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Enol-Ugi Reaction for the Synthesis of Amino Acid Derived Coumarins
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1  Universidad de Extremadura


Multicomponent reactions are highly convergent processes that are advantageously used for the synthesis of complex and diverse molecular libraries. We have recently demonstrated that enols react with amines, carbonyl compounds and isocyanides to give stable enamines, in a reaction similar to the classical Ugi condensation. In particular, heterocyclic enols can conveniently afford diversely functionalized heterocycles in an experimentally simple manner. Coumarins constitute a large family of plant metabolites possessing significant biological activities. In particular, 3- and 4-aminocoumarins constitute the structural core of numerous compounds with distinct therapeutic activities as, for example, antiproliferative and anti-HIV agents.

Here we wish to report the enol-Ugi reaction of 3- and 4-hydroxycoumarins, containing electron-withdrawing groups at positions 4 and 3 respectively, to give 3- and 4-aminocoumarins in a highly atom-economic and convergent process.

Keywords: Multicomponent reactions, enols, isocyanide, aminocoumarins, hydroxycoumarins
Comments on this paper
shrikant pharande
About mechanism
I have read your article here and its really nice work.
But I have one doubt about mechanism of reaction. Here you shown that imine formed after condensation of reagent 1 and 2 and that imine abstracts proton of enol 3 (as proton of iminium ion is in blue color). On which basis you are saying that iminium ion proton belongs to enol and not of condensed water. Have you confirmed this through experimental studies?
Mahmoud Al-Jibouri
The mechanism of reaction should be in details of it's steps with regarding the IR and NMR data

Ana G. Neo
Reply about mechanism
Thank you very much for your interest in our work.

In relation to your question, we think that the imine is protonated by a proton of the enol because the enol is much more acidic than water. The enols that we use have an acidity similar (or superior) to carboxylic acids used in the Ugi reaction, in which the mechanism have been extensively studied and it is established that the imine is protonated by the carboxylic acid.
On the other hand, we use previously pre-formed imines, thus in the reaction medium there is not water present. However, the 4-component reaction (in which the imine is formed “in situ” from an aldehyde and an amine, and, hence, there is water in the reaction medium) also work very well.

Thank you very much for your interesting comment.
Mahmoud Al-Jibouri
Can you define Ugi reaction. As well as i repeat my request to send me IF papers including the synthesis and characterization of 3-acetyl-4-hydroxy coumarine
my e-mails

Mahmoud Al-Jibouri
Comment on request of coumarine derivatives
I have intersted your paper regarding coumarine derivatives then i would like to assist me in attaching papers about synthesis of 3-acetyl-4-hydroxy coumarine and their characterization by NMR, UV, MS and IR spectroscopy