One-pot synthesis of α-acyloxycarboxamidobarbiturates from alloxans, carboxylic acids, and isocyanides

Article abstract of DOI:10.3184/174751912X13379442777234

A simple, efficient, and high yielding one-pot protocol for the synthesis of novel highly substituted á-acyloxycarboxamidobarbiturates has been developed by a three-component reaction of alloxans, various carboxylic acids, and alkyl or aryl isocyanides in acetonitrile at room temperature.

Full text of DOI:10.3184/174751912X13379442777234

432 RESEARCH PAPER
JULY, 432–436
JOURNAL OF CHEMICAL RESEARCH 2012
One-pot synthesis of α-acyloxycarboxamidobarbiturates from alloxans,
carboxylic acids, and isocyanides
Mohammad Bagher Teimouri*
Faculty of Chemistry, Omidiyeh Branch, Islamic Azad University, Omidiyeh, Iran
A simple, efficient, and high yielding one-pot protocol for the synthesis of novel highly substituted α-acyloxycarbox-
amidobarbiturates has been developed by a three-component reaction of alloxans, various carboxylic acids, and
alkyl or aryl isocyanides in acetonitrile at room temperature.
Keywords: alloxan, carboxylic acid, isocyanide, multicomponent reaction, Passerine reaction
The barbiturates, therapeutically used as sedatives, hypnotics,
anaesthetics and anticonvulsants, are a class of drugs derived
from barbituric acid, a synthetic condensation product of
malonic acid and urea. They differ mainly in the substitution
pattern at the C-5 position with some also including an
N-methyl at N-1.1
Reportedly, in the course of the last century over 2,500
barbiturates have been synthesised with more than 50 of these
presently marketed for clinical use throughout the world.2
Their use was widespread and many still have some use today.
One hundred years after the introduction in clinical pharma-
cology of the original compound, oxybarbiturates, in general,
continue to be the selected drugs in the treatment of some
serious forms of insomnia and in some types of epilepsy.3
Furthermore, barbiturates are frequently used for the treatment
of intracranial hypertension after severe head injury.4 Under
these conditions, they can decrease cerebral metabolic demands,
oxygen need and intracranial pressure.5
protocols for the synthesis of peptide bond, one of the
important methods is the Passerini three-component reaction
(P-3CR).20 The most commonly used P-3CR, is one in which
a carboxylic acid, an oxo compound and an isocyanide are
reacted to result in α-acyloxycarboxamide products. This
group of compounds is present in the structures of many
natural products, such as the pharmacologically active depsi-
peptides.21,22 Also the P-3CR reaction can lead to interesting and
potentially bioactive peptidomimetic compounds and offers an
inexpensive and rapid way to generate compound libraries.23,24
Alloxan (pyrimidine-2,4,5,6(1H,3H)-tetrone) and its deriva-
tives are very interesting vicinal tricarbonyl compounds, which
have four electrophilic C=O sites.25 Our literature survey
at this stage revealed that, there is no report yet available on
the use of alloxan derivatives in the Passerini reaction. In the
present study, the formation of poly-functional α-acyloxycar-
boxamidobarbiturates by a three-component condensation
reaction of isocyanides is reported.
The one-pot three-component condensation reactions of
alloxan derivatives 1 with various carboxylic acids 2 in the
presence of alkyl or aryl isocyanides 3 proceeded at room
temperature in acetonitrile and were complete after 24 h to
afford the corresponding α-acyloxycarboxamidobarbiturates
The structure and conformation of the C-5 side chains of
the barbiturates have been suggested to be determinants of the
different biological activities. For instance, slight structural
modifications in many depressant barbiturates such as pheno-
barbital, the most widely used anticonvulsant worldwide and
the oldest still in use, produce compounds with excitatory or
1
4 in good yields (Scheme 2). H and 13C NMR spectra of
convulsant activity, e.g., 5-benzyl-5-ethylbarbituric acid,6–9
a
the crude products clearly indicated the formation of α-acyl-
oxycarboxamidobarbiturates 4. No other products could be
detected by NMR spectroscopy. Compounds 4a–m are stable
white solids, whose structures were established by IR, 1H, 13C
NMR spectroscopy and elemental analysis. The full results are
summarised in Table 1.
