A new and convenient method for synthesis of barbituric acid derivatives

Article abstract of DOI:10.1007/BF03246226

In continuation of our current studies on the reaction between isocyanides and electron-defficient alkenes, we would like to report our recent reseaarch on synthesizing novel derivatives of barbituric acid. The reaction of alkylidene-substituted Meldrum's acid with alkyl isocyanides in the presence of urea led to the production of the corresponding 2-(hexahydro-2,4,6- trioxopyrimidin- 5-yl)-N,2-dimethylpropanamide in good to high yields. The structure of the products was in agreement with their spectroscopic data.

Full text of DOI:10.1007/BF03246226

J. Iran. Chem. Soc., Vol. 8, No. 1, March 2011, pp. 287-291.
JOUIRrNaAnLiaOnF THE
Chemical Society
ꢀꢀꢀꢀꢀꢀꢀꢀ
A New and Convenient Method for Synthesis of Barbituric Acid Derivatives
A. Habibi* and Z. Tarameshloo
Faculty of Chemistry, Tarbiat Moallem University, No. 49, P. Code 15719-14911, Mofateh Avenue, Tehran, Iran
(Received 26 June 2010, Accepted 14 August 2010)
In continuation of our current studies on the reaction between isocyanides and electron-defficient alkenes, we would like to
report our recent reseaarch on synthesizing novel derivatives of barbituric acid. The reaction of alkylidene-substituted Meldrum's
acid with alkyl isocyanides in the presence of urea led to the production of the corresponding 2-(hexahydro-2,4,6-trioxopyrimidin-
5-yl)-N,2-dimethylpropanamide in good to high yields. The structure of the products was in agreement with their spectroscopic
data .
Keywords: Isocyanide, Multi-component reaction, Barbituric acid, Alkylidene-substituted Meldrum’s acid
INTRODUCTION
the chemical diversity space, multi-component reactions
(MCRs) are noteworthy tools for the quick and efficient
synthesis of an extensive variety of organic compounds [8,9].
For the last two decades multi-component reactions have been
exploited by combinatorial chemists, as a source of appendage
diversity. The new possibilities for the development of the
MCRs design took place with the introduction of diverse-
oriented synthesis (DOS) [10,11]. Ideally, MCRs are suited for
the creation of compounds having structural diversity in a
combinatorial manner that ensures their leading position in
DOS. Along with the various approaches to MCRs, isocyanide
multi-component reactions (IMCRs) are very powerful
condensations in DOS [12-14]. The classical representations
of this class are Passerini and Ugi reactions [12]. In order to
expand their utility and gain access to drug-like heterocyclic
compounds, several research groups are currently developing
modifications of these classical reactions [9,12-15].
Among heterocyclic compounds, pyrimidines play an
essential role in chemistry and biological systems. Barbituric
acid (2,4,6-trioxohexahydropyrimidine) is one of the most
interesting derivatives of pyrimidines [1-3]. The barbituric
acid moiety is present in various synthetic compounds with
pharmaceutical and industrial applications [4-7]. Owing to
various pharmaceutical activities of 2,4,6-trioxohexahydro-
pyrimidine and its derivatives, they have been used
extensively in medicine and bioorganic researches. Barbituric
acid itself, has been used as a reactant to form a large class of
barbiturate drugs which are used as hypnotics, sedatives,
anticonvulsants, anesthetics and as central nervous system
depressants [2-3]. Due to the applications of barbiturates,
exploration of new routes for the synthesis of these
compounds is axiomatic.
Exploration of novel protocols for the synthesis of
desirable organic compounds is a growing trend in organic
synthesis. Among the new methodologies for a rapid access to
ꢀ
Meldrum's acid (2,2-dimethyl-1,3-dioxane-4,6-dione, iso-
propylidne malonate) and its derivatives are important
molecules that are extensively used as intermediates in organic
synthesis. Meldrum's acid is susceptible to electrophilic attack
at C5 and nucleophilic attack at C4 and C6. In addition, its
*Corresponding author. E-mail: habibi@.tmu.ac.ir
ꢀ

Habibi & Tarameshloo
unique ring-opening reactions make it a tremendously
attractive and useful building block [13,14].
points were measured on an Electrothermal 9200 apparatus. IR
spectra were recorded on a FT-IR 102MB BOMEM apparatus.
