Relevant Heterocyclic Compounds)

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