To survey the generality and scope of this one-pot three-
component protocol, the methodology was applied to the
synthesis of a variety of 5-[(alkyl or arylamino)carbonyl]-
2,4,6-trioxohexahydropyrimidin-5-yl carboxylate derivatives
4a–m. With the optimal conditions in hand, we extended the
reaction to other carboxylic acids and the results are indicated
in Table 1. Seven derivatives of carboxylic acids including aro-
matic, aliphatic and α,β-unsaturated carboxylic acids, afforded
α-acyloxycarboxamidobarbiturates in from good to excellent
isolated yields. To explore the scope of this reaction with
respect to reactive isocyanides, we have examined seven alkyl
or aryl isocyanides. We have found that the reaction proceeds
very efficiently with both sterically hindered and less hindered
alkyl or aryl isocyanides.
homologue of phenobarbital (Scheme 1).
The peptide bond is an important functional group in organic
chemistry, biochemistry and medicine.10–12 Peptides play cru-
cial roles in the human body and other organisms.13–15 Due to
the biological significance of molecules with the barbiturate
moiety we have combined amides and barbiturates as molecu-
lar entities through carbon–carbon bond formation in order to
create new molecules. Considering the versatile activities of
these structures, we think it would be of interest to combine
the barbiturate moiety and the peptide bond in view of their
promising applications in medicinal chemistry and biological
investigations.
The peptide bond is traditionally synthesised by the reaction
of an amine with an activated carboxylic acid.16–19 Among the
The central carbonyl group in vicinal tricarbonyl compounds
is a strongly electrophilic entity, accounting for the fact that
tricarbonyls are hydrated at this site.26 In solution, the alloxan
hydrate is in equilibrium with the parent tricarbonyl, and in
this form, they undergo reactions with a broad range of nucleo-
philes. A probable mechanistic rationale portraying a sequence
of events for this three-component coupling is postulated in
Scheme 3. The first step is believed to be the formation of a
loosely hydrogen-bonded adduct 5 from the alloxan derivative
and the carboxylic acid followed by α-addition of the electro-
philic carbonyl carbon and the nucleophilic oxygen atom of
Scheme 1
* Correspondent. E-mail: m.teimouri@ippi.ac.ir

JOURNAL OF CHEMICAL RESEARCH 2012 433
Scheme 2
Table 1 Structure of compounds 4a–m
Entry
R
R’
R”
Product
Yield/%a
1
CH3
83
2
CH3
85
3
4
5
CH3
CH3
CH3
79
91
78
H
H
6
7
CH3
86
90
CH3

434 JOURNAL OF CHEMICAL RESEARCH 2012
Table 1 Continued
Entry
8
R
H
R’
R”
Product
Yield/%a
92
9
H
H
88
79
10
CH3
11
12
H
H
CH3
76
78
13
H
80
a Purified yield, which is >95% as determined by 1H NMR spectroscopy.
a Bruker DRX-400 Avance spectrometer at 400.13 and 100.77 MHz,
respectively, with CDCl3, CD3SOCD3 or CD3COCD3 as solvents and
calibrated using the residual undeuterated solvent as an internal refer-
ence. Chemical shifts are reported in parts per million (ppm) relative
to TMS as internal reference. Analytical TLC was carried out on
precoated plates (Merck silica gel 60, F254) and visualised with
UV light. All chemical reagents were obtained from Merck, Fluka,
Acros or Aldrich and were used without further purification.
the carboxylic acid to the isocyanide carbon atom with forma-
tion of a 6 via cyclic transition state comprising all three parent
compounds. The α-adduct which cannot be isolated rearranges
in an intramolecular transacylation to the stable α-acyloxycar-
boxamidobarbiturate 4.
In summary, alloxan was introduced for the first time as a
novel oxo component in a Passerini reaction. Several carboxy-
lic acids and alkyl or aryl isocyanides were able under these
reaction conditions to afford diverse α-acyloxycarboxamido-
barbiturates of potential synthetic and pharmaceutical interest
in good to excellent yields. The present method carries the
advantage of being performed under neutral conditions and
requires no activation or modification of the reactants.
