Decarbonylation of tetrasubstituted barbituric acids as a versatile method for preparation of N,N',2,2-tetrasubstituted malonamides

Article abstract of DOI:10.1016/S0040-4039(00)00852-2

A procedure for the preparation of 1,3,5,5-tetrasubstituted- 2,3,4(1H,3H,5H)pyrimidinetriones (barbituric acids) through alkylation of the less substituted 2,3,4(1H,3H,5H)pyrimidinetriones (barbituric acids) and decarbonylation of the tetrasubstituted product into the N,N,2,2- tetrasubstituted-manlonamides are described. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00852-2

Tetrahedron Letters 41 (2000) 5325±5328
Decarbonylation of tetrasubstituted barbituric acids as a
versatile method for preparation of N,N0,2,2-tetrasubstituted
malonamides
Branko S. Jursic*
Department of Chemistry, University of New Orleans, New Orleans, Louisiana 70148, USA
Received 20 April 2000; accepted 25 May 2000
Abstract
A procedure for the preparation of 1,3,5,5-tetrasubstituted-2,3,4(1H,3H,5H)pyrimidinetriones (barbi-
turic acids) through alkylation of the less substituted 2,3,4(1H,3H,5H)pyrimidinetriones (barbituric acids)
and decarbonylation of the tetrasubstituted product into the N,N0,2,2-tetrasubstituted-manlonamides are
described. # 2000 Elsevier Science Ltd. All rights reserved.
Keywords: 2,3,4(1H,3H,5H)pyrimidinetriones (barbituric acids); 1,3,5,5-tetrasubstituted-barbituric acid; N,N0,2,2-tetra-
substituted-malonamides; malonamides.
Malonamide derivatives have a broad range of general applications. For instance, quinolyl
malonamide derivatives are used in metal complexation.1 The uptake of metal ions by extraction
chromatography was achieved by using dimethyl dibutyl tetradecyl-1,3-malonamide (DMDBT-
DMA) as the stationary phase.2 There is also one special application of malonamide derivatives
in pharmaceutical chemistry, which is their control of epileptic seizures.3 In general, epilepsy
refers to any of a variety of disorders marked by disturbed electrical rhythms of the central nervous
system, and typically manifests itself in the form of convulsive attacks or seizures. Currently, the
prevalence of epilepsy is between 3 and 6 per 1000 of the population.
It was discovered that certain malonamides exhibit anticonvulsant activity. Of all studied
malonamide derivatives, the most promising results were obtained for the N-benzyl-2,2-disub-
stituted malonamides, where the 2-alkyl substituents are lower alkyls with 2 to 8 carbon atoms.3,4
The best method for the preparation of N-benzyl-2,2-dialkylmalonamides5 has been through
C-alkylation of ethyl cyanoacetate, transformation of the product into N-benzyl-2,2-dialkylated-
cyanoacetamide by further reaction with benzyl amine, and ®nally hydrolysis of the cyano
group.6,7 The last reaction is carried out under rather extreme reaction conditions (PPA/H2SO4).
* Corresponding author.
0040-4039/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00852-2

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To the best of our knowledge, there are no systematic studies of the biological activity of N,N0-
disubstituted malonamides as anti-epileptic drugs. One of the reasons is that these compounds are
not easily accessible. Here we would like to present a general method for the preparation of these
amides by decarbonylation of 2,3,4(1H,3H,5H)pyrimidinetriones (barbituric acids).
Contrary to the decarboxylation reaction, the decarbonylation reaction is not common in
organic synthesis.8 However, there are several practical procedures for decarbonylation of certain
acids such as formic, oxalic, triarylacetic, a-hydroxy, and a-keto acids. However, decarbonylation
of tetrasubstituted barbituric acids result in almost quantitative yields of malonamides (Table 1).
Table 1
Isolated yields for N-alkylated-5,5-disubstituted barbituric acids 1 and N,N0,2,2-tetrasubstituted malonamides 2
Many of the barbituric acid derivatives are commercially available or they can be readily pre-
pared from diethyl malonates and urea.9 On the other hand, 1,3,5,5-tetrasubstituted barbituric
acid can be prepared in almost quantitative yield by alkylation of the 5,5-disubstituted barbituric
acid.10 Unfortunately, preparation of 1,3-asymmetric tetrasubstituted barbituric acid by double
N-alkylation usually produces a mixture of all three products, which are hard to separate. But if
preparation starts with pure mono N-alkylated barbituric acid, introducing a second N0-alkyl
group and isolation of product is almost quantitative. In both cases the reaction of alkylation
consisted of simple mixing of equivalent amounts of barbituric acid, sodium hydroxide, and the
alkylating reagent in water/ethanol.10 The reaction mixture was stirred at room temperature for
several hours, and re¯uxed for several additional hours. The isolation of the product comprises of

