N,N-dimethylformamide-promoted reaction of isocyanides and barbituric acids: An easy synthesis of 5-[(alkyl or arylamino)methylene]barbituric acids

Article abstract of DOI:10.3184/030823410X12682371167951

N,N-dimethylformamide promoted the reaction of alkyl or arylisocyanides with barbituric acid derivatives which led to 5-[(alkyl or arylamino)methylene] barbituric acids in good yields at room temperature. The work-up of reactions was very simple and the c

Full text of DOI:10.3184/030823410X12682371167951

140 RESEARCH PAPER
MARCH, 140–144
JOURNAL OF CHEMICAL RESEARCH 2010
N,N-dimethylformamide-promoted reaction of isocyanides and barbituric
acids: an easy synthesis of 5-[(alkyl or arylamino)methylene]barbituric
acids
Mohammad Bagher Teimouria,b* and Ahmad Tayyebia
aFaculty of Chemistry, Omidiyeh Branch, Islamic Azad University, Omidiyeh, Iran
bPetrochemical Department, Iran Polymer and Petrochemical Institute, PO Box 14965-115, Tehran, Iran
N,N-dimethylformamide promoted the reaction of alkyl or arylisocyanides with barbituric acid derivatives which led to 5-[(alkyl or
arylamino)methylene]barbituric acids in good yields at room temperature. The work-up of reactions was very simple and the crude
products were sufficiently pure to be used without further purification. This procedure provides an alternative method for the synthesis of
aminomethylenebarbituric acids.
Keywords: barbituric acid, N,N-dimethylformamide, heterodiene, isocyanide
Among three chemical characteristics of isocyanides, the
α-addition, the α-acidity and the easy formation of radicals,
the first has attracted the most attention of organic chemists.1
The α-addition by nucleophiles and electrophiles on the carbon
atom of the isocyano functionality is the main characteristic
of isocyanides with other common organic functional groups.
The formal divalency of the isocyanides provides a challenge
to the successful development of the α-addition reactions.2,3
All reactions of isocyanides are conversions of divalent carbon
atoms into products with tetravalent carbon atoms.4,5
The reactions of 1,3-dicarbonyl compounds with isocya-
nides6–11 and isocyanates12 are well documented. In our earlier
publications,13,14 we described two relatively facile routes to
fused furo[2,3-d]pyrimidine-2,4(1H,3H)-diones 1. These com-
pounds were obtained by treatment of 1,3-dimethylbarbituric
acid with aromatic aldehydes and isocyanides in hot water13 or
small amount of N,N-dimethylformamide (DMF) at room tem-
perature14 (Scheme 1, Path A). Based on the three-component
reaction, more efforts were made to investigate the reactions of
unsubstituted barbituric acid. In 2007, some unexpected results
were obtained when barbituric acid was used.15 The condensa-
tion reactions between alkyl isocyanide, substituted benzalde-
hydes and barbituric acid were performed in water/acetonitrile
(1:1) under reflux conditions to give N-alkyl-N-[aryl-(2,4,6-
trioxohexahydropyrimidin-5-yl)methyl]formamides 2 in 3 h
(Scheme 1, Path B).
During an attempt to prepare 6-(tert-octylamino)-5-phenyl-
2-thioxo-2,3-dihydrofuro[2,3-d]pyrimidin-4(1H)-one 3 from
tert-octyl isocyanide, benzaldehyde, and 2-thiobarbituric acid
in DMF, a white crystalline solid precipitated from the reaction
mixture when left to stand 30 min at room temperature (Scheme
1, Path C). Structural elucidation by 1H and 13C NMR spectros-
copy revealed this precipitate to be 5-[(tert-octylamino)
methylene]-2-thioxodihydropyrimidine-4,6(1H,5H)-dione 4a
without the participation of benzaldehyde, which did not enter
into the reaction. This interesting result led us to further inves-
tigate the scope of this methodology to access 5-[(alkyl or ary
lamino)methylene]barbituric acids. Here we report an efficient
reaction of isocyanides and barbituric acids in DMF at room
temperature which afforded methylenebarbituric acids.
Scheme 1
* Correspondent. E-mail: m.teimouri@ippi.ac.ir

