Reactions at the Carboxyl Functions

The focus so far on reactions of the malonate methylene moiety does not diminish the utUity of synthesis routes that exploit the reactivity on the ester (or acid) groups. In spite of their less frequent use, such strategies have important roles in appropriate cases. 

The coupling of 3-tert-butyl [1 - C]malonate (393) with the /3-amino acid derivative 395 to give amide 396 was developed as an alternative route to the 1,4 addition of 395 to the corresponding [l- C]acrylate 394, which might have failed due to radiation-induced polymerization. Subsequent treatment with 2,4-bis(4-methoxyphenyl)-l,3,2,4-dithiadi-phosphetane-2,4-disulfide (Lawesson s reagent) followed by Raney nickel-mediated desulfurization of the thioamide function formed converted 396 into the target /3-amino acid ester 397. Intramolecular ester condensation upon treatment of 397 with sodium methoxide and concluding saponification and decarboxylation of the f-butyl ester function afforded the trisubstituted 4-[2- C]piperidone derivative 398. 

Treatment of diethyl [2- C]malonate with two equivalents of formamide and sodium ethoxide at elevated temperature provided 4,6-dihydro[5- C]pyrimidine 14021. which served as a key intermediate in the synthesis of 5-amino-4-iodo[5- C]pyrimidine and the corresponding dehalogenated species, both important pharmacophoric substructures in the design of new pharmacologically active drug candidates.  

R = Ph, R R = H hexobarbital, 406, R =Me R = cyclohexen-l-yl, R =Me, R = H) °. [5- C]Barbituric acid (408), the simplest member of this class and routinely prepared by two alternative procedures from urea and [2- C]malonic acid or its diethyl 

Reaction conditions 1. neat components 180 °C, 5 h 2. EtONa, EtOH 110°C  

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Figure 6.117 Preparation and applications of [2d C]glycerol 6.5.2 Reactions at the Carboxyl Functions...

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