The reactions of diaminomaleonitrile with isocyanates and either aldehydes or ketones revisited

Article abstract of DOI:10.1021/jo010595w

A reinvestigation of the reactions of urea derivatives of diaminomaleonitrile 2 with aldehydes or ketones in the presence of triethylamine has established that the products of these reactions are not pyrimidino[5,4-d]pyrimidines 9 as previously reported, but 8-oxo-6-carboxamido-1,2-dihydropurines 12, which are oxidized rapidly in air to the corresponding 6-carboxamidopurines 13. Similarly, the reaction of Schiff base derivatives of DAMN 5 with isocyanates in the presence of triethylamine gives the substituted 2-oxoimidazoles 20 and not the pyrimidine derivatives 8 as previously claimed. The compounds 20 cyclize in solution and are easily oxidized to 8-oxopurine-6-carbonitriles 22, which give the same 8-oxopurine-6-carboxamides 13 upon further hydrolysis.

Full text of DOI:10.1021/jo010595w

8436
J . Org. Chem. 2001, 66, 8436-8441
Th e Rea ction s of Dia m in om a leon itr ile w ith Isocya n a tes a n d
Eith er Ald eh yd es or Keton es Revisited
Brian L. Booth,† Alice M. Dias, M. Fernanda Proenc¸a,* and Magdi E. A. Zaki
Departamento de Quı´mica, Universidade do Minho, Campus de Gualtar, 4710 Braga, Portugal
fproenca@quimica.uminho.pt
Received J une 12, 2001
A reinvestigation of the reactions of urea derivatives of diaminomaleonitrile 2 with aldehydes or
ketones in the presence of triethylamine has established that the products of these reactions are
not pyrimidino[5,4-d]pyrimidines 9 as previously reported, but 8-oxo-6-carboxamido-1,2-dihydro-
purines 12, which are oxidized rapidly in air to the corresponding 6-carboxamidopurines 13.
Similarly, the reaction of Schiff base derivatives of DAMN 5 with isocyanates in the presence of
triethylamine gives the substituted 2-oxoimidazoles 20 and not the pyrimidine derivatives 8 as
previously claimed. The compounds 20 cyclize in solution and are easily oxidized to 8-oxopurine-
6-carbonitriles 22, which give the same 8-oxopurine-6-carboxamides 13 upon further hydrolysis.
Sch em e 1
In tr od u ction
Diaminomaleonitrile (DAMN, 1), a tetramer of hydro-
gen cyanide, is a versatile precursor to a number of
nitrogen heterocycles, which include imidazoles and
purines,1 pyrroles,2 pyrimidines, 3 pyrazines, 4 diazepines,
1b,5
and triazepines.6
A previous detailed study7 of the reaction of DAMN
with isocyanates together with either an aldehyde or a
ketone in the presence of triethylamine reported that the
products of these reactions were pyrimidino[5,4-d]pyri-
midines 9, formed either by pathways A or B as shown
in Scheme 1. The author was able to isolate an interme-
diate supposed to have structure 6 and to show that it
was thermally stable in hot acetonitrile. In the presence
of base, the author postulated that isomerization occurs
around the CdC bond to give an intermediate 7, which
* To whom the correspondence should be addressed.
† Adress: Chemistry Department, University of Manchester Insti-
tute of Science and Technology, Manchester M60 1QD, UK.
(1) (a) Sheppard, W. A.; Webster, O. W. J . Am. Chem. Soc. 1973,
95, 2695. (b) Begland, R. W.; Hartter, D. R.; J ones, F. N.; Sam, D. J .;
Sheppard, W. A.; Webster, O. W.; Weigert, F. J . J . Org. Chem. 1974,
39, 2341. (c) Ohtsuka, Y. J . Org. Chem. 1976, 41, 713. (d) Booth, B. L.;
Proenc¸a, M. F. J . Chem. Soc., Chem. Commun. 1981, 788. (e) Booth,
B. L.; Coster, R. D.; Proenc¸a, M. F J . Chem. Soc., Perkin Trans. 1 1987,
1521. (f) Alves, M. J .; Booth, B. L.; Proenc¸a, M. F. J . Chem. Soc., Perkin
Trans. 1 1990, 1705. (g) Alves, M. J .; Booth, B. L.; Freitas, A. P.;
Proenc¸a, M. F J . Chem. Soc., Perkin Trans. 1 1992, 913. (h) Booth, B.
