Barbiturate synthesis, malonates

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... 

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... 

Beryllium, calcium, boron, and aluminum act in a similar manner. Malonic acid is made from monochloroacetic acid by reaction with potassium cyanide followed by hydrolysis. The acid and the intermediate cyanoacetic acid are used for the synthesis of polymethine dyes, synthetic caffeine, and for the manufacture of diethyl malonate, which is used in the synthesis of barbiturates. Most metals dissolve in aqueous potassium cyanide solutions in the presence of oxygen to form complex cyanides (see Coordination compounds). 

The final step in the synthesis of all barbiturates consists in either condensation of a suitably substituted malonic or cyano-acetic ester with urea by means of sodium ethoxide (scheme a) or... 

The barbiturates were widely used as sedative-hypnotic drugs. Barbital was introduced as a drug in 1903. The method of synthesis for thousands of its analogs has undergone little change. Urea reacts with various derivatives of malonic acid, usually a diethyl ester of a dialkyl substituted malonic acid. This is a classic example of a nucleophilic acyl substitution. A derivative of ammonia reacts with esters to form an amide, only in this case a cyclization to a strainless six-membered ring results because of the proximity of the bifunctionality. 

Diesters are malonates, and are often used for the synthesis of barbiturates. Malonyl dichlorides can be used in place of a malonyl diesters, in which case the reaction can be performed at room temperature, as demonstrated by the synthesis of A-phenyl and A -pyridyl 2-thiobarbituric acids 666 from malonyl dichloride 664 and A, iV -diarylureas 665 <2002AJC287>. 

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). 

Dicarbonyl compounds, such as malonate derivatives, can also be classified under two categories. As well as reacting simply as a three-atom bis-electrophilic fragment (as in the synthesis of barbiturate 10.25 (page 77), an alternative reactivity is available. Condensation (by nucleophilic attack) of the active methylene carbon and electrophilic reaction at just one of the carbonyl groups is a two-atom nucleophilic/electrophilic profile, as seen in the preparation of coumarin 9.16. 

Chapter 43 Malonic Ester Synthesis Synthesis of a Barbiturate... 

A further example is the zinc stearate-catalyzed addition of malonic ester derivatives to acetylene. The reaction also takes place with monosubstituted malonic esters [46]. C-vinyl malonic esters have found an application, for example, in the synthesis of barbiturates. 

The synthesis of barbiturate 36 (see Scheme 4.7) was performed next. The sodium enolate of diethyl malonate was reacted with 43, providing 44, which was converted to 2,2-disubstituted malonate 45 by reaction with allyl bromide. Reaction of 45 with urea in the presence of t-BuOK as base afforded the barbiturate 46, which was submitted to oxidative one-carbon demolition by the action of KMn04 to give carboxylic acid 47. Compound 47 was esterified with ethanol to give the target 36, but unfortunately in modest yields. 

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). 

Its structure was established by an independent synthesis (E. Fischer and Ach, 1895) from malonic acid and urea giving barbituric acid (see p 404) and its 5-amino derivative 37. On treatment with potassium cyanate, 37 yielded pseudouric acid 38 which on cyclodehydration gave uric acid 33 ... 

The synthesis of barbituric acid can be best accomplished from diethyl malonate and urea, with an alkaline catalyst, such as sodium ethoxide in ethanol [113]. Barbituric acid-2- C has been prepared from urea- C and diethyl malonate [114]. The 4- C and 5- C compounds have been obtained by the pyrolysis of diethyl oxalacetate-3- C, which produced an equimolar mixture of 4- and 5- C barbituric acid after a rather lengthy procedure [115]. 

Propose syntheses of the following derivatives of diethyl malonate, each of which is a starting material for synthesis of a barbiturate. 

The synthesis of riboflavin begins (Scheme 12.115) with the formation of barbituric acid by the condensation of diethyl malonate [(CH3CH202C)2CH2] with urea [(NH2)2C=0] in ethanolic sodium ethoxide. Then, the barbituric acid can either (a) be oxidized directly to the hydrate of alloxan or (b) first be converted to the ben-zylidine adduct and then oxidized to the same compound. Both oxidations are... 

In a recent flexible synthesis, barbiturates of type 45 are obtained in a threesequential procedure from malonic add monoesters and carbodiimides in the presence of base (usually Na0H/H20) followed by alkylation [273] ... 

The synthesis of barbiturates is relatively simple and relies on reactions that are now familiar enolate alkylations and nucleophilic acyl substitutions. Starting with diethyl malonate, or malonic ester, alkylation of the corresponding enolate ion with simple alkyl halides provides a wealth of different disubstituted malonic esters. Reaction with urea, (H2N)2C=0, then gives the product barbiturates by a twofold nucleophilic acyl substitution reaction of the ester groups with the -NH2 groups of urea (Figure 22.7). Amobarbi-tal (Amytal), pentobarbital (Nembutal), and secobarbital (Seconal) are typical examples. 

Scheme 4.1. Synthesis of barbituric acid as first carried out by von Baeyer, Subsequently, it was discovered that the dIester form of malonic acid (the compound on the left) and Its derivatives could likewise be condensed with urea (the compound In the middle), often in better yield.

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