Ugi Four-Center Three-Component Reaction as a Direct Approach to Racetams

Cioc, Răzvan C.; Riempst, Lola Schaepkens van; Schuckman, Peter; Ruijter, Eelco; Orru, Romano V. A.

doi:10.1055/s-0036-1588672

Cited by 15 publications

(7 citation statements)

References 8 publications

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“…This compound was conveniently prepared by Eschenmoser sulfide contraction [29,30], as shown in Scheme 2. The route entailed initial alkylation of the anion of pyrrolidin-2-one (16) with ethyl bromoacetate to afford the known compound ethyl 2-(2-oxopyrrolidin-1-yl)acetate (17) [31][32][33] in 77% yield. Thionation of 17 with Lawesson's reagent in toluene at 80 °C gave the thione 18 as a yellow oil (86%).…”

Section: Resultsmentioning

confidence: 99%

Silica gel and microwave-promoted synthesis of dihydropyrrolizines and tetrahydroindolizines from enaminones

Klintworth¹,

Morgans²,

Scalzullo³

et al. 2021

Beilstein J. Org. Chem.

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A wide range of N-(ethoxycarbonylmethyl)enaminones, prepared by the Eschenmoser sulfide contraction between N-(ethoxycarbonylmethyl)pyrrolidine-2-thione and various bromomethyl aryl and heteroaryl ketones, underwent cyclization in the presence of silica gel to give ethyl 6-(hetero)aryl-2,3-dihydro-1H-pyrrolizine-5-carboxylates within minutes upon microwave heating in xylene at 150 °C. Instead of functioning as a nucleophile, the enaminone acted as an electrophile at its carbonyl group during the cyclization. Yields of the bicyclic products were generally above 75%. The analogous microwave-assisted reaction to produce ethyl 2-aryl-5,6,7,8-tetrahydroindolizine-3-carboxylates from (E)-ethyl 2-[2-(2-oxo-2-arylethylidene)piperidin-1-yl]acetates failed in nonpolar solvents, but occurred in ethanol at lower temperature and microwave power, although requiring much longer time. A possible mechanism for the cyclization is presented, and further functionalization of the newly created pyrrole ring in the dihydropyrrolizine core is described.

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Section: Resultsmentioning

confidence: 99%

Silica gel and microwave-promoted synthesis of dihydropyrrolizines and tetrahydroindolizines from enaminones

Klintworth¹,

Morgans²,

Scalzullo³

et al. 2021

Beilstein J. Org. Chem.

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“…There is great potential to synthesize complex drug molecules from deuterated small molecules with modular approaches. Examples of approved drugs which can be made by an MCR route, but are not necessarily produced by an MCR include, atorvastatin, 11 praziquantel, 12 ivosidenib, 13 lidocaine, 14 telaprevir, 14 olanzapine, 15 clopidogrel, 15 lacosamide, 4 carfentanil, 16 nirmatrelvir, 17 amenamevir, 18 or levetiracetam 19 (Figure 3). Olanzapine is a particularly intriguing example on the potential impact of MCR in isotope labeling, since it has been shown to be producible by several convergent MCR routes.…”

Section: Accepted Manuscriptmentioning

confidence: 99%

Multicomponent Reactions: A Promising Approach to Isotope Labeling

Domling,

Elsinga,

Xiao

et al. 2024

Synlett

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Isotopic labeling is an attractive modality that has been widely used in many aspects of chemistry, the life sciences, and medical research; especially deuterated drugs and radioactive molecules have been used in the diagnosis and treatment of cancer and neurodegenerative diseases. The widespread application and rapid development of isotopically -labeled molecules has led to an increased demand for new isotopic labeling chemical methods to synthesize highly specific molecules bearing defined nuclides. Multicomponent reactions (MCRs) are modular build-up approaches for the rapid generation of complex molecules often containing biologically relevant scaffold structures. There is great potential to use MCRs to construct isotopically labeled molecules because assembly speed and reaction diversity are key advantages of MCR. In this review, we provide an overview of the recent literature on this topic that can provide insight into the application of MCRs in the field of isotopic labeling.

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“…O levetiracetam é obtido através da utilização de uma reação de Ugi 4-centros-3-componentes (a reação possui os quatro grupos funcionais reativos clássicos, mas o ácido γ-aminobutírico fornece dois desses grupos), formando assim um anel γ-lactâmico. Os dois diastereoisómeros formados são subsequentemente separados para obter o fármaco na forma enantiomericamente pura (Esquema 3) [36]. No caso da lacosamida, uma reação de Ugi de quatro componentes é aplicada, usando uma amina quiral para induzir a formação preferencial de um diastereoisómero, que após desproteção leva à formação da substância ativa na forma enantiomericamente pura (Esquema 3) [37].…”

Section: Um Caso Particular De Rmc -A Reação De Ugiunclassified