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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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Sch1:  

Mentions: First, procedures A–D were examined for the Knoevenagel condensation of barbituric acids with aromatic aldehydes containing only one formyl group and HDA reactions with enol ether. 5-Arylidenebarbituric acids 3a–3c, as potential heterodienes in Diels-Alder reactions, were synthesized by condensations of N,N′-dimethylbarbituric acid (1a) or barbituric acid (1b) with aromatic aldehydes 2a–2c in water without catalyst and at room temperature according the procedure described in the literature [37] (Scheme 1). The condensations occurred smoothly and were completed in just an hour, giving excellent yields (95–98 %) of Knoevenagel products 3a–3c. The cycloaddition reactions of 3a–3c with a tenfold excess of ethyl vinyl ether 4 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 1. New 2H-pyrano[2,3-d]pyrimidine-2,4(3H)-diones 5a–5c were obtained in 77–88 % yields (Scheme 1; Table 1). Next, three-component one-pot synthesis of uracils 5a–5c by domino Knoevenagel/Diels-Alder reactions was investigated in methylene chloride (conditions C) or in aqueous medium (conditions D). The experimental procedure was simple: equimolar amounts of barbituric acid 1a or 1b and aromatic aldehyde 2a–2c were mixed with a tenfold excess of enol ether 4 in methylene chloride (conditions C) or in aqueous medium (conditions D) (Scheme 1; Table 1). The progress of the reactions was monitored by TLC. The ratios of the cis/trans diastereoisomers of the pyrano[2,3-d]pyrimidine-2,4-diones 5a–5c were determined on the basis of 1H NMR spectra of the crude products, analyzing the signals of protons 5-H and 7-H. The unexpected 5-methyl-substituted derivatives of pyrano[2,3-d]pyrimidines 6a–6b were obtained in aqueous medium (conditions D). This was determined on the basis of the 1H NMR spectra of the crude products. Formation of these compounds can be explained as the result the three-component reaction of barbituric acid 1a or 1b, the in situ generated acetaldehyde and ethyl-vinyl ether 4. The addition of water to ether 4 catalyzed by barbituric acid provides a hemiacetal, which undergoes ethanol elimination to produce the enol tautomer or finally keto tautomer of acetaldehyde. Only compounds cis-6a and trans-6a were separated in small amounts by column chromatography.Scheme 1


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

Sch1:  
Mentions: First, procedures A–D were examined for the Knoevenagel condensation of barbituric acids with aromatic aldehydes containing only one formyl group and HDA reactions with enol ether. 5-Arylidenebarbituric acids 3a–3c, as potential heterodienes in Diels-Alder reactions, were synthesized by condensations of N,N′-dimethylbarbituric acid (1a) or barbituric acid (1b) with aromatic aldehydes 2a–2c in water without catalyst and at room temperature according the procedure described in the literature [37] (Scheme 1). The condensations occurred smoothly and were completed in just an hour, giving excellent yields (95–98 %) of Knoevenagel products 3a–3c. The cycloaddition reactions of 3a–3c with a tenfold excess of ethyl vinyl ether 4 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 1. New 2H-pyrano[2,3-d]pyrimidine-2,4(3H)-diones 5a–5c were obtained in 77–88 % yields (Scheme 1; Table 1). Next, three-component one-pot synthesis of uracils 5a–5c by domino Knoevenagel/Diels-Alder reactions was investigated in methylene chloride (conditions C) or in aqueous medium (conditions D). The experimental procedure was simple: equimolar amounts of barbituric acid 1a or 1b and aromatic aldehyde 2a–2c were mixed with a tenfold excess of enol ether 4 in methylene chloride (conditions C) or in aqueous medium (conditions D) (Scheme 1; Table 1). The progress of the reactions was monitored by TLC. The ratios of the cis/trans diastereoisomers of the pyrano[2,3-d]pyrimidine-2,4-diones 5a–5c were determined on the basis of 1H NMR spectra of the crude products, analyzing the signals of protons 5-H and 7-H. The unexpected 5-methyl-substituted derivatives of pyrano[2,3-d]pyrimidines 6a–6b were obtained in aqueous medium (conditions D). This was determined on the basis of the 1H NMR spectra of the crude products. Formation of these compounds can be explained as the result the three-component reaction of barbituric acid 1a or 1b, the in situ generated acetaldehyde and ethyl-vinyl ether 4. The addition of water to ether 4 catalyzed by barbituric acid provides a hemiacetal, which undergoes ethanol elimination to produce the enol tautomer or finally keto tautomer of acetaldehyde. Only compounds cis-6a and trans-6a were separated in small amounts by column chromatography.Scheme 1

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