Malonic diamide

REMFRY-HULL Pyrimidine Synthesis Synthesis of pyrimidines by condensation of malon diamides with carboxylic esters. 

Sugai and coworkers [30] have studied the substrate specificity and enantio-selectivity of NHase and amidase from R. rhodochrous IFO 15564 by applying a series of a,a-disubstituted malononitriles, which the NHase converted into the corresponding malonic diamides. Subsequently, the amidase preferentially hydrolyzed the pro-(R) amide in an enantiotopic group-selective manner. The introduction of a fluorine atom at the a-position caused an inhibitory effect on the amidase. A direct application of this route led to the synthesis of ( )-a-cyano- -fluoro-a-phenylacetic acid (CFPA). 

Barbituric acid can be considered as a cyclized malonic acid diamide (malonyl-urea). It is therefore a cyclic diketone that may be classified, in the sense of the compounds discussed in Section 12.6, as a coupling component with a methylene group activated by two carbonyl groups in the a- and a -positions. The reaction with arenediazonium salts was studied by Nesynov and Besprozvannaya (1971). These authors obtained coupling products (in good yield) that they considered to be arylhydrazones. Coupling with 4-(phenylazo)benzenediazonium chloride was studied by Chandra and Thosh (1991). The lH NMR spectra of these compounds are consistent with the arylhydrazone structure 12.68. 

Nitrition of ketones 313 and malonic acid diamide 312 also leads to the formation of furoxans 314 (Scheme 78) C1999CHE1415, 2004T1671, 2005MRC563>. 

Malonic acid diamide, m4 Malonylurea, bl Margaryl alcohol, hi a Mellitic acid, b20 MEM chloride, m74 Menadione, m321 1,8-Mentanediamine, d51 / -Mentha-1,8-diene, L17, L18 / -Mentha-6,8-dien-2-one, c20 Mercaptobenzene, tl 56... 

The acetic anhydride-induced cyclodehydration of the symmetrical diamide 411, derived from the tetrahydro-benzothiophene / -amino ester 410 and diethyl malonate, afforded the thieno[2,3-r7 [h3]oxazine derivative 413 rather than the expected bis-oxazine 412 (Scheme 78). The reaction probably takes place through sequential cyclizations, in which the pyridine ring of 413 is produced by condensation of the exocyclic double bond of the enamine tautomeric form of the 1,3-oxazine moiety and the mixed anhydride formed by the carboxylic group and acetic anhydride <2003PS245>. 

Masamune and co-workers reported that t-pr-box 22 can also be obtained from (5)-valinol by a similar strategy (see above). Thus, 21 was reacted with diethyl-malonate and the resulting diamide was treated with thionyl chloride followed by sodium hydroxide in a mixture of ethanol and tetrahydrofuran (THF) to yield t-pr-box 22 (Fig. 9.5). The synthesis of i-pr-box 22 can also be achieved directly by treatment of 21 with diethyl iminomalonate in the presence of triethylamine. ... 

The pyrido[l,2-a]pyrimidines (63) were obtained by Shur and Israelstam by reacting 2-aminopyridines and diethyl malonate in polyphosphoric acid at 160-170°C. 2-Aminopyridine and diethyl malonate at 13(TC gave the diamide (65 R = H), which could then be cyclized in polyphosphoric acid at 160 C to pyrido[l,2-ci]pyrimidine (63 R = H). From 2-amino-6-methyl-pyridine and 2-amino-5-halopyridines at temperatures up to 170°C, only the diamides (66) were isolated.41... 

If a C3 unit needs to be introduced bearing a carbon chain, then there are several options. A P-amino add could be used as a precursor in a parallel synthesis to those discussed above. Alternatively, a strategy based on malonate syntheses could be employed. Co-condensation of a C-substituted malonate with a primary diamine in boiling ethanol gives reasonable yields of cyclic diamide which may be reduced with borane in THF to yield the desired polyamine (Scheme 1.12 and Protocol 5).18 Another possibility is to prepare a linear bis-toluenesulfonate ester from a malonate by reduction (e.g. LiBH4) and tosylation, followed by a standard toluenesulfonamide cyclisation reaction. Yet another variant, this time giving racemic product, is to react a coumarin derivative with a linear polyamine (Scheme 1.12).1819 In this case, a... 

NHC(0)R 149). Malonic acid reacts with SF5NCO at BO C to give both the amide acid, SF5NHC(0)CH2C00H, and the diamide, SFsNHC(O)-CH2C(0)NHSF5 149). This diamide is also obtained from the reaction of SF5NH2 with carbon suboxide 149). 

The barbiturate series of hypnotics are easily and cheaply made from phosgene [577]. Typically, a dialkyl malonic ester is treated with strong aqueous ammonia to give the diamide of the substituted malonic acid. Equation (4.14). This substance is then heated in an autoclave with phosgene for several hours at about 100 C to give the corresponding dialkyl barbituric acid [577]. 

The diamides of malonic acid (124) confirm the 1-2 ring opening and were also detected among the degradation products.305,308,312-315 Compounds... 

The simultaneous addition of the two starting materials over an extended time period is not convenient. Tabushi and coworkers found that high-dilution techniques were not required for the reaction of diesters (including malonates) with diamines to form the cyclic bis-amides (Tabushi et al., 1976, 1977). The cyclic diamides were reduced to form the polyaza-crowns. This method, along with the yV-tosyl method for ring closure, are the most common procedures for the preparation of peraza-crowns. The yields for these ester plus amine... 

The p-cyanophenyl derivative of [14lN4-diamide was prepared in a 19% yield from the p-cyanophenyl-substituted diethyl malonate (Morphy et al., 1988). Chiral cyclic diamides were prepared from chiral tetraamines in... 

N4S-diamide systems in 19% and 36% yields, respectively, by the reaction of diethyl malonate with the appropriate polyamine (Kimura et ah, 1984b). 

The chemistry of selenazoles is reviewed in a book <04MI777>. Addition of malonic dinitrile with phosphorus pentaselenide in aqueous ethanol affords selenomalonic diamide 282, which undergoes double cyclization with phenacyl bromide to furnish bis(selenazole) 283 <04S875>. 2-Acyl-l,3-selenazoles 287 are prepared in two steps from bromomethyl ketones 284 and selenoamides 285. A facile preparation of l,3-selenazole-5-carboxylic acids 289 is based on the cyclization of selenazadienes 288 with chloroacetyl chloride <048233>. 

Trochimczuk A.W. Chelating resins with N-substituted diamides of malonic acid as ligands. European Polymer Journal 1998 341657-1662. 

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