Synthesis of 4a–m; typical procedure
To a magnetically stirred solution of 1,3-dimethylaloxan (0.189 g,
1.0 mmol) and 2,4-dichlorobenzoic acid (0.191 g, 1.0 mmol)
in CH3CN (10 cm3) was added 1,1,3,3-tetramethlbutyl isocyanide
(0.140 g, 1.0 mmol) at room temperature (25 °C). The reaction mix-
ture was then stirred for 24 h. The solvent was removed under reduced
pressure and the viscous residue was purified by column chromato-
graphy (Merck 230–400 mesh) using n-hexane-EtOAc (4:1) as eluent
to give 4a as a white powder (0.415 g, 83%). The dried product thus
obtained showed a single spot on TLC and was pure enough for all
analytical purposes.
Experimental
Melting points were measured on a Büchi 535 apparatus and are
uncorrected. Elemental analyses were performed using an Elementar
Vario EL III instrument. FT-IR Spectra were recorded on a Bruker
Equinox-55 spectrometer. 1H and 13C NMR spectra were recorded on

JOURNAL OF CHEMICAL RESEARCH 2012 435
Scheme 3
1,3-Dimethyl-2,4,6-trioxo-5-{[(1,1,3,3-tetramethylbutyl)amino]
carbonyl} hexahydropyrimidin-5-yl 2,4-dichlorobenzoate (4a): M.p.
143–145 °C; FT-IR (KBr) (νmax, cm−1): 3409 (N–H), 1693, 1665, 1629
Calcd for C17H19N3O6 (361.34): C, 56.51; H, 5.30; N, 11.63. Found: C,
56.63; H, 5.34; N, 11.65%.
1,3-Dimethyl-2,4,6-trioxo-5-{[(1,1,3,3-tetramethylbutyl)amino]
carbonyl}hexahydropyrimidin-5-yl formate (4f): White powder
(0.306 g, 86%); m.p. 133–135 °C (dec.); IR (KBr) (νmax, cm−1): 3306
1
(C=O); H NMR (CDCl3, 400.1 MHz): δH 0.94 (9 H, s, CMe3), 1.38
(6 H, s, CMe2), 1.69 (2 H, s, CH2), 3.34 (6 H, s, 2 NCH3), 6.74 (1 H, s,
NH), 7.34–7.87 (3 H, m, arom.); 13C NMR (CDCl3, 100.7 MHz):
162.7, 162.5, 158.3, 150.6, 140.5, 135.1, 134.0, 131.5, 127.7, 125.3,
80.6, 57.0, 51.3, 31.5, 31.3, 29.4, 28.8; Anal. Calcd for C22H27Cl2N3O6
(500.37): C, 52.81; H, 5.44; N, 8.40%. Found: C, 52.72; H, 5.42; N,
8.43%.
1
(N–H), 1747, 1695, 1658 (C=O); H NMR (CDCl3, 400.1 MHz): δH
0.97 (9 H, s, CMe3), 1.39 (6 H, s, CMe2), 1.68 (2 H, s, CH2), 3.33
(6 H, s, 2 NCH3), 6.50 (1 H, br s, NH), 8.07 (1 H, s, O=CH); 13C NMR
(CDCl3, 100.7 MHz): 162.7, 158.2, 157.5, 150.6, 79.4, 57.1, 52.0,
31.7, 31.5, 29.7, 28.8; Anal. Calcd for C16H25N3O6 (355.38): C, 54.07;
H, 7.09; N, 11.82. Found: C, 53.94; H, 7.06; N, 11.79%.
