Application of dimedone enamines as dienophiles: stereoselective synthesis of amino enols of fused uracils containing a sugar moiety by hetero-Diels–Alder reactions of barbituric acid 5-ylidene alditols with dimedone enamines
“…It should be noted that the α, β-unsaturated carbonyl compound 3 is a latent form of the crossconjugated endion system of the easily react with enolic dienophiles via heterocyclization of Diels-Alder. At the same time, a pyran cycle is formed [20][21][22].…”
The aim of this work is the synthesis of new tetraheterocyclic compounds of interest as potential biologically active substances that include the isoxazole and chromone moieties in their structure. The synthesis of such compounds was carried out with two stages. By Knoevenagel condensation of 3-methyl-1,2-isoxazol-5(2H)-on with salicylic aldehyde (4Z)-4-(2-hydro-xybenzyliden)-3-methyl-1,2-oxazol-5(4H)-on was obtained. In this reaction an excess of half of the aldehyde equivalent was used to increase the yield of the product. Pyperidine was used as a catalyst. The reaction was carried out by boiling the components in ethyl acetate. The reaction of the resulting benzylidenisoxazole derivative with cyclohexane-1,3-dione or dimedone was performed by boiling the components in ethanol without the use of a catalyst. The interaction mechanism includes heterodiene Dielsa-Aldera condensation followed by dehydration of one water molecule. As a result, 3-methyl-4-(2-hydroxyphenyl-5,6,7,8-tetrahydroisoxazolo[5,4-b]chromene-5(4H)-one and 3,7,7-trimethyl-4-(2-hydroxyphenyl)-5,6,7,8,9-tetrahydroisoxazolo[5,4-b]chromen-5(4H)–one were obtained. Purification of the synthesized compounds was carried out by crystallization from ethanol. All the obtained compounds were characterised by IR 1H NMR and UV spectroscopies. In 1H NMR spectra there are signals of the methyl groups of the isoxazole ring of compounds at 2.26, 2.29, 2.34 ppm respectively. In the UV spectrum of a plane molecule of (4Z)-4-(2-hydroxybenzyliden)-3-methyl-1,2-oxazol-5(4H)-on there is a long-wave absorption maximum (400.9 nm) corresponding to the joint system of conjugated bonds of the isoxazole and aromatic rings. The structures of the obtained compounds were confirmed by high resolution mass-spectrometry analysis. In the spectra of 3-methyl-4-(2-hydroxyphenyl-5,6,7,8-tetrahydroisoxazolo[5,4-b]chromene-5(4H)-one and 3,7,7-trimethyl-4-(2-hydroxyphenyl)-5,6,7,8,9-tetrahydroisoxazolo[5,4-b]chromen-5(4H)–one the[M + Na]+ ion peaks were observed. The presence of fragment peaks [M + Na – CO]+ and [M + Na – CO – H2O]+ confirms the presence of hydroxy and carbonyl groups in the molecules.
“…It should be noted that the α, β-unsaturated carbonyl compound 3 is a latent form of the crossconjugated endion system of the easily react with enolic dienophiles via heterocyclization of Diels-Alder. At the same time, a pyran cycle is formed [20][21][22].…”
The aim of this work is the synthesis of new tetraheterocyclic compounds of interest as potential biologically active substances that include the isoxazole and chromone moieties in their structure. The synthesis of such compounds was carried out with two stages. By Knoevenagel condensation of 3-methyl-1,2-isoxazol-5(2H)-on with salicylic aldehyde (4Z)-4-(2-hydro-xybenzyliden)-3-methyl-1,2-oxazol-5(4H)-on was obtained. In this reaction an excess of half of the aldehyde equivalent was used to increase the yield of the product. Pyperidine was used as a catalyst. The reaction was carried out by boiling the components in ethyl acetate. The reaction of the resulting benzylidenisoxazole derivative with cyclohexane-1,3-dione or dimedone was performed by boiling the components in ethanol without the use of a catalyst. The interaction mechanism includes heterodiene Dielsa-Aldera condensation followed by dehydration of one water molecule. As a result, 3-methyl-4-(2-hydroxyphenyl-5,6,7,8-tetrahydroisoxazolo[5,4-b]chromene-5(4H)-one and 3,7,7-trimethyl-4-(2-hydroxyphenyl)-5,6,7,8,9-tetrahydroisoxazolo[5,4-b]chromen-5(4H)–one were obtained. Purification of the synthesized compounds was carried out by crystallization from ethanol. All the obtained compounds were characterised by IR 1H NMR and UV spectroscopies. In 1H NMR spectra there are signals of the methyl groups of the isoxazole ring of compounds at 2.26, 2.29, 2.34 ppm respectively. In the UV spectrum of a plane molecule of (4Z)-4-(2-hydroxybenzyliden)-3-methyl-1,2-oxazol-5(4H)-on there is a long-wave absorption maximum (400.9 nm) corresponding to the joint system of conjugated bonds of the isoxazole and aromatic rings. The structures of the obtained compounds were confirmed by high resolution mass-spectrometry analysis. In the spectra of 3-methyl-4-(2-hydroxyphenyl-5,6,7,8-tetrahydroisoxazolo[5,4-b]chromene-5(4H)-one and 3,7,7-trimethyl-4-(2-hydroxyphenyl)-5,6,7,8,9-tetrahydroisoxazolo[5,4-b]chromen-5(4H)–one the[M + Na]+ ion peaks were observed. The presence of fragment peaks [M + Na – CO]+ and [M + Na – CO – H2O]+ confirms the presence of hydroxy and carbonyl groups in the molecules.