Mass spectra were recorded on a AGILENT TECHNOLOGY
(HP)-5973 mass spectrometer operating at an ionization
potential of 70 eV (EI). 1H and 13C NMR spectra were
recorded on a Bruker AVANCE-300 MHz spectrometer
employing tetramethylsilane as an internal reference.
Among its derivatives, alkylidene-substituted Meldrum's
acid has attractive features. There are a lot of examples
reported for using them as dienophiles in hetero Diels-Alder
reaction, as well as Michael acceptors [15-17]. One of the
most interesting applications of Meldrum's acid and its
derivatives is their application in MCRs especially in
isocyanide-based multi-component reactions (IMCRs) [18-
20].
General Procedure for the Preparation of
Compounds 4
As part of our current studies on the reaction between
alkylidene-substituted Meldrum's acid and alkyl isocyanides in
the presence of RXH as a proton source [18-20], here, we
report a novel and one-pot three-component reaction of
alkylidene-substituted Meldrum's acid 1, alkyl isocyanide 2
and urea 3 that leads to the production of a new derivatative of
5-substituted barbituric acid 4 (Scheme 1).
To a stirred solution of alkylidene-substituted Meldrum's
acid 1 (2 mmol) and urea 3 (2 mmol) in DMSO/CH2Cl2 (10
ml) was added a solution of alkyl isocyanide 2 (2 mmol) in 5
ml CH2Cl2 in over 10 min. The mixture was then allowed to
stir for 24 h. The dichloromethane was removed under reduced
pressure, and ice water was added to produce white
precipitate. This crude product was purified by recrystalization
with ethanol or petroleum benzene.
EXPERIMENTAL
Spectra Data of the Products
Chemicals and Apparatus
All chemicals and solvents were purchased from Fluka and
Merck chemical company and used as received. Melting
N-tert-butyl-2-(hexahydro-2,4,6-trioxopyrimidin-5-yl)-
2-methylpropanamide (4a). Colorless powder (0.17 g, 68%),
m.p.: 169 °C;ꢀ IR (KBr) (νmax/cm-1): 1571 (NH bend, 1694 (4
O
HN
R
NH
O
O
R
O
R
O
CH2Cl2/DMSO
R.T.
+
+
R'N
C
O
O
O
O
H2N
NH2
H
N
R'
R
4a-h
2
3
1
4
R'
R
tert- butyl
tert- butyl
a
Methyl
b
c
tert- butyl
cyclohexyl
d
Methyl
e
f
cyclohexyl
cyclohexyl
g
cyclohexyl
h
tert- butyl
Scheme 1. Multi-component reaction al kylidene Meldrum's acid, alkyl isocyanide and urea
288
ꢀ

A New and Convenient Method for Synthesis of Barbituric Acid Derivatives
C=O), 3139, 3325, 3431 (3 NH). 1H NMR (300.1 MHz,
s, CH), 3.97 (1H, tt, J = 12.3, J = 3.75 Hz, CH-NH), 5.68,
8.10, 10.27 (3H, s, 3NH). 13C NMR (75.5 MHz, CDCl3): δ =
21.05 (2Me), 24.93, 25.41, 25.70, 28.58, 28.74 (5CH2 of
cyclohexyl), 43.63 (CMe2), 52.21 (CH-NH), 57.59 (CH),
154.26, 167.92, 172.92, 180.92 (4C=O). MS m/z (%) = 295
(M+, 4), 214 (100), 171 (40), 154 (60), 128 (70), 83 (85), 61
(90). Anal. Calcd. for C14H21N3O4 (295.15): C, 56.94; H, 7.17;
N, 14.23%. Found: C, 58.07; H, 7.12; N, 13.53%.
CDCl3): δ = 1.25 (3H, s, Me), 1.43 (3H, s, Me), 1.59 (9H, s,
CMe3) 3.37 (1H, s, CH), 5.55, 8.09, 10.20 (3H, s, 3NH). 13C
NMR (75.5 MHz, CDCl3): δ = 21.18, 25.16 (2Me), 28.24
(CMe3), 43.68 (CMe2), 57.53 (CMe3), 59.19 (CH), 153.96,
167.90, 173.95, 181.77 (4 C=O). MS m/z (%): 269 (M+, 20.5),
214 (79.5), 171 (31), 154 (48), 149 (79.5), 83 (100), 61 (91).
Anal. Calcd. for C12H19N3O4 (269.14): C, 53.52; H, 7.11; N,
15.60%. Found: C, 53.68; H, 7.02; N, 15.82%.
