Barbituric acid synthesis

Heterocycles are almost invariably formed by inter- and intramolecular Schiff base or lactam formation. We cite here the classical Knorr pyrrole synthesis (see Scheme 1.3.4) and Baeyer s barbituric acid synthesis, where the amide nitrogen atoms of urea are nucleophilic enough to add to malonic acid esters (Scheme 1.4.2). 

Diethyl malonate has uses other than m the synthesis of carboxylic acids One particu larly valuable application lies m the preparation of barbituric acid by nucleophilic acyl substitution with urea... 

Barbituric acid — see also Pyrimidine-2,4,6-trione, perhydro-acidic pK, 3, 60 bromination, 3, 70 fluorination, 3, 70 structure, 3, 68 tautomerism, 2, 27 in thermography, 1, 392 Barbituric acid, iV-alkyl-chlorination, 3, 70 Barbituric acid, 5-aminomethylene-synthesis, 3, 524 Barbituric acid, 5-arylidene-pyridopyrimidines from, 3, 227 Barbituric acid, 1,3-dicyclohexyl-synthesis, 3, 113 Barbituric acid, 2-thio-sensitizing dye... 

The one-pot MCR of methylene active nitriles 47 has been used in the synthesis of both pyrano- and pyrido[2,3-d]pyrimidine-2,4-diones in a single-mode microwave reactor [90]. Microwave irradiation of either barbituric acids 61 or 6-amino- or 6-(hydroxyamino)uracils 62 with triethyl-orthoformate and nitriles 47 (Z = CN, C02Et) with acetic anhydride at 75 °C for 2-8 min gave pyrano- and pyrido[2,3-d]pyrimidines in excellent yield and also provided a direct route to pyrido[2,3-d]pyrimidine N-oxides (Scheme 27). 

The manufacture of P.Y.139 may serve as an example for the synthesis of a me-thine pigment. P.Y.139 is the condensation product of diiminoisoindoline with 2 moles of barbituric acid [18]. 

Bassani has reported the substrate-templated photochemical synthesis of barbituric acid receptors by irradiating a solution of olefin 104 in the presence of template 105 (see Scheme 49) [122]. In the absence of such template, the major cycloadducts formed are the head-to-head (106) and head-to-tail dimers (107) (see Scheme 49). However, in the presence of barbituric acid, the distribution of products changes and the head-to-head cycloadduct is formed in higher proportions than the rest. 

Synthesis of Immunogen (Hapten) The barbiturate, 5-ally 1-5-(1-carboxyisopropyl) barbituric acid (I) is first converted to 5-allyl-5-(1 -p-n i trophenyloxycarbonylisopropyl) barbituric acid (II) by the interaction of the base with /7-nitrophenol in N, N-dimethylformamide (DMF) as shown below ... 

It would be extremely tedious for you to read the synthesis of all the barbituric acid derivatives that exist today, so I will limit you to the more widely used and important ones. I have grouped the listed barbiturates by their clinical action and the duration of that action. 

The first positive results in the synthesis of these heterocyclic compounds by MCR of aminoazoles, aldehydes, and barbituric acids were published in 2008 by Shi et al. [111]. They also used green chemistry methodology and carried out treatment of the starting materials in water under microwave irradiation. The temperature optimization procedure and search for the best catalytic system allowed selecting one equivalent of p-TSA and 140°C as optimum conditions for the synthesis. With application of the procedure elaborated 24 novel pyrazolopyr-idopyrimidines 76 were generated (Scheme 33). 

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. 

