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Synthesis of fused uracils: pyrano[2,3-d]pyrimidines and 1,4-bis(pyrano[2,3-d]pyrimidinyl)benzenes by domino Knoevenagel/Diels-Alder reactions.

Pałasz A - Monatsh. Chem. (2012)

Bottom Line: Knoevenagel condensation of barbituric acids with aromatic aldehydes containing one or two formyl groups was carried out. 5-Arylidenebarbituric acids underwent smooth hetero-Diels-Alder (HDA) reactions with enol ethers to afford cis and trans diastereoisomers of pyrano[2,3-d]pyrimidine-2,4-diones and 5,5'-(1,4-phenylene)bis[2H-pyrano[2,3-d]pyrimidine-2,4(3H)-dione] derivatives in excellent yields (75-88 %).All reactions were carried out without catalyst at room temperature.The reactions of malononitrile with Knoevenagel condensation products of barbituric acids and heteroaromatic aldehydes or terephthalaldehyde were examined and did not provide corresponding pyranopyrimidines. .

View Article: PubMed Central - PubMed

Affiliation: Department of Organic Chemistry, Jagiellonian University, Kraków, Poland.

ABSTRACT

Abstract: Knoevenagel condensation of barbituric acids with aromatic aldehydes containing one or two formyl groups was carried out. 5-Arylidenebarbituric acids underwent smooth hetero-Diels-Alder (HDA) reactions with enol ethers to afford cis and trans diastereoisomers of pyrano[2,3-d]pyrimidine-2,4-diones and 5,5'-(1,4-phenylene)bis[2H-pyrano[2,3-d]pyrimidine-2,4(3H)-dione] derivatives in excellent yields (75-88 %). Syntheses were realized by Knoevenagel condensation and HDA reaction in four different reaction conditions: Knoevenagel condensation in water and Diels-Alder reaction in methylene chloride solution, Knoevenagel condensation in water and Diels-Alder reaction without solvent, three-component one-pot reaction in methylene chloride solution, or three-component one-pot reaction in water. All reactions were carried out without catalyst at room temperature. The reactions of malononitrile with Knoevenagel condensation products of barbituric acids and heteroaromatic aldehydes or terephthalaldehyde were examined and did not provide corresponding pyranopyrimidines.

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Sch2:  

Mentions: In the second step of the studies, it was decided to test the synthetic approach to the Knoevenagel condensation of barbituric acid with an aromatic aldehyde containing two formyl groups, terephthalaldehyde. HDA reactions with enol ether were performed in conditions A–D. Condensation of N,N′-dimethylbarbituric acid with terephthalaldehyde (2d) was carried out in water without catalyst and at room temperature, giving Knoevenagel product 3d with 97 % yield after 1 h (Scheme 2). It is worth noting that there is only one synthetic method for this compound described in the literature [38], but it required drastic conditions, with acetic acid and sulfuric acid as the reactive media. The cycloaddition reactions of 3d with a tenfold excess of enol ethers 4a–4c were performed with methylene chloride as the solvent (conditions A) or in the absence of solvent (conditions B) at room temperature for the time given in Table 2. Also three-component one-pot syntheses of compounds 7a–7c by domino Knoevenagel/Diels-Alder reactions were investigated in conditions C and D. Equimolar amounts of N,N′-dimethylbarbituric acid and 1,4-benzenedicarbaldehyde were mixed with a tenfold excess of enol ethers 4a–4c in methylene chloride (conditions C) or in aqueous medium (conditions D) (Scheme 2; Table 2). 5,5′-(1,4-Phenylene)bis[2H-pyrano[2,3-d]pyrimidine-2,4(3H)-dione] derivatives 7a–7c were obtained in 75–82 % yields. The progress of the reactions was monitored by TLC. The ratios of the cis/trans diastereoisomers of cycloadducts 7a–7c were determined on the basis of 1H NMR spectra of crude products, analyzing the signals of protons 5-H and 7-H. Cycloadducts cis-7a–7c were the major products. The unexpected pyrano[2,3-d]pyrimidines 6a–6c (conditions D) and 8a–8c (conditions C, D) were also obtained in small amounts. It was determined on the basis of the 1H NMR spectra of the crude products. Formation of compounds 6a–6c was explained above. Cycloadducts 8a–8c were obtained as the result of Knoevenagel reaction of barbituric acid 1a and only one formyl group of dicarbaldehyde 2d. Only compounds cis-6a, trans-6a, cis-8a, and trans-8a were isolated by column chromatography.Scheme 2


Synthesis of fused uracils: pyrano[2,3-d]pyrimidines and 1,4-bis(pyrano[2,3-d]pyrimidinyl)benzenes by domino Knoevenagel/Diels-Alder reactions.