5-[(Cyclohexylamino)carbonyl]-1,3-dimethyl-2,4,6-trioxohexahy-
dropyrimidin-5-yl (2E)-3-phenylacrylate (4g): White powder (0.385 g,
90%); m.p. 193–195 °C (dec.); IR (KBr) (νmax, cm−1): 3260 (N–H),
1744, 1712, 1661 (C=O); 1H NMR (CDCl3, 400.1 MHz): δH 1.24–1.95
(10 H, m, 5 CH2), 3.36 (6 H, s, 2 NCH3), 3.68–3.72 (1 H, m, NHCH),
6.58 (1 H, d, 3JHH = 7.7 Hz, NH), 6.64 and 7.77 (2 H, d, 3JHH = 16.0 Hz,
CH=CH-Ph), 7.38–7.56 (5 H, m, arom.); 13C NMR (CDCl3, 100.7
MHz): 164.7, 163.6, 159.7, 150.8, 149.8, 133.6, 131.7, 129.3, 128.8,
114.4, 49.9, 32.7, 29.6, 25.5, 24.9; Anal. Calcd for C22H25N3O6
(427.45): C, 61.82; H, 5.90; N, 9.83. Found: C, 61.97; H, 5.91; N,
9.87%.
5-[(Cyclohexylamino)carbonyl]-1,3-dimethyl-2,4,6-trioxohexahy-
dropyrimidin-5-yl 2,4-dichlorobenzoate (4b): White powder (0.400 g,
85%); m.p. 106–108 °C; FT-IR (KBr) (νmax, cm−1): 3337 (N–-H), 1700,
1
1672, 1609 (C=O); H NMR (CDCl3, 400.1 MHz): δH 1.18–1.93
(10 H, m, 5 CH2), 3.37 (6 H, s, 2 NCH3), 3.68–3.74 (1 H, m, NHCH),
6.81 (1 H, d, 3JHH = 6.3 Hz, NH), 7.38–7.91 (3 H, m, arom.); 13C NMR
(CDCl3, 100.7 MHz): 162.9, 162.7, 159.2, 150.7, 140.8, 135.3, 134.3,
131.7, 127.9, 125.4, 80.6, 49.8, 32.6, 29.7, 25.4, 24.6; Anal. Calcd for
C20H21Cl2N3O6 (470.30): C, 51.08; H, 4.50; N, 8.93. Found: C, 51.26;
H, 4.51; N, 8.95%.
Methyl N-{[5-(benzoyloxy)-1,3-dimethyl-2,4,6-trioxohexahydropy-
rimidin-5-yl]carbonyl}glycinate (4c): White powder (0.309 g, 79%);
m.p. 140–142 °C; FT-IR (KBr) (νmax, cm−1): 3354 (N–H), 1749, 1705,
1669 (C=O); 1H NMR (CDCl3, 400.1 MHz): δH 3.36 (3 H, s, OCH3),
2,4,6-Trioxo-5-{[(1,1,3,3-tetramethylbutyl)amino]carbonyl}
hexahydropyrimidin-5-yl (2E)-3-phenylacrylate (4h): White powder
(0.396 g, 92%); m.p. 200–202 °C; FT-IR (KBr) (νmax, cm−1): 3335
3
3.79 (2 H, s, CH2), 4.07 (1 H, t, JHH = 4.6 Hz, NHCH2), 7.42–8.08
1
(5 H, m, arom.); 13C NMR (CDCl3, 100.7 MHz): 169.0, 164.5, 163.0,
160.8, 150.6, 135.0, 130.5, 129.1, 127.0, 79.6, 53.1, 41.8, 30.1; Anal.
Calcd for C17H17N3O8 (391.33): C, 52.18; H, 4.38; N, 10.74. Found: C,
52.30; H, 4.40; N, 10.70%.
(O-H), 3300, 3240, 3115 (N–H), 1768, 1704, 1646 (C=O); H NMR
(DMSO-d6, 400.1 MHz): δH 0.93 (9 H, s, CMe3), 1.35 (6 H, s, CMe2),
1.70 (2 H, s, CH2), 6.95 and 7.85 (2 H, d, 3JHH = 16.0 Hz, CH=CH-Ph),
7.46–7.48 and 7.73–7.74 (6 H, 2 m, arom. + NH), 11.97 (2 H, s,
NHCONH); 13C NMR (DMSO-d6, 100.7 MHz): 164.7, 159.8, 150.5,
149.1, 134.1, 132.1, 129.6, 129.1, 116.4, 79.5, 56.6, 50.8, 31.9, 31.7,
29.4; Anal. Calcd for C22H27N3O6 (429.46): C, 61.53; H, 6.34; N, 9.78.
Found: C, 61.68; H, 6.31; N, 9.81%.