5327
the evaporation of the alcohol, extraction with chloroform, and recrystallization. It is also
important to notice that the amount of the base in process of alkylation is very important. If a
substantial excess (ꢀ50%) of the base (NaOH) is used, a considerable amount of decarbonylation
product is isolated as a byproduct. About 10% excess of the base seems to produce the best
alkylation results.
Decarbonylation of the tetrasubstituted barbituric acids is also a very simple procedure.11
A
mixture of tetrasubstituted barbituric acid and 2.2 equivalents of sodium hydroxide in ethanol/
water was re¯uxed for several hours. After the evaporation of ethanol, N,N0-disubstituted malon-
amides 2 were isolated by chloroform extraction or recrystallized to a white solid insoluble in
water. It is not necessary to perform N-alkylation of barbituric acid and then decarbonylation of
the alkylated product separately. These reactions can be carried out as a one-pot synthesis.12 In
this case, the isolated yields of the malonamides are even higher (Table 1) and purity of the iso-
lated malonamides comparable (more than 98%) to their two-step synthesis.
Unfortunately, the decarbonylation procedure is not helpful for the preparation of amides if one
of the NH groups of the barbituric acid is free. The hydroxide ion is a stronger base than it is nucleo-
phile for the ring opening, therefore a salt of barbituric acid is formed. Once formed, decarbonylation
of the salt does not occur. In fact, the monoalkylated 1-benzyl-5,5-diethyl-2,4,6(1H,3H,5H)pyr-
imidinetrione was separated from the dialkylated 1,3-dibenzyl-5,5-diethyl-2,4,6(1H,3H,5H)pyr-
imidinetrione by transformation of the latter into the easily separable N,N0-dibenzyl-2,2-diethyl-
malonamide.
References
1. Hiratani, K. US Patent No. 5,071,989, 1991.
2. Mohapatra, P. K.; Sriram, S.; Badheka, L. P. Sep. Sci. Technol. 2000, 35, 39; Chan, Gabriel, Y. S.; Drew, M. G. B.;
Madic, C. J. Chem. Soc., Dalton Trans. 1997, 647; Iveson, P. B.; Drew, M. G. B.; Madic, C. J. Chem. Soc., Dalton
Trans. 1999, 3605; Hiratani, K.; Taguchi, K.; Ohashi, K. Chem. Lett. 1989, 2073.
3. Darling, C. N. US Patent No. 4,537,781, 1985.
4. The Pro®le of Anticonvulsant Activity and Acute Toxicity of 56098 and Some Prototype Antiepileptic Drugs in Mice
and Rates, with reported dated 7/2/82 and number 38. Results are taken from Ref 1.
5. Draling et al. In J. Pharm. Sci. 1979, 69, 108.
6. Dermer, O. C.; King, J. J. Org. Chem. 1943, 8, 168.
7. Patel et al. Journal Sci. Industr. Res. 1961, 20B, 457.
8. March, J. Advanced Organic Chemistry, 4th ed.; John Wiley & Sons: New York, 1992; pp. 732±733.
9. For instance, see: Vogel's Text-Book of Synthetic Organic Chemistry, 3rd ed.; New York, 1966; pp. 1001±1005.
10. A general method for preparation of tetrasubstituted barbituric acids. Preparation of 5,5-dibenzyl-1,3-dimethyl-
2,3,4(1H,3H,5H)pyrimidinetrione (1j): The 5,5-dibenzyl-2,3,4(1H,3H,5H)pyrimidinetrione (3.08 g, 0.01 mol) was
dissolved in an aqueous (50 mL) sodium hydroxide (0.88 g, 0.022 mol) and ethanol (50 ml). The solution of
dimethyl sulfate (2.52 g, 0.02 mol) was added. Temperature of the reaction mixture shortly afterwards increased
and the reaction mixture became a suspension. Stirring of the reaction mixture was continued while re¯uxing for 3
hours. Ethanol was evaporated and the remaining white suspension was extracted with chloroform (3Â150 ml).
Combined chloroform extracts were washed with aqueous sodium hydroxide (20% sodium hydroxide, 3Â50 ml),
dried and evaporated. The solid residue was slurred in cold petroleum ether and separated by ®ltration. The yield
of the reaction was 97%; m.p. ꢀ225ꢁC with decomposition. 1H NMR (300 MHz, CDCl3) ꢀ 7.22 (2H, t), 7.19 (4H,
dd); 7.07(4H, t) 3.45(6H, s), and 2.96 (3H, s); 13C NMR (CDCl3) ꢀ 170.6 (C-4,C-6), 149.8 (C-2), 134.9, 129.1,
128.4, 127.5 (aromatics), 61.0 (C-5), 45.1 (CH2), and 27.9 (CH3) ppm; MS (CI) m/z 336 (M+), 308 (M+^CO),
281(M+^CONCH2), 245(M+^C6H5CH2), 217 (C6H5CˆC(CONHCH3)+2), 188 (C6H5CHˆC(CO)CONHCH3+), 1
9 (C6H5CHˆCH±CONˆCH+2), 131 (C6H5CHˆCHCO+), 103 (C6H5CHˆCH+), 91(C6H5CH2+); anal. calcd for C20
H20N2O3: C, 71.41; H, 5.99; N, 8.33. Found: C, 71.33; H, 6.03; N, 8.27.