Pałasz A - Monatsh. Chem. (2012)

 
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4495049&req=5

Sch2:  
Mentions: In the second step of the studies, it was decided to test the synthetic approach to the Knoevenagel condensation of barbituric acid with an aromatic aldehyde containing two formyl groups, terephthalaldehyde. HDA reactions with enol ether were performed in conditions A–D. Condensation of N,N′-dimethylbarbituric acid with terephthalaldehyde (2d) was carried out in water without catalyst and at room temperature, giving Knoevenagel product 3d with 97 % yield after 1 h (Scheme 2). It is worth noting that there is only one synthetic method for this compound described in the literature [38], but it required drastic conditions, with acetic acid and sulfuric acid as the reactive media. The cycloaddition reactions of 3d with a tenfold excess of enol ethers 4a–4c were performed with methylene chloride as the solvent (conditions A) or in the absence of solvent (conditions B) at room temperature for the time given in Table 2. Also three-component one-pot syntheses of compounds 7a–7c by domino Knoevenagel/Diels-Alder reactions were investigated in conditions C and D. Equimolar amounts of N,N′-dimethylbarbituric acid and 1,4-benzenedicarbaldehyde were mixed with a tenfold excess of enol ethers 4a–4c in methylene chloride (conditions C) or in aqueous medium (conditions D) (Scheme 2; Table 2). 5,5′-(1,4-Phenylene)bis[2H-pyrano[2,3-d]pyrimidine-2,4(3H)-dione] derivatives 7a–7c were obtained in 75–82 % yields. The progress of the reactions was monitored by TLC. The ratios of the cis/trans diastereoisomers of cycloadducts 7a–7c were determined on the basis of 1H NMR spectra of crude products, analyzing the signals of protons 5-H and 7-H. Cycloadducts cis-7a–7c were the major products. The unexpected pyrano[2,3-d]pyrimidines 6a–6c (conditions D) and 8a–8c (conditions C, D) were also obtained in small amounts. It was determined on the basis of the 1H NMR spectra of the crude products. Formation of compounds 6a–6c was explained above. Cycloadducts 8a–8c were obtained as the result of Knoevenagel reaction of barbituric acid 1a and only one formyl group of dicarbaldehyde 2d. Only compounds cis-6a, trans-6a, cis-8a, and trans-8a were isolated by column chromatography.Scheme 2

Bottom Line: Knoevenagel condensation of barbituric acids with aromatic aldehydes containing one or two formyl groups was carried out. 5-Arylidenebarbituric acids underwent smooth hetero-Diels-Alder (HDA) reactions with enol ethers to afford cis and trans diastereoisomers of pyrano[2,3-d]pyrimidine-2,4-diones and 5,5'-(1,4-phenylene)bis[2H-pyrano[2,3-d]pyrimidine-2,4(3H)-dione] derivatives in excellent yields (75-88 %).All reactions were carried out without catalyst at room temperature.The reactions of malononitrile with Knoevenagel condensation products of barbituric acids and heteroaromatic aldehydes or terephthalaldehyde were examined and did not provide corresponding pyranopyrimidines. .

View Article: PubMed Central - PubMed

Affiliation: Department of Organic Chemistry, Jagiellonian University, Kraków, Poland.

ABSTRACT

Abstract: Knoevenagel condensation of barbituric acids with aromatic aldehydes containing one or two formyl groups was carried out. 5-Arylidenebarbituric acids underwent smooth hetero-Diels-Alder (HDA) reactions with enol ethers to afford cis and trans diastereoisomers of pyrano[2,3-d]pyrimidine-2,4-diones and 5,5'-(1,4-phenylene)bis[2H-pyrano[2,3-d]pyrimidine-2,4(3H)-dione] derivatives in excellent yields (75-88 %). Syntheses were realized by Knoevenagel condensation and HDA reaction in four different reaction conditions: Knoevenagel condensation in water and Diels-Alder reaction in methylene chloride solution, Knoevenagel condensation in water and Diels-Alder reaction without solvent, three-component one-pot reaction in methylene chloride solution, or three-component one-pot reaction in water. All reactions were carried out without catalyst at room temperature. The reactions of malononitrile with Knoevenagel condensation products of barbituric acids and heteroaromatic aldehydes or terephthalaldehyde were examined and did not provide corresponding pyranopyrimidines.

Graphical abstract: .

No MeSH data available.


Related in: MedlinePlus