A Green Approach to the Synthesis of Fused Uracils: Pyrano[2,3-d]pyrimidines. ‘On-Water’ One-Pot Synthesis by Domino Knoevenagel/Diels-Alder Reactions

Abstract

On-water' Knoevenagel condensations of 2-thiobarbituric acid and N,N-dimethylbarbituric acid with aromatic and heteroaromatic aldehydes were carried out without a catalyst and at room temperature. Condensations in aqueous suspensions occurred rapidly, giving excellent yields. Solvent-free hetero-Diels-Alder reactions of 5-arylidene derivatives of barbituric acids with ethyl vinyl ether were investigated at room temperature and pyrano [2,3-d]pyrimidines of potential pharmacological activity were obtained in excellent yields. Three-component one-pot syntheses of annulated uracils were performed in aqueous suspensions. Reactions of barbituric acids, aldehydes, and ethyl vinyl ether were carried out at ambient temperature, whereas the one-pot synthesis with barbituric acids, aldehydes, and styrene or N-vinyl-2-oxazolidinone required the heating of aqueous suspensions at 60°C. 'On-water' cycloadditions were characterized by high diastereoselectivity in contrast to reactions carried out in homogeneous organic media (dichloromethane, toluene). They allowed the cis adducts to be obtained preferentially or exclusively. The presented green methods avoid the use of catalysts, the heating of reaction mixtures for long times at high temperatures, and the use of organic solvents, and make the synthesis of a variety of pyrano[2,3-d]pyrimidines chemically efficient. The results reveal water as the medium of choice for the examined cycloadditions.Water is the solvent of choice for nature to carry out syntheses of complex organic molecules. Water is a clean, inexpensive, environmentally friendly reaction medium. Therefore the choice of water as solvent for organic reactions in the laboratory is obvious. However, water as a solvent was ruled out from organic reactions during the preceding decades. The situation changed in 1980 by the pioneering work of Breslow and Rideout, who demonstrated that Diels-Alder reactions of water-soluble reagents would be greatly accelerated in aqueous solution. 1a In 2005, Sharpless and co-workers demonstrated that the Diels-Alder reaction of the water-insoluble reactants showed substantial rate acceleration in aqueous suspension over homogeneous solution. 1b Hydrophobic interactions of reagents with water are invoked for the observed effects.Barbituric acids and their derivatives are reported to have a wide range of pharmacological activities. For example, 5,5-disubstituted derivatives, known as barbiturates, are a family of valuable drugs that depress nerve activity. 2 5-Arylidene derivatives of barbituric acids are bioactive compounds 3 and are also important intermediates in the preparation of other pharmaceuticals, for example annulated uracils. Uracil and its fused derivatives, such as pyrano[2,3-d]pyrimidines, pyrido[2,3-d]pyrimidines, pyrazo[3,4-d]pyrimidines, or pyrimido[4,5-d]pyrimidines, are reported to have a wide range of biological activities such as antiallergic, 4 antihypertensive, 5 cardiotonic, 6 bronchiodilator, 7 antibronchitic, 8 or antitumor 9 activity.The preparation of the above...

Benign by design: catalyst-free in-water, on-water green chemical methodologies in organic synthesis

“…On-water Knoevenagel condensations of 2-thiobarbituric acid and N,N-dimethylbarbituric acid with aromatic and heteroaromatic aldehydes under catalyst-free conditions have also been explored. 155…”

Small Heterocyclic D‐π‐D‐π‐A Push‐Pull Molecules with Complex Electron Donors

“…All target chromophores 1-4 except 2 d [41] are new compounds. However, several structural analogues with a different N-alkyl thiobarbituric unit are known; namely analogues of 1 a-e, [58][59][60][61] 2 a, 2 c, 2 d, [34,40,[62][63][64] 3 a, [62,65] and 4 a, 4 c. [40,[62][63][64]66] The preparations and characterizations of new aldehydes 7 c, 7 e, and 8 e are given in the SI. The starting aldehydes 5 a-e, 6 a, 7 a, and 8 a as well as N,N'dibutyl-2-thiobarbituric acid (DBTBA) are commercially available.…”

“…All target chromophores 1 – 4 except 2 d [41] are new compounds. However, several structural analogues with a different N ‐alkyl thiobarbituric unit are known; namely analogues of 1 a – e , [58–61] 2 a , 2 c , 2 d , [34,40,62–64] 3 a , [62,65] and 4 a , 4 c [40,62–64,66] . The preparations and characterizations of new aldehydes 7 c , 7 e , and 8 e are given in the SI.…”

Recent Advances in Inverse-Electron-Demand Hetero-Diels–Alder Reactions of 1-Oxa-1,3-Butadienes

“…The described reactions give easy and rapid access to both cis - 47 as trans - 48 diastereoisomers of uracils and pure diastereoisomers can be very easily isolated by column chromatography. Also, solvent-free HDA reactions of 5-arylidene derivatives of barbituric acids 50 with ethyl vinyl ether 51 were investigated at room temperature and pyrano[2,3- d ]pyrimidines 52 and 53 were obtained in excellent yields (Scheme 9 ) [ 84 ]. Three-component one-pot syntheses of fused uracils were performed in aqueous suspensions.…”