L.; Dias, A. M.; Proenc¸a, M. F. J . Chem. Soc., Perkin Trans. 1 1992,
2119. (i) Alves, M. J .; Booth, B. L.; Al-Duaij, O. Kh; Eastwood, P.;
Nezhat, L.; Proenc¸a, M. F.; Ramos, A. S. J . Chem. Res., Synop. (S)
1993, 402-403; J . Chem. Res., Miniprint 1993, 2701-2719. (j) Alves,
M. J .; Booth, B. L.; Proenc¸a, M. F. J . Heterocycl. Chem. 1994, 31, 345.
(k) Costa, F. A. T.; Booth, B. L.; Pritchard, R. G.; Proenc¸a, M. F.
Synthesis 2000, 9, 1269.
(2) (a) Alves, M. J .; Booth, B. L.; Carvalho, M. A.; Pritchard, R. G.;
Proenc¸a, M. F. J . Heterocycl. Chem. 1997, 739. (b) Alves, M. J .; Booth,
B. L.; Carvalho, M. A.; Pritchard, R. G.; Proenc¸a, M. F. J . Heterocycl.
Chem. 1999, 36, 193.
(3) (a) Ohtsuka, Y. J . Org. Chem. 1978, 43, 3231. (b) Costa, F. A.
T.; Booth, B. L.; Pritchard, R. G.; Proenc¸a, M. F. J . Chem. Soc., Perkin
Trans. 1 1999, 1853. (b) Al-Azmi, A.; Booth, B. L.; Pritchard, R. G.;
Proenc¸a, M. F. J . Chem. Soc., Perkin Trans. 1 2001, 485.
(4) Popp, F. D. J . Heterocycl. Chem. 1974, 11, 79.
(5) Booth, B. L.; Dias, A. M.; Proenc¸a, M. F. J . Heterocycl. Chem.
1996, 855.
(6) Alves, M. J .; Booth, B. L.; Eastwood, P.; Pritchard, R. G.; Proenc¸a,
M. F. J . Chem. Soc., Chem. Commun, 1993, 834.
(7) Ohtsuka, Y. J . Org. Chem. 1976, 41, 629.
cyclizes rapidly to 8; compound 7 could never be isolated.