JOURNAL OF CHEMICAL RESEARCH 2010 141
The condensation reactions of alkyl or aryl isocyanides 5
with barbituric acid derivatives 6 proceeded spontaneously
at room temperature in a small amount of DMF and were
completed after 30 min to afford corresponding 5-[(alkyl or
arylamino)methylene]barbituric acid derivatives 4 in good
isolated yields (Scheme 2). The results are summarised in
Table 1.
isocyanides. It was found that 2-thiobarbituric acid, 1,3-
diethyl-2-thiobarbituric acid, barbituric acid and 1,3-
dimethylbarbituric acid can tolerate the reaction conditions
with good yields. Also, the results show that the reaction is
quite general with a variety of structurally diverse alkyl or aryl
isocyanides affording the expected products 4.
The 1H NMR spectrum of 4a exhibited three single
sharp line readily recognised as arising from two tert-butyl
(δH 0.92 ppm), two geminal methyl groups (δH 1.40 ppm) and
The scope and limitations of this reaction were explored
using four barbituric acid derivatives and six alkyl or aryl
Scheme 2
Table 1 Synthesis of aminomethylenebarbituric acids 4a–1 in DMF
Entry
R
R’
X
Product
Yielda/%
91
1
H
S
2
3
H
H
S
S
88
91
4
5
H
H
S
S
93
85
6
7
S
84
84
H
O

142 JOURNAL OF CHEMICAL RESEARCH 2010
Table 1 Continued
Entry
8
R
R’
H
X
O
Product
Yielda/%
80
9
10
11
12
CH3—
CH3—
CH3—
CH3—
O
O
O
O
83
90
81
83
a Refers to isolated yield. The products 4c, 4d, 4e, 4i, 4j, 4k and 4l have been already prepared.9,11
two methylene protons (δH 1.65 ppm) along with a doublet
(δH 8.14 ppm, 3JHH = 15.0 Hz) for the vinylic methine. A fairly
broad doublet (δH 10.78 ppm, JHH = 15.0 Hz) is observed for
weak base can catalyse the imine-enamine tautomerisation of
strong CH-acid 8 to 5-[(alkyl or arylamino)methylene]barbitu
ric acid 4 as a weaker NH-acid.
3
the enamine NH group. The vicinal proton–proton coupling
constant (3JHH) as a function of torsion angle can be obtained
from the Karplus equation.16 Observation of 3JHH = 15.0 Hz for
two vicinal protons (NH–CH=) in compound 4a indicates a
trans arrangement for these centres. Furthermore, the chemi-
cal shift of the NH group indicates that this moiety must have
participated in a six-membered intramolecular hydrogen bond
formation with the vicinal carbonyl group as shown in Scheme
2. Two singlets (δH 11.81 and 11.91 ppm) were observed for
the two NH groups of thiobarbituric moiety.
In order to confirm that the reaction was truly catalysed by
DMF, we carried out many parallel experiments. We examined
the reaction of tert-octyl isocyanide with 2-thiobarbituric
acid in the presence of catalytic amount (50 mol%) of DMF.
The desired product 4a was isolated in 95% yield after 30 min
at room temperature. Very low amounts of 4a (<5%) obtained
in the absence of DMF under similar reaction conditions.
Furthermore, we examined the above-mentioned reaction in
the presence of catalytic amount (50 mol%) of DMSO as
another polar aprotic solvent. The reaction gave product 4a of
less than 10%. While, this reaction in the presence of 50 mol%
of N,N-dimethylacetamide (DMAc) or N-methylpyrrolidone
(NMP) formed 4a in 83% and 80% isolated yields, respec-
tively. These results highlighted the decisive role of DMF,
DMAc and NMP (N,N-substituted amidic polar solvents) on
the efficiency of the reaction.
In summary, we have reported the synthesis of 5-[(alkyl or
arylamino)methylene]barbituric acids via a DMF-promoted
reaction between barbituric acid derivatives and alkyl or
aryl isocyanides at room temperature in 30 min. The main
advantages of this methodology with respect to the other
methods9,11,12,19–22 are: (i) the reaction is simple to perform;
(ii) the reaction occurs at room temperature; (iii) the yields
are good to high; (iv) there is no need for any other catalyst;
(v) the reaction completes within a short period of time; and
(vi) purification of the products is not necessary.
The 1H decoupled 13C NMR spectrum of 4a showed 10 dis-
tinct resonances in agreement with the suggested structure.
Partial assignment of these resonances is given in experimental
section.
High rates of reactions at room temperature have enabled
us to establish a significant catalytic role for DMF in reaction
of barbituric acids with isocyanides. A reasonable possibility
for DMF-catalysed reaction has been suggested in Scheme 3.
The first step may involve formation of a six-membered cyclic
chair-like intermediate 7. In this situation, the insertion of
isocyanide 5 into the C–H bond of barbituric acid 6 is facili-
tated by strong attraction of active hydrogens with highly
electronegative oxygen and nitrogen atoms of DMF moiety
(double non-conventional hydrogen bonds)17,18 in intermediate
7 to form 5-[(alkyl or arylimino)methyl]babituric acid 8 as a
strong CH-acid. As shown in Scheme 3, DMF as a bidentate