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11. A general procedure for decarbonylation of barbituric acids. Preparation of N,N0-dibenzyl-2,2-diethylmalonamide
(2i). 5,5-Dienthyl-1,3-diphenylmethyl-2,3,4(1H,3H,5H)-pyrimidinetrione (3.64 g, 0.01 mol) solution in 95%
ethanol (100 mL) was dissolved in aqueous (100 mL) sodium hydroxide (0.8 g, 0.02 mol) and re¯uxed overnight.
Ethanol was evaporated and the white solid residue was separated by ®ltration. White crystals were washed with
water (3Â50 mL) and recrystallized from 95% ethanol. The yield of the product was 3.38 g (97%). 1H
NMR (300 MHz, CDCl3) ꢀ 7.85 (2H, t, J2=0.019, NH), 7.29 (10H, m, C6H5); 4.44 (4H, d, J2=0.019, 1.91
(4H, q, J2=0.024, CH2CH3), 0.84 (6H, t, J2=0.024, CH2CH3) 1.81 (4H, q, J2=0.025, CH2CH3) and 0.74
(6H, t, J2=0.025, CH2CH3) ppm; 13C NMR (CDCl3) ꢀ 172.9 (C-1), 138.1, 128.4, 127.4 and 127.1 (aromatics),
58.0 (C-2), 43.4 (CH2-benzyl), 30.1 (CH2-ethyl), and 9.3 (CH3±ethyl) ppm; MS m/z 339 (M+1+); 338 (M+), 232
(M+^NHCH2Ph); anal. calcd for C21H26N2O2: C, 74.53; H, 7.74; N, 8.28. Found: C, 74.41; H, 7.85; N, 8.15.
12. A general procedure for direct preparation of malonamides from 5,5-disubstituted barbituric acid. Preparation, N,N0-
dimethyl-2,2-diethylmalonamide (2e): Sodium 5,5-diethylbarbiturate (2.06 g, 0.01 mol) was dissolved in aqueous
(20 mL) sodium hydroxide (0.44 g, 0.011 mol). Into this solution, ethanolic (50 ml) solution of dimethyl sulfate
(2.52 g, 0.02 mol) was added. The clear reaction mixture was stirred at room temperature for 0.5 hour and the
solvent was evaporated. The oily residue was dissolved in 60% ethanol (100 mL), and sodium hydroxide (1.76 g,
0.044 mol) was added. The reaction mixture was re¯uxed for 1 hour. Ethanol was evaporated. White crystals in
water residue was extracted with chloroform (3Â50 mL). Combined chloroform layers were dried and evaporated
to dryness. The remaining white crystals were slurred in cold petroleum ether and ®ltered a€ording 1.8 g (97%) of
the product. 1H NMR (300 MHz, CDCl3) ꢀ 7.64 (2H, t, J2=0.016, NH), 2.76 (6H, d, J2=0.016, NCH3), 1.81 (4H,
q, J2=0.025, CH2CH3) and 0.74 (6H, t, J2=0.025, CH2CH3) ppm; 13C NMR (CDCl3) ꢀ 173.8 (C-1), 57.9 (C-2),
26.2 (CH2), and 9.3 (CH3) ppm; MS (CI) m/z 187 (M+1+), 186 (M+), 171 (M+^CH3), 158 (M+1+^C2H5), 143
(M+1+^CH3NHCH3), 129 (M+-OCNCH3), 100 (CH3CH2CHCONHCH+3); anal. calcd for C9H18N2O2: C, 58.04;
H, 9.74; N, 15.04. Found: C, 57.96; H, 9.83; N, 14.96.