In pathway A, double-bond isomerization is again pro-
posed under base-catalysis during the condensation of 2
with the aldehyde or ketone. Intermediate 3 could not
be isolated and this was attributed to its rapid cyclization
to pyrimidine 4, and subsequent cyclization followed by
oxidation in air to give the isolated product, assigned
10.1021/jo010595w CCC: $20.00 © 2001 American Chemical Society
Published on Web 11/13/2001

Reactions of Diaminomaleonitrile with Isocyanates
J . Org. Chem., Vol. 66, No. 25, 2001 8437
Sch em e 2
Sch em e 3
the characteristic nitrile absorptions at 2249 and 2205
cm-1 and the carbonyl absorption at 1644 cm-1 in the IR
spectrum. On reaction of 2 with aldehydes or ketones
(either as neat liquids or in methanol) in the presence of
triethylamine at room temperature, white-pale yellow
solids precipitated in good yields exactly as described by
Ohtsuka and previously assigned the pyrimidine struc-
ture 4. Although our spectroscopic data for 4 (R1 ) R2 )
Me, R3 ) Ph) are in good agreement with those reported,7
we now believe that this compounds is the 1,2-dihydro-
purine-6-carboxamide 12a (see Scheme 2). Structures 4
and 12a are isomeric and cannot be distinguished by
elemental analysis. The main evidence for structure 12a
1
rather than 4 comes from a reassessment of the H/13C
1
NMR spectroscopic data. In the H NMR spectrum the
two methyl groups are equivalent and appear at δ 1.31
and are clearly bonded to an sp3 carbon atom, as
substantiated by the peak at δ 70.11 ppm assigned to
C-2 in the 13C NMR spectrum. This is incompatible with
the structure 4 in which the two methyl groups of the
imine are nonequivalent and would be expected to show
different chemical shift values, being bonded to an sp2
carbon. The singlet at δ 4.97 (1H) is typical of the
pyrimidine N-H in 1,2-dihydropurines,8,9 while the sin-
glet at δ 9.75 (1H) can be assigned to the acidic NH of
the imidazole ring. Also typical of a 6-carboxamido group
in 1,2-dihydropurines are the different chemical shifts
of the amide protons, with one appearing as a singlet at
δ 7.61 and the other as a singlet masked by the aromatic
multiplet at δ 7.40-7.50 ppm. All the features compare
well with those of 6-carboxamido-1,2-dihydropurines,
previously reported8,9 and prepared using the reactions
described in Scheme 3. The closest analogues to the
structure 9. The same product was also obtained from 8
after prolonged hydrolysis of the cyano group using
hydrogen peroxide in acetic acid.
For some time, we have been interested in the geo-
metrical isomerism of DAMN derivatives in the belief
that this type of reaction is much more common than is
supposed in the current literature. For this reason, we
were intrigued by the above report by Ohtsuka and
decided to reinvestigate his reactions to try to confirm
that isomerism does occur under the conditions he had
outlined.
Resu lts a n d Discu ssion
(8) Alves, M. J .; Booth, B. L.; Carvalho, M. A.; Dias, A. M.; Proenc¸a,
M. F. J . Chemical Res., Synop. 1996, 212; J . Chem. Res., Miniprint
1996, 1101.
(9) Beagley, B.; Booth, B. L.; Eastwood, P. R.; Kieger, S.; Pritchard,
R. G.; Alves, M. J .; Carvalho, M. A.; Proenc¸a, M. F. Acta Crystallogr.
1995, C49, 1467.
(10) Alves, M. J .; Booth, B. L.; Carvalho, M. A.; Eastwood, P. R.;
Nezhat, L.; Pritchard, R. G.; Proenc¸a, M. F. J . Chem. Soc., Perkin
Trans. 2 1994, 1949.
The reactions of DAMN with phenyl or benzyl isocy-
anate proceeded as expected to give the urea derivatives
2a and 2b in excellent yields (Scheme 2). Compound 2a
has been previously described by Ohtsuka7 and our
spectroscopic data are in complete agreement with his.
Compound 2b has not been reported previously, but has

8438 J . Org. Chem., Vol. 66, No. 25, 2001
Booth et al.
Sch em e 4
the structure as 19A. Confirmation of this comes from
the three-bonds interaction of the NH (δ 7.83) and the
NH2 (δ 5.61) protons with C-4 (δ 116.2). In contrast, in
the minor isomer 19B only the CH2 protons (δ 4.72)
interact with C-5 (δ 153.9), while the NH proton (δ 8.02)
interacts with a signal at δ 150.5 ppm, assigned to the
cyanoformimidoyl carbon atom, while the NH2 protons
(δ 5.32) interact with a 13C signal at δ 114.5, which is
1
thus attributed to C-4. When both the H and 13C NMR
spectra were run at 70 °C, only one set of signals was
observed, which coincide with those of tautomer 19A,
indicating that this is the more thermodynamically stable
1
of the two tautomers. At this temperature, the H NMR
signals are slightly shifted from those observed at room
temperature. So, for example, the imidazole NH moves
from δ 10.70 (19A) and δ 10.40 (19B) at room tempera-
ture to δ 9.94 ppm, which may indicate that these protons
are hydrogen bonded to a different extent with the DMSO
solvent at room temperature.