5-[(Cyclohexylamino)carbonyl]-2,4,6-trioxohexahydropyrimidin-
5-yl benzoate (4i): White powder (0.329 g, 88%); m.p. 180–182 °C;
FT-IR (KBr) (νmax, cm−1): 3277, 3113 (N–H), 1769, 1703, 1670 (C=O);
1H NMR (DMSO-d6 + CDCl3, 400.1 MHz): δH 0.77–1.84 (10 H, m,
5 CH2), 3.48–3.60 (1 H, m, NHCH), 7.35–8.14 (6 H, 3 m, arom.
+ NH), 11.82 (2 H, s, NHCONH); 13C NMR (DMSO-d6 + CDCl3,
100.7 MHz): 164.7, 160.1, 150.1, 134.8, 130.8, 128.8, 127.1, 79.6,
49.8, 32.0, 25.3, 25.2; Anal. Calcd for C18H19N3O6 (373.36): C, 57.90;
H, 5.13; N, 11.25. Found: C, 58.03; H, 5.09; N, 11.31%.
1,3-Dimethyl-5-[(2-naphthylamino)carbonyl]-2,4,6-trioxohexahy-
dropyrimidin-5-yl 5-bromopentanoate (4d): White powder (0.459 g,
91%); m.p. 86–88 °C; FT-IR (KBr) (νmax, cm−1): 3475 (N–H), 1683,
1
1610 (C=O); H NMR (CDCl3, 400.1 MHz): δH 1.86–1.96 (4 H, m,
3
BrCH2CH2CH2CH2C=O), 2.67 (2 H, t, JHH = 7.1 Hz, BrCH2CH2
CH2CH2C=O), 3.35–3.44 (8 H, m, 2 NCH3 + BrCH2CH2CH2CH2C=O),
7.42–7.48 and 7.74–7.80 (6 H, 2 m, arom.), 8.14 (1 H, s, arom.), 8.49
(1 H, s, NH); 13C NMR (CDCl3, 100.7 MHz): 171.0, 163.2, 158.5,
150.6, 133.6, 133.1, 131.5, 129.3, 128.0, 127.8, 127.1, 126.1, 119.8,
118.1, 79.7, 33.1, 32.5, 31.5, 29.9, 29.8, 23.2; Anal. Calcdfor
C22H22BrN3O6 (504.33): C, 52.39; H, 4.40; N, 8.33. Found: C, 52.50;
H, 4.44; N, 8.35%.
1,3-Dimethyl-2,4,6-trioxo-5-{[(3-phenylpropyl)amino]carbonyl}
hexahydropyrimidin-5-yl formate (4e): White powder (0.282 g, 78%);
m.p. 110–112 °C (dec.); IR (KBr) (νmax, cm−1): 3460 (N–H), 1727,
1706, 1666 (C=O). 1H NMR (CDCl3, 400.1 MHz): δH 1.87 (2 H, qu,
5-[(tert-Butylamino)carbonyl]-2,4,6-trioxohexahydropyrimidin-
5-yl acetate (4j): White powder (0.226 g, 79%); m.p. 149–151 °C;
FT-IR (KBr) (νmax, cm−1): 3354, 3249 (N–H), 1770, 1714, 1670 (C=O);
1H NMR (Acetone-d6, 400.1 MHz): δH 1.33 (9 H, s, C(CH3)3), 2.21
3
3JHH = 7.1 Hz, NHCH2CH2CH2Ph), 2.63 (2 H, t, JHH = 7.1 Hz,
NHCH2CH2CH2Ph), 3.29–3.34 (8 H, m, NHCH2CH2CH2Ph +
2 NCH3), 6.70 (1 H, br s, NH), 7.14–7.29 (5 H, m, arom.), 8.05 (1 H,
s, O=CH); 13C NMR (CDCl3, 100.7 MHz): 162.5, 159.9, 157.6,
150.50, 140.9, 128.8, 128.5, 126.4, 79.2, 40.1, 33.2, 30.6, 29.7; Anal.