An interesting entry to functionalized dihydropyrans has been intensively studied by Tietze in the 1990s using a three-component domino-Knoevenagel Hetero-Diels-Alder sequence. The overall transformation involves the transient formation of an activated heterodienophile by condensation of simple aldehydes with 1,3-dicarbonyls such as barbituric acids [127], Meldrum s acid [128], or activated carbonyls. In situ cycloaddition with electron-rich alkenes furnished the expected functionalized dihydropyrans. Two recent examples concern the reactivity of 1,4-benzoquinones and pyrazolones as 1,3-dicarbonyl equivalents under microwave irradiation. In the first case, a new three-component catalyst-free efficient one-pot transformation was proposed for the synthesis of pyrano-1,4-benzoquinone scaffolds [129]. In this synthetic method, 2,5-dihydroxy-3-undecyl-1,4-benzoquinone, paraformaldehyde, and alkenes were suspended in ethanol and placed under microwave irradiations to lead regioselectively the corresponding pyrano-l,4-benzoquinone derivatives (Scheme 38). The total regioselectivity was... 

Muravyova EA, Shishkina SV, Musatov VI, Knyazeva IV, Shishkin OV, Desenko SM, Chebanov VA (2009) Chemoselectivity of multicomponent condensations of barbituric acids, 5-aminopyrazoles, and aldehydes. Synthesis 1375-1385... 

Cyanoguanidine is used in fertilizers as a stabilizer of NC in org synthesis of melamine, barbituric acid guanidine salts in pharmaceutical products dyestuffs and in expls. Some examples of expls contg cyanoguanidine are as follows ... 

Bacteriochlorins, 851 Barbituric acid metal complexes, 798 Barium alkoxides synthesis, 336 Barium complexes phthalocyanines, 863 porphyrins, 820 Becium homblei copper accumulation, 964 Benzaldehyde, 2-amino-self-condensation aza macrocycles from, 900 Benzamide, o-mercapto-metal complexes, 655 Benzamide oximes metal complexes, 274 Benzamidine, /V, V -diphenyl-metal complexes. 275 Benzene, 1,2-diamino-reactions with dicarbonyl compounds aza macrocycles from, 902 Benzene, 4 methylthionitroso-metal complexes, 804 Benzenedithiolates metal complexes, 605... 

Dave and Shah have reported a Gould-Jacod type reaction for the microwave-assisted synthesis of thieno[3,2-e]pyrimido[ 1,2-c]pyrimidines via intermediate thieno[2,3-d ] pyrimidines (Scheme 3.46)73. A one-pot synthesis of pyrano [2,3-d]pyrimidines was also described by Kidwai and co-workers starting from thiobarbituric acids. The thio-barbituric acid intermediates were also prepared by microwave heating, using basic alumina as the solid support (Scheme 3.46)74. 

Urea may be recognised as a structural feature in the triketo form disconnection then reveals diethyl malonate as the other reagent. The synthesis of barbituric acid is therefore effected (Expt 8.36) by condensation of diethyl malonate with urea in the presence of sodium ethoxide. Barbituric acid undergoes nitration in the 5-position on treatment with fuming nitric acid, and reduction of the nitro derivative (98) yields 5-aminobarbituric acid (99) (uramil). 

Since the work of Kelly, there have been very few reports that focus upon applications of synthetic linear templates to chemical synthesis. Most recent studies have focused on systems that self-replicate [13]. A synthetic system based on a barbituric acid has been shown to organize two cinnamates in apolar media, by way of N-H N and N-H O forces, for a regiocontrolled [2 + 2] ultraviolet-(UV) induced cycloaddition reaction (Figure 3b) [16]. Similar to the system of Kelly, a mixture of products was attributed to free rotation about C-C bonds of the reactants. 

Using similar chemistry l,3-diaryl-2-thiobarbituric acid is acylated with chloroacetyl chloride in the presence of triethylamine. Subsequent (9-alkylation under the mildly basic conditions of sodium acetate yields the 5-oxo derivative <91H(32)907>. It is not necessary to use barbituric acid derivatives to accomplish synthesis of furopyrimidines. Other 6-oxopyrimidines serve well in developing analogues. For example, in a reaction similar to that described above, the acylated pyrimidine (215) undergoes cyclization to a 4-(substituted)amino compound (216) (Equation (74)) <92MI 707-03). 

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