The reaction of 19b with 3 equiv of p-anisaldehyde in
ethanol gave 13f in 58% yield. This compound was
identical to that isolated earlier in 70% yield from the
reaction of 2b with p-anisaldehyde and triethylamine in
ethanol (see Scheme 2). All the carboxamido-8-oxopurines
show two singlets, each one integrating for one proton,
in the δ 8.50-8.60 and δ 7.90-8.00 ppm region for the
NH protons of the 6-carboxamido group. An unusually
sharp, one proton singlet in the region of δ 11.70-12.00
ppm can be assigned to the imidazole NH. In the 13C
NMR spectra the signals for C-2, C-4, and C-8 appear in
the δ 152-155 region and the CdO around δ 165 ppm.
Attempts to isolate the imidazole 19a from 2a and DBU
under similar conditions failed as only a brown solution
was obtained, but on addition of two equivalents of
p-anisaldehyde to this solution the 6-carboxamidopurine
13a was isolated in 47% yield, indicative of the formation
of 19a .
These results establish that the products of the urea
derivatives 2 of DAMN with aldehydes or ketones in the
presence of triethylamine are the 8-oxo-6-carboxamido-
1,2-dihydropurines 12, which in the case of aldehydes,
are readily oxidized to 8-oxo-6-carboxamidopurines 13 in
solution. The mechanism of these reactions could follow
the pathway outlined in Scheme 2 or that demonstrated
in Scheme 4 and both appear equally plausible.
present work are the intermediates 16 (R1 ) R2 ) Me,
R3 ) Ph)8 and the tautomers 17A and 17B (R1 ) R2 )
Me, R3 ) Ph),9 for which the structures have been fully
established by X-ray crystallography. It is noteworthy
that when R2 ) H, compounds 17, in solution, are rapidly
oxidized to the corresponding purines 18, which mirrors
the reported behavior of compound 4. Indeed, when 2a
or b were caused to react with aldehydes, the isolated
product was the purine derivatives 13 rather than the
dihydropurines 12 (see Scheme 2). The exception being
the reaction between 2a and p-anisaldehyde, where it
was possible to isolate the intermediate 12b (82%), when
the solid product was removed from the reaction mixture
1
after 10 min. at room temperature. The H NMR spec-
trum of this compound shows coupling between the
pyrimidine NH (δ 5.34, d, J ) 4.5 Hz) and the adjacent
CH proton (δ 5.67, d, J ) 4.5 Hz), a clear indication of
the 1,2-dihydropurine structure. On refluxing 12b in
ethanol over 1 h it oxidizes to 13b, which was isolated
in 50% yield.
It can be seen from Scheme 3 that in the presence of a
base the amidines 14 cyclize rapidly to a 5-amino-4-
cyanoformimidoylimidazole intermediate 15, which can
be isolated when a mild base, such as DBU, is employed.