JOURNAL OF CHEMICAL RESEARCH 2010 143
Scheme 3
1H NMR (500.1 MHz, DMSO-d6): δH 2.44 (3 H, s, CH3), 5.12 (1 H,
d, 3JHH = 6.6 Hz, SO2CH2NH), 7.48 and 7.67 (4 H, 2 d, 3JHH = 8.7 Hz,
C6H4), 8.04 (1 H, d, 3JHH = 14.1 Hz, NH–CH=), 10.27 (1 H, m, NH…
O=C), 11.92 and 12.00 (2 H, 2 s, HNCSNH); 13C NMR (125.7 MHz,
DMSO-d ):δ 178.1(C=S), 163.4and161.4(2C=O), 160.0(NCH=C),
145.4, 1363.2,C130.1 and 128.8 (arom. carbons), 94.1 (NCH=C), 67.4
(SO2CH2), 21.1 (CH3); Anal. Calcd for C13H13N3O4S (339.39): C,
46.01; H, 3.86; N, 12.38. Found: C, 45.73; H, 3.83; N, 212.42%.
5-[(Cyclohexylamino)methylene]-1,3-diethyl-2-thioxodihydropy-
rimidine-4,6 (1H,5H)-dione (4f): White powder (0.260g, 84 %); m.p.
129–131 °C; IR (KBr) (νmax/cm−1): 3434 (N–H), 1685, 1647 (C=O)
1607 (C=C), 1106 (C=S); 1H NMR (500.1 MHz, CDCl ): δH 1.24 and
1.26 (3 H, 2 t, 3JHH = 6.9 Hz, 2 CH2CH3), 1.30–2.00 (103H, m, 5 CH2),
3.39 (1 H, m, NCH), 4.49 and 4.51 (4 H, 2 q, 3JHH = 6.9 Hz, 2 CH2CH3),
8.25 (1 H, d, 3JHH =14.6 Hz, NH–CH=), 10.60 (1 H, br s, NH. . .O=C);
13C NMR (125.7 MHz, CDCl3): δC (ppm) 178.9 (C=S), 163.1 and
161.1 (2 C=O), 158.3 (NCH=C), 92.6 (NCH=C), 59.1 NCH), 42.8
and 42.2 (2 CH2), 33.4, 24.9 and 24.2 (5 CH2), 12.4 and 12.3 (2CH3);
Anal. Calcd for C15H N O2S (309.42): C, 58.22; H, 7.49; N, 13.58.
Found: C, 58.39; H, 72.3533; N, 13.49%.
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
a Bruker DRX-500 Avance spectrometer at 500.1 and 125.8 MHz,
respectively, with CDCl or CD3SOCD as solvents and calibrated
using residual undeuterat3ed solvent as an3internal reference. Chemical
shifts are reported in parts per million relative to TMS as internal ref-
erence. Analytical TLC was carried out on pre-coated plates (Merck
silica gel 60, F254) and visualised with UV light. All chemical
reagents were obtained from Aldrich, Merck or Acros and were used
without further purification. The products 4c–4e and 4i–4l are known
1
compounds, which were identified by IR and H NMR spectral data
and comparing their melting points with literature reports.11,13
Typical procedure for the preparation of 4a
To a solution of 2-thiobarbituric acid (0.144 g, 1.0 mmol) in DMF
(0.5 mL) in a screw-capped vial was added tert-octyl isocyanide
(0.140 g, 1 mmol) via a syringe and was shaken for 1 min. The
reaction mixture was then kept for about 30 min at room temperature
(25 °C) and the completion of reaction was confirmed by TLC
(EtOAc–hexane 1:1). Then, the resulting solids were filtered and
washed with diethyl ether (10 mL) to yield 4a as white powder
(0.257 g, 91 %). The dried product thus obtained showed a single spot
on TLC and was pure enough for all analytical purposes.
5-[(Cyclohexylamino)methylene]pyrimidine-2,4,6(1H,3H,5H)-
trione (4g): White powder (0.199 g, 84 %); m.p. 278–280 °C; IR
(KBr) (νmax/cm−1): 3434, 3193, 3083 (N–H), 1705, 1667, 1644 (C=O);
1H NMR (500.1 MHz, DMSO-d6): δH (ppm) 1.37–1.86 (10 H, m,
3
5CH2), 3.52–3.54 (1 H, m, NHCH), 8.14 (1 H, d, J = 14.6 Hz,
NH–CH=), 10.17(1 H, dd, 3JHH = 14.6 Hz, 3JHH = 7.7 HzH, HNH…O=C),
10.52 and 10.64 (2 H, 2 s, HNCONH); 13C NMR (125.7 MHz, DMSO-
d6): δC (ppm) 166.1 and 163.7 (2 HN–C=O), 156.6 (NCH=C), 150.8
(HNCONH), 89.2 (NCH=C), 57.7 (NHCH), 32.5, 24.4 and 24.0
(5 CH of cyclohexyl); Anal. Calcd for C11H N O (237.25): C, 55.69;
H, 6.327; N, 17.71. Found: C, 56.08; H, 6.421;5N3, 137.59%.
5-{[(1,1,3,3-Tetramethylbutyl)amino]methylene}-2-thioxodihydro-
pyrimidine-4,6(1H,5H)-dione (4a): M.p. 282–284 °C; IR (KBr) (νmax
/
cm−1): 3456, 3112 (N–H), 1687, 1621 (C=O), 1162 (C=S); H NMR
1
(500.1 MHz, DMSO-d6): δH 0.92 (9 H, s, CMe ), 1.40 (6 H, s, CMe2),
1.65 (2 H, s, CH ), 8.14 (1 H, d, JHH = 15.03Hz, NH–CH=), 10.78
3
(1 H, d, JHH = 125.0 Hz, NH. . .O=C), 11.81 and 11.91 (2 H, 2 s,
3
5-[({[(4-Methylphenyl)sulfonyl]methyl}amino)methylene]pyrimidine-
2,4,6(1H,3H,5H)-trione (4h): White powder (0.258 g, 80 %); m.p.
298–300 °C; IR (KBr) (νmax/cm−1): 3454, 3238 (N–H), 1693, 1649
(C=O), 1358, 1147 (SO ); 1H NMR (500.1 MHz,DMSO-d6): δH (ppm)
2.41 (3 H, s, CH ), 5.102(1 H, s, SO CH2NH), 7.48 and 7.67 (4 H, 2 d,
3JHH = 8.1 Hz, C36H4), 8.00 (1 H, s, 2NH–CH=), 10.10 (1 H, m, NH…
O=C), 10.74 and 10.80 (2 H, 2 br s, HNCONH); 13C NMR (125.7
MHz, DMSO-d6): δC (ppm) 165.7 and 163.3 (2 HN–C=O), 159.1
(NCH=C), 150.6 (HNCONH), 145.3, 133.3, 130.0 and 128.7 (arom.
carbons), 92.6 (NCH=C), 67.3 (SO2CH2), 21.1 (CH3); Anal. Calcd for
HNCSNH); 13C NMR (125.7 MHz, DMSO-d6): δC 177.5 (C=S), 164.1
and 161.6 (2 C=O), 154.9 (NCH=C), 91.1 (NCH=C), 58.3 (CH2), 53.9
(CMe2), 31.3 (CMe3), 31.0 (CMe ), 28.6 (CMe ); Anal. Calcd for
C H21N O2S (283.39): C, 55.10; H3, 7.47; N, 14.823. Found: C, 55.22;
H1,37.39;3N, 14.95%.
5-[({[(4-Methylphenyl)sulfonyl]methyl}amino)methylene]-2-thiox-
odihydropyrimidine-4,6(1H,5H)-dione (4b): White powder (0.298 g,
88 %); m.p. 315–317 °C; IR (KBr) (ν /cm−1): 3403, 3288, 3220 (N–
H), 1705, 1655 (C=O), 1620 (C=C), m1a3x63, 1141 (SO2), 1138 (C=S);

144 JOURNAL OF CHEMICAL RESEARCH 2010
8
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C H13N O5S (323.32): C, 48.29; H, 4.05; N, 13.00. Found: C, 48.12;
H1,34.09;3N, 12.94%.
10 M.H. Mosslemin, I. Yavari, M. Anary-Abbasinejad, M.R. Nateghi, J.
Fluorine Chem., 2004, 125, 1497.
We would like to thank Islamic Azad University (Omidiyeh
Branch) Research Council for their financial support.
11 M.T. Maghsoodlou, N. Hazeri, S.M. Habibi-Khorassani, V. Solimail,
G. Marandi and Z. Razmjoo, J. Chem. Res.(S), 2008, 198.
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15 M. Anary-Abbasinejad, M. Kamali-Gharamaleki and A. Hassnabadi,
J. Chem. Res., 2007, 594.
Received 22 February 2010; accepted 10 March 2010
Paper101016 doi: 10.3184/030823410X12682371167951
Published online: 22 March 2010
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