N-cyclohexyl-1-(hexahydro-2,4,6-trioxopyrimidin-5-yl)
cyclohexane carboxamide (4e). Colorless powder (0.14 g,
40%): m.p.: 187 °C; IR (KBr) (νmax/cm-1) 1557 (NH bend),
N-tert-butyl-1-(hexahydro-2,4,6-trioxopyrimidin-5-yl)
cyclohexane carboxamide (4b). Colorless powder (0.22 g,
73%): m.p.: 178 °C; IR (KBr) (νmax/cm-1) 1567 (NH bend),
1
1694, 1713, 1776 (4 C=O), 3145, 3410 (3NH). H NMR
1
1693, 1779 (4 C=O), 3146, 3247, 3418 (3NH). H NMR
(300.1 MHz, CDCl3): δ = 1.22- 2.14 (20H, 10CH2 of
2cyclohexyl), 3.51 (1H, s, CH), 3.96 (1H, tt, J = 12.2, J = 3.76
Hz, CH-NH), 5.40, 8.15, 10.45 (3H, s, 3NH).13C NMR (75.5
MHz, CDCl3): δ = 21.99, 22.09, 24.93, 25.01, 25.73, 25.80,
27.52, 28.44, 28.83, 35.7 (10CH2 of 2cyclohexyl), 48.17 (C of
cyclohexyl), 52.06 (CH-NH), 58.15 (CH), 154.50, 168.91,
172.73, 181.02 (4 C=O). MS m/z (%) = 335 (M+, 16), 254
(79), 211 (27), 194 (86), 84 (100), 61 (72). Anal. Calcd. for
C17H25N3O4 (335.18): C, 60.88; H, 7.51; N, 12.53%. Found: C,
59.73; H, 8.11; N, 12.14%.
(300.1 MHz, CDCl3): δ = 1.17-2.16 (10H, m, 5CH2 of
cyclohexyl), 1.57 (9H, s, CMe3), 3.50 (1H, s, CH), 5.50, 8.16,
10.60 (3H, s, 3NH). 13C NMR (75.5 MHz, CDCl3): δ = 21.99,
22.17, 25.04, 27.32, 30.87 (5CH2 of cyclohexyl), 28.19
(CMe3), 35.80 (C of cyclohexyl), 48.2 (CMe3), 58.7 (CH),
154.81, 169.27, 173.46, 182.17 (4C=O). MS m/z (%): 309
(M+, 18), 253 (54), 241 (30), 211 (58), 197 (63.5), 184 (44),
83 (100), 61 (87). Anal. Calcd. for C15H23N3O4 (309.17): C,
58.24; H, 7.49; N, 13.58%. Found: C, 57.51; H, 7.82; N,
13.05%.
N-cyclohexyl-1-(hexahydro-2,4,6-trioxopyrimidin-5-yl)
cycloheptane carboxamide (4f). Colorless powder (0.14 g,
40%): m.p.: 187 °C; IR (KBr) (νmax/cm-1) 1571 (NH bend),
1696, 1777 (4C=O), 3146, 3329, 3424 (3NH). 1H NMR (300.1
MHz, CDCl3): δ = 1.21- 2.12 (22 H, 10CH2 of cyclohexyl and
cycloheptyl), 3.46 (1H, s, CH), 3.94 (1H, tt, J = 12.4, J = 3.3
Hz, CH-NH), 5.41, 8.13, 10.20 (3H, s, 3NH). 13C NMR (75.5
MHz, CDCl3): δ = 23.40, 23.54, 24.99, 25.76, 28.55, 28.71,
29.69, 29.97, 30.30, 31.69, 38.86 (5CH2 of cyclohexyl and
6CH2 of cycloheptyl), 50.77 (C of cycloheptyl), 52.04 (CH-
NH), 59.96 (CH), 154.20, 168.56, 172.83, 181.73 (4C=O). MS
m/z (%) = 349 (M+, 21), 254 (79), 268 (38), 197 (86), 84
(100), 61 (52).ꢀAnal. Calcd. for C18H27N3O4 (349.2): C, 61.87;
H, 7.79; N, 12.03%. Found: C, 61.53; H, 7.36; N, 12.04%.
N-cyclohexyl-1-(hexahydro-2,4,6-trioxopyrimidin-5-yl)
cyclopentanecarboxamide (4g). Colorless powder (0.21 g,
67%): m.p.: 178 °C; IR (KBr) (νmax/cm-1) 1575 (NH bend),
1695 (4C=O), 3127, 3332, 3440 (3NH). 1H NMR (300.1 MHz,
CDCl3): δ = 1.22- 2.14 (18H, 5 CH2 of 2cyclohexyl and 4CH2
of cyclopentyl), 3.53 (1H, s, CH), 3.97 (1H, tt, J = 12.3, J =
3.7 Hz, CH-NH), 5.48, 8.12, 10.33 (3H, s, 3NH). 13C NMR
N-tert-butyl-1-(hexahydro-2,4,6-trioxopyrimidin-5-yl)-
4-methylcyclohexane carboxamide (4c). Colorless powder
(0.14g, 45%): m.p.: 209ꢀ°C; IR (KBr) (νmax/cm-1) 1578 (NH
bend), 1689, 1725, 1774 (4C=O), 3162, 3241, 3315, 3428
1
(3NH). H NMR (300.1 MHz, CDCl3): δ = 0.96 (3H, d, J =
6.26 Hz, Me), 1.58 (9H, s, CMe3) 1.45-1.90 (9H, m, 4CH2 and
CH of cyclohexyl), 3.29 (1H, s, CH), 5.43, 8.12, 10.60 (3H, s,
3NH). 13C NMR (75.5 MHz, CDCl3): δ = 21.32 (Me), 28.27,
30.11 (4CH2 of cyclohexyl), 29.78 (CMe3), 30.68 (CH of
cyclohexyl), 34.63 (C of cyclohexyl), 46.41 (CMe3), 58.75
(CH), 154.81, 169.27, 173.46, 182.17 (4 C=O). MS m/z (%) =
323 (M+, 26.5), 306 (17), 263 (41), 207 (90), 165 (33), 137
(43.3), 61 (75). Anal. Calcd. for C16H25N3O4 (323.18): C,
59.42; H, 7.79; N, 12.99%. Found: C, 58.60; H, 7.68; N,
12.29.
N-cyclohexyl-2-(hexahydro-2,4,6-trioxopyrimidin-5-yl)-
2-methyl propanamide (4d). Colorless powder (0.17g, 60%):
m.p.: 167 °C, IR (KBr) (νmax/cm-1) 1585 (NH bend), 1695
1
(4C=O), 3161, 3430 (3NH). H NMR (300.1 MHz, CDCl3):
δ = 1.14- 2.17 (16H, 5CH2 of cyclohexyl and 2Me), 3.45 (1H,
ꢀ
289

Habibi & Tarameshloo
(75.5 MHz, CDCl3): δ = 24.98, 25.45, 25.75, 28.62, 28.74,
CH2Cl2 and at room temperature afforded new derivatives of
barbituric acid 4. The 1H and 13C NMR spectrum of the crude
product clearly indicated the formation of 4. No product other
than 4 could be detected by NMR spectroscopy. The structures
of these products were deduced from their elemental analyses
and their IR, 1H NMR, 13C NMR and Mass spectra data.
The IR spectrum of 4a showed three bands at 3431, 3325
and 3139 cm-1 arising from NH stretching. And also include
C=O stretching that appeared at 1694 cm-1. 1H NMR spectrum
of 4a exhibited four singlet sharp lines readily recognized as
arising from two methyl (δ = 1.25 and 1.43 ppm), tert-butyl
(δ = 1.59 ppm) and methine (δ = 3.37 ppm) protons. Also,
three broad singlets (δ = 5.55, 8.09 and 10.20 ppm) which
belonged to three NH amide and imide groups.
32.53, 38.97 (CH2 of cyclohexyl and CH2 of cyclopentyl),
52.21 (C of cyclopentyl), 53.62 (CH-NH), 58.54 (CH), 154.28,
168.68, 172.91, 181.44 (4 C=O). MS m/z (%) = 321 (M+, 5),
240 (100), 197 (50), 180 (68.5), 152 (41), 109 (55), 61(90).
Anal. Calcd. for C16H23N3O4 (321.17): C, 59.80; H, 7.21; N,
13.08%. Found: C, 59.87; H, 7.04; N, 13.07%.
N- tert-butyl -1-(hexahydro-2,4,6-tri oxopyrimidin-5-yl)
cyclopentane carboxamide (4h). Colorless powder (0.23 g,
78%): m.p.: 172 °C; IR (KBr) (νmax/cm-1): 1576 (NH bend),
1699 (4C=O), 3155, 3341, 3453 (3NH). 1H NMR (300.1 MHz,
CDCl3): δ = 1.58 (9H, s, CMe3), 1.62-2.09 (8H, m, 4CH2 of
cyclopentyl), 3.48 (1H, s, CH), 5.68, 8.13, 10.48 (3H, s, 3NH).