It seemed reasonable to assume that a similar cyclization
may occur with the urea derivatives 2 in the presence of
base and this may provide an alternative synthetic route
to compounds 12 and 13. Consequently, a catalytic
amount of DBU was added to a solution of 2b in
acetonitrile and a slow reaction occurred to give a new
compound 19b in 74% yield (Scheme 4). The IR spectrum
of the yellow solid shows a single cyano absorption of
medium intensity at 2214 cm-1 consistent with cycliza-
It will be recalled that pathway B (Scheme 1) proposed
by Ohtsuka7 suggested that the first intermediate formed
was a Schiff-base derivative 5, which then reacted with
the isocyanate. It was important, therefore, to establish
whether 5 could also be a precursor to compounds 12 and
13. Reaction between DAMN and benzaldehyde gave 5
(R1 ) Ph, R2 ) H) in 98% yield (Scheme 5). On further
reaction of this compound with phenyl isocyanate in
acetonitrile in the presence of triethylamine, a white solid
was obtained in 93% yield. According to Ohtsuka,7 this
compound should have the pyrimidine structure 8 (R1 )
R3 ) Ph, R2 ) H), although the evidence was based only
on elemental analysis and IR spectroscopic data [ν (Ct
N) 2200 cm-1 and strong absorptions at 1740 and 1630
cm-1]. We now believe that this compound has structure
20 (Scheme 5). Compound 20 is an isomer of 8 and is
indistinguishable from elemental analysis. The IR spec-
trum agrees with that reported by Ohtsuka.7 Both the
1H and 13C NMR spectra in d6-DMSO show two sets of
bands indicative of isomers in the ratio of 3:1, which we
believe correspond to the geometrical isomers 20A and
1
tion. In the H and 13C NMR spectra in DMSO-d6, two
sets of peaks can be seen consistent with the presence of
the tautomers A and B in a 2:1 ratio. The identification
of the tautomers was made on the basis of HMBC data,
considering the three-bond interaction of the CH2 and the
NH/NH2 protons. Careful analysis indicates that for the
major isomer both the CH2 (δ 4.68) and NH (δ 7.83)
protons interact with C-5 (δ 153.6) and this establishes

Reactions of Diaminomaleonitrile with Isocyanates
J . Org. Chem., Vol. 66, No. 25, 2001 8439
Sch em e 5
spectrum. After a further 3 days in DMSO-d6, signals for
the known 6-carboxamidopurine 13a started to appear.
This product was isolated and shown to be identical in
all respects to the product isolated earlier by heating 12b
in ethanol, and this establishes beyond doubt the reac-
tions outlined in Scheme 5.
In conclusion, this present investigation has demon-
strated that the previously reported reactions of urea
derivatives of DAMN with carbonyl compounds in the
presence of triethylamine do not give pyrimidino[5,4-d]-
pyrimidines by a mechanism involving rotation about the
CdC bond. Instead, these reactions give the isomeric
8-oxo-6-carboxamido-1,2-dihydropurines and 8-oxo-6-car-
boxamidopurines (in the case of aldehyde precursors) by
a mechanism that may involve initial cyclization to
2-oxoimidazole intermediates.
Exp er im en ta l Section
IR spectra were recorded on a Perkin-Elmer 1600 series
FTIR spectrometer, 1H and 13C NMR spectra on a Varian Unity
Plus spectrometer. Mass spectra were recorded on a GC-MS
Automass 120 or on a Kratos Concept instrument.
N-(2-Am in o-1,2-d icya n ovin yl)-N′-p h en ylu r ea (2a ). A
solution of DAMN (0.60 g, 5.55 mmol) in dry acetonitrile (10
mL) was kept stirring in an ice bath, under a nitrogen
atmosphere, in a round-bottom flask equipped with a serum
cap. Phenyl isocyanate (0.70 g, 5.88 mmol) was added dropwise
with a syringe through the serum cap, and 10 min later a
precipitate started to appear. The mixture was stirred at room
temperature for 24 h, when the cream solid was filtered and
washed with acetonitrile and diethyl ether. The product was
identified as the title compound (1.19 g, 5.24 mmol, 95%).
Characterization: mp 180-185 °C dec (lit.1b mp 180-210 °C
1
dec); H NMR (DMSO-d6, 300 MHz) δ 8.80 (s, 1 H), 7.54 (s, 1
H), 7.42 (d, J ) 7.5 Hz, 2 H), 7.26 (t, J ) 7.5 Hz, 2 H), 7.18 (s,
2 H), 6.97 (t, J ) 7.5 Hz, 1 H); IR (Nujol mull) 2247 (m, CN),
2209 (s, CN), 1635 (s, CdO).
20B, which are both stabilized by intramolecular hydro-
gen bonding. Interestingly, Ohtsuka also observed two
N-(2-Am in o-1,2-d icya n ovin yl)-N′-ben zylu r ea (2b). Ben-
zyl isocyanate (0.65 g, 4.9 mmol) was added with a syringe to
a suspension of diaminomaleonitrile (0.48 g, 4.40 mmol) in dry
acetonitrile (5 mL), kept stirring under a nitrogen atmosphere
in an ice bath. A homogeneous solution was formed after 30
min, and after another 20 min a white solid started to
precipitate out of solution. After 17 h at 4 °C, the solid was
filtered and washed with acetonitrile and diethyl ether. The
product was identified as the title compound (0.86 g, 3.60
mmol, 82%). Characterization: mp above 173 °C dec; 1H NMR
(DMSO-d6, 300 MHz) δ 7.52 (s, 1 H), 7.40-7.20 (m, 5 H), 7.04
1
sets of bands in the H NMR spectrum of compound 8
(R1 ) 4-ClC6H4, R2 ) H, R3 ) Ph), but did not comment
1
upon their significance.7 Unfortunately, neither the H
nor the 13C NMR spectral data are sufficient to prove the
structure conclusively, the main features being the imine
C-H, the imine N-H and the imidazole N-H at δ 8.78,
8.52, and 11.91, respectively, for isomer A, and at δ 8.93,
8.56, and 12.06, respectively, for isomer B. In the 13C
NMR spectrum a DEPT experiment has established the
imine carbon atom at δ 158.35 for isomer A and at δ
159.36 ppm for isomer B. The main evidence for structure
20 is that on standing in a solution of DMSO-d6 for 46 h
at room temperature the spectrum changes and two clear
(s, 2 H), 6.95 (t, J ) 6.0 Hz, 1 H), 4.23 (d, J ) 6.0 Hz, 2 H); 13
C
NMR (DMSO-d6, 75 MHz) δ 154.8, 140.0, 128.2, 127.1, 126.7,
126.0, 117.3, 114.4, 91.4, 43.1; IR (Nujol mull) 2249 (w, CN),
2205 (s, CN), 1644 (s, CdO); MS (EI, 70 eV) m/z (rel int) 241
(M+, 90). Anal. Calcd for C12H11N5O: C, 59.75; H, 4.56; N,
29.05. Found: C, 59.81; H, 4.81; N, 28.72.
1
doublets appear in the H NMR spectrum at δ 6.01 (J )
6 Hz, 1H) identified as an NH proton by exchange with
D2O and at δ 5.76 ppm (J ) 6 Hz, 1H) identified as a CH
proton. We tentatively assign this new compound as 21
on the basis that the CH is now sp3 and coupling between
the adjacent protons (CH and NH) is observed. When a
suspension of 20 in acetic acid and hydrogen peroxide
was stirred at room temperature for 4 days it gave a low
yield (19%) of a white solid believed to be the purine-6-
carbonitrile 22. The IR spectrum for this compound
shows a weak ν (CtN) absorption at 2254 cm-1 and an
intense absorption at 1750 cm-1 for a CdO group. An
absorption of medium intensity at 3228 cm-1 is indicative
2,2-Dim eth yl-8-oxo-9-p h en yl-1,2-d ih yd r op u r in e-6-ca r -
boxa m id e (12a ). Triethylamine (50 µL) was added to a
suspension of diaminomaleonitrile urea 2a (0.15 g, 0.66 mmol)
in acetone (20 mL), and the reaction mixture was stirred at
room temperature. A solid precipitate started to develop after
3 h, and the reaction mixture was stirred for another 21 h.
The solid was filtered and washed with acetone and diethyl
ether to give the title compound (0.12 g, 0.42 mmol, 64%) as a
cream solid. Characterization: mp 236-237 °C; 1H NMR
(DMSO-d6, