Barbituric acid Knoevenagel reaction

The Knoevenagel reaction consists in the condensation of aldehydes or ketones with active methylene compounds usually performed in the presence of a weakly basic amine (Scheme 29) [116], It is well-known that aldehydes are much more reactive than ketones, and active methylene substrates employed are essentially those bearing two electron-withdrawing groups. Among them, 1,3-dicarbonyl derivatives are particularly common substrates, and substances such as malonates, acetoacetates, acyclic and cyclic 1,3-diketones, Meldrum s acid, barbituric acids, quinines, or 4-hydroxycoumarins are frequently involved. If Z and Z groups are different, the Knoevenagel adduct can be obtained as a mixture of isomers, but the reaction is thermodynamically controlled and the major product is usually the more stable one. 

Interestingly enough, a closely related protocol was successfully proposed for the synthesis of spirooxindoles-containing tetrahydrochromene skeletons when aromatic aldehydes were switched for isatin derivatives. This high-yielded reaction was performed with dimedone, 4-hydroxycoumarin, or barbituric acids in water using triethylbenzylammonium chloride (TEBA) as catalyst (Scheme 36) [125]. A Knoevenagel condensation occurred first between isatin and malonitrile derivative, followed by Michael addition of 1,3-dicarbonyl substrates and cyclization to the cyano moiety. 

One of the most reactive 1,3-dicarbonyl compounds used in the domino-Knoevenagel-hetero-Diels-Alder reaction is N,N-dimethyl barbituric acid 2. It has been shown that the fairly stable products can easily been transformed into other compounds via a reduction of the urea moiety with DIBAL-H [20]. Thus, reaction of 30 with DIBAL-H at 78 °C led to 46, which can be hydrolyzed to give 47 (Scheme 5.9). In a similar way, 48 was transformed into 50 via 49 and 12 to 52 via 51. The obtained compounds containing a lactone and an amide moiety can again be further transformed using DIBAL-H followed by an elimination. In this way, dihydropyran 54 is obtained from 50 via 53 as one example. 

Malonomonoamides can be condensed with aldehydes to give acrylamides or cinnanamides, but condensation with malonodiamides is of only minor impjortance. In contrast to Meldrum s acid (58), Knoevenagel reactions of barbituric acid (56) and A A -dimethylbarbituric acid have been less explored. However, several aliphatic, aromatic and heteroaromatic aldehydes are known to react easily and with high yields in most cases. Reactions of 1,2-dimethyl-3,5-pyrazolidinedione (93) with several aliphatic and aromatic aldehydes using standard conditions yield Knoevenagel products in good yield. A similar reactivity is observed with 2-phenyl-3,5-dioxoisoxazolidine (94) and oxazepanediones (45 see Section 1.11.2.5). Recently, the oxidations of alcohols to carbonyl compxiunds and thiols to disulfides with 5-arylidene-l,3-dimethylbarbituric acids (95) have been described Mechanistically (95) mimics enzymic oxidation by flavin adenine dinucletide (FAD). ... 

Less common are literature examples in which mechanochemical reaction was carried out at elevated temperature. Naimi-Jamal reported the heating of double-walled ball-mill beaker equipped with fittings for circulating water at 96°C (boiling water as circulant) [45]. One-pot solvent-free synthesis of pyrano[2,3-d]pyrimidine-2,4(lFf,3F0-diones 154 was achieved by simply ball milling a stioichiometric mixture of an aromatic aldehyde, malononitrile, and barbituric acid, without addition of solvent and catalyst (Scheme 2.53). Quantitative yields were obtained (Table 2.47) and products generally did not require purification, the solid products were just dried at 80°C in vacuum and recrystaUized, if necessary. Reaction presumably takes place by initial Knoevenagel condensation of aromatic aldehyde with malononitrile to afford the intermediate Michael acceptor, which subsequently reacts with barbituric acid. Tautomerization of Michael adduct is followed by intramolecular cyclocondensation and another tautomerization to afford pyrano[2,3-d]pyrimidine-2,4(177,37f)-diones 154. 

Selenophene-2-aldehyde takes part in the Hantzsch synthesis [Eq. (I)]108 and reacts readily with ammonia, aromatic amines and diamines,109 hippuric, barbituric, and malonic acids, malononitrile,70 and rhodanine.109 /3-(Selenien-2-yl)acrylic acid has been obtained from selenophene-2-aldehyde by the Perkin reaction and by Knoevenagel condensation with malonic acid.70 Esters of /9-(selenien-2-yl)acrylic acid are easily formed by condensation of the aldehyde... 

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