13C NMR (75.5 MHz, CDCl3): δ = 25.33, 25.70, 31.98, 39.14
(4CH2 of cyclopentyl), 28.22 (CMe3), 53.76 (C of
cyclopentyl), 58.93 (CMe3), 59.53 (CH), 154.67, 169.12,
173.60, 182.42 (4 C=O). MS m/z (%) = 295 (M+, 100), 235
(34), 208 (100), 61 (89). Anal. Calcd. for C14H21N3O4
(295.15): C, 56.94; H, 7.17; N, 14.23%. Found: C, 56.89; H,
7.35; N, 14.05%.
1
The H decoupled 13C NMR spectrum of 4a showed ten
distinct resonances in agreement with the suggested structure.
The mass spectra of 4a showed molecular ion peaks at
1
appropriate m/z values. The H and 13C NMR spectra of 4b-i
have similar signals to 4a except for the differences in the
proton or carbon-13 resonances of the substituent.
On the basis of what we know about the chemistry of
isocyanide [1-3], and according to our previous reports [18-
20], a plausible mechanism of the three-component reaction
between alkylidene-substituted Meldrum's acid 1, isocyanide
2, and urea 3 is presented in Scheme 2. The first step of the
RESULTS AND DISCUSSION
Three-component reaction of alkylidene-substituted
Meldrum's acid 1, alkyl isocyanide 2 and urea 3 in DMSO/
O
..
O
O
C
O
O
O
O
H2N
NH2
O
O
O
O
O
O
R
R
R
N
R'
R
R
R
N
R'
R'
N
C
5
1
O
O
H2N
O
O
O
..
HN
R
NH
NH
N
H
NH2
O
+H
-H
+H
-H
O
C
O
O
O
R
NH
NH
R'
R
R
NH
R
R'
R'
R
O
O
O
6
7
4
Scheme 2. Proposed mechanism for the reaction
290
ꢀ

A New and Convenient Method for Synthesis of Barbituric Acid Derivatives
mechanism involves the [4+1] cycloaddition reaction of the
Baltimore, MA, 1963, pp. 26-27.
electron-deficient heterodiene moiety of alkylidene-substituted
Meldrum's acid with the isocyanide, producing an
iminolactone intermediate 5. Then, conjugate addition of urea
to enone moiety of 5, results in the opening of a five-
membered ring to form intermediate 6, which eliminates
[5 ] R. Acheson, Introduction to the Chemistry of Hetero-
Cyclic Compounds, Interscience Publishers, New York,
1967, pp. 339-342.
[6 ] D. Brown, R. Evans, T. Batterham, The Pyrimidines
Supplement I, Wiley Interscience, New York, 1970, pp.
199-201.
acetone to form ketene
7 by well-precedented [21]
electrocyclic ring opening of O-alkylated Meldrum’s acids.
Nucleophilic attack of urea through the second nitrogene atom
to the ketene intermediate 7 produces the final product 4.
[7 ] W. Zhou, M.J. Kurth, Polymer 42 (2000) 345.
[8 ] J. Zhu, H. Bienaymé (Eds.), Multicomponent
Reactions, Wiley-VCH, Verlag GmbH & Co. KGaA,
Weinheim, 2005.
CONCLUSIONS
[9 ] A. Dömling, Chem. Rev. 106 (2006) 17.
[10 ] D.S. Tan, Nature Chemical Biology 1 (2005) 74.
[11 ] M.D. Burke, S.L. Schreiber, Angew. Chem. Int. Ed.
Engl. 43 (2004) 46.
[12 ] I. Ugi, Isonitrile Chemistry, Academic Press, London,
1971.
[13 ] H. McNab, Chem. Soc. Rev. 7 (1978) 345.
[14 ] B.C. Chen, Heterocycles 32 (1991) 529.
[15 ] A.S. Ivanov, Chem. Soc. Rev. 37 (2008) 789.
[16 ] J. Gerencser, G. Dorman, F. Darvas, QSAR Comb. Sci.
5-6 (2006) 439.
We have introduced an efficient and simple method for the
synthesis of new barbituric acid derivatives. This method
enjoys a mild reaction condition, moderate to good yield, a
fast and convenient one-pot three-component reaction which
make it offer a better alternative to the conventional methods.
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Commercial Products, Williams
&
Wilkins Co,
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291