(3 H, s, CH3), 7.61 (1 H, br s, NH), 10.76 (2 H, br s, NHCONH); 13
C
NMR (Acetone-d6, 100.7 MHz): 168.9, 164.0, 159.9, 149.0, 79.2,
52.3, 27.5, 18.9; Anal. Calcd for C11H15N3O6 (285.25): C, 46.32; H,
5.30; N, 14.73. Found: 46.19; H, 5.28; N, 14.70%.

436 JOURNAL OF CHEMICAL RESEARCH 2012
5-[(Cyclohexylamino)carbonyl]-2,4,6-trioxohexahydropyrimidin-
5-yl acetate (4k): White powder (0.237 g, 76%); m.p. 208–210 °C;
FT-IR (KBr) (νmax, cm−1): 3400, 3225, 3110 (N–H), 1766, 1729, 1667
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(C=O); H NMR (Acetone-d6, 400.1 MHz): δH 1.12–2.18 (10 H, m,
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5 CH2), 2.88 (3 H, s, CH3), 3.63–3.68 (1 H, m, NHCH), 7.84 (1 H, br
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MHz): 169.0, 164.0, 159.8, 148.9, 79.1, 49.4, 31.9, 25.2, 24.9, 18.9;
Anal. Calcd for C13H17N3O6 (311.29): C, 50.16; H, 5.50; N, 13.50.
Found: C, 50.27; H, 5.48; N, 13.46%.
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5
6
5-[(Benzylamino)carbonyl]-2,4,6-trioxohexahydropyrimidin-5-yl
butyrate (4l): White powder (0.271 g, 78%); m.p. 166–168 °C; FT-IR
(KBr) (νmax, cm−1): 3335, 3308, 3294 (N–H), 1719, 1701, 1678 (C=O);
7
3
1H NMR (DMSO-d6, 400.1 MHz): δH 0.87 (3 H, t, JHH = 7.4 Hz,
CH2CH2CH3), 1.57 (2 H, sex., 3JHH = 7.4 Hz, CH2CH2CH3), 2.52 (2 H,
t, 3JHH = 7.4 Hz, CH2CH2CH3), 4.30 (2 H, d, 3JHH = 6.1 Hz, NHCH2),
8
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P.R. Andrews, G.P. Jones and D. Lodge, Eur. J. Pharmacol., 1979, 55,
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7.14–7.30 (5 H, m, arom.), 9.30 (1 H, t, JHH = 6.1 Hz, NH), 12.10
(2 H, br s, NHCONH); 13C NMR (DMSO-d6, 100.7 MHz): 172.5,
165.0, 161.4, 150.4, 138.8, 129.0, 127.7, 127.5, 79.1, 43.1, 34.8, 18.4,
13.7; Anal. Calcd for C16H17N3O6 (347.32): C, 55.33; H, 4.93; N,
12.10. Found: C, 55.51; H, 4.90; N, 12.11%.
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5-[(Cyclohexylamino)carbonyl]-2,4,6-trioxohexahydropyrimidin-
5-yl butyrate (4m): White powder (0.272 g, 80%); m.p. 179–181 °C;
FT-IR (KBr) (νmax, cm−1): 3265, 3100 (N–H), 1728, 1705, 1630 (C=O);
3
1H NMR (DMSO-d6, 400.1 MHz): δH 0.84 (3 H, t, JHH = 7.4 Hz,
CH2CH2CH3), 1.02–1.67 (12 H, m, 5 CH2 + CH2CH2CH3), 2.54 (2 H,
t, 3JHH = 7.4 Hz, CH2CH2CH3), 8.36 (1 H, d, 3JHH = 8.3 Hz, NH), 11.95
(2 H, br s, NHCONH); 13C NMR (DMSO-d6, 100.7 MHz): 172.6,
165.1, 160.3, 150.4, 79.1, 49.8, 34.7, 32.3, 25.6, 25.4, 18.3, 13.7;
Anal. Calcd for C15H21N3O6 (339.34): C, 53.09; H, 6.24; N, 12.38.
Found: C, 53.29; H, 6.21; N, 12.41%.
Thanks are due to Islamic Azad University (Omidiyeh Branch)
Research Council for the financial support.
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Received 17 March 2012; accepted 1 May 2012
Paper 1201219 doi: 10.3184/174751912X13379442777234
Published online: 26 June 2012