“…Our group also described a convenient and efficient method for the synthesis of chromeno[2,3- d ]pyrimidine-2,4-diones containing different sugar moieties [ 84 ]. Dimedone enamines were used as dienophiles in hetero-Diels–Alder reactions.…”
Section: -Glycosides As Antidiabetic Agentsmentioning
confidence: 99%
“…None of the C -glycosyl derivatives of chromeno[2,3- d ]pyrimidines 339 have been examined as inhibitors in the treatment of type 2 diabetes. Scheme 53 Synthesis of C -glycosides-chromeno[2,3- d ]pyrimidines 339 containing different sugar moieties [ 84 ] …”
Section: -Glycosides As Antidiabetic Agentsmentioning
confidence: 99%
“… Synthesis of C -glycosides-chromeno[2,3- d ]pyrimidines 339 containing different sugar moieties [ 84 ] …”
Section: -Glycosides As Antidiabetic Agentsmentioning
This review is an effort to summarize recent developments in synthesis of
O
-glycosides and
N
-,
C
-glycosyl molecules with promising antidiabetic potential. Articles published after 2000 are included. First, the
O
-glycosides used in the treatment of diabetes are presented, followed by the
N
-glycosides and finally the
C
-glycosides constituting the largest group of antidiabetic drugs are described. Within each group of glycosides, we presented how the structure of compounds representing potential drugs changes and when discussing chemical compounds of a similar structure, achievements are presented in the chronological order.
C
-Glycosyl compounds mimicking
O
-glycosides structure, exhibit the best features in terms of pharmacodynamics and pharmacokinetics. Therefore, the largest part of the article is concerned with the description of the synthesis and biological studies of various
C
-glycosides. Also
N
-glycosides such as
N
-(β-
d
-glucopyranosyl)-amides,
N
-(β-
d
-glucopyranosyl)-ureas, and 1,2,3-triazolyl derivatives belong to the most potent classes of antidiabetic agents. In order to indicate which of the compounds presented in the given sections have the best inhibitory properties, a list of the best inhibitors is presented at the end of each section. In summary, the best inhibitors were selected from each of the summarizing figures and the results of the ranking were placed. In this way, the reader can learn about the structure of the compounds having the best antidiabetic activity. The compounds, whose synthesis was described in the article but did not appear on the figures presenting the structures of the most active inhibitors, did not show proper activity as inhibitors. Thus, the article also presents studies that have not yielded the desired results and show directions of research that should not be followed. In order to show the directions of the latest research, articles from 2018 to 2019 are described in a separate Sect.
5
. In Sect.
6
, biological mechanisms of action of the glycosides and patents of marketed drugs are described.
“…Enamines take part in Diels–Alder reactions with reverse electron demand with various classes of dienes, providing access to highly involved molecular frameworks. Electron‐rich enamines have found use in inverse electron demand [4 + 2] cycloadditions, but there are no reports of the use of weaker dienophiles such as enamines of dimedone . A second group of generally used compounds are enaminones which come from the addition of aliphatic and aromatic amines to activated alkynes carrying carbonyl groups.…”
A Schiff base based on chitosan was synthesized through treatment of chitosan and p-dimethylaminobenzaldehyde in methanol solution. This biopolymeric Schiff base was used to prepare a new first row transition metal complex of Ni(II). The biopolymeric Schiff base and the synthesized tetra-coordinated complex were characterized using Fourier transform infrared, 1 H NMR and 13 C NMR techniques. Then, an efficient synthetic method for functionalized 1H-pyrazolo[1,2-b] phthalazine-5,10-diones was successfully developed using one-pot domino reaction of ninhydrin and malononitrile with 3-arylamino-5,5-dimethyl-2-cyclohexenones catalysed by the chitosan-based Schiff base complex of Ni(II) at room temperature. The advantages of this protocol are easy work-up, short reaction times and high yield of products and also the catalyst can be readily isolated from the reaction mixture and recycled without loss of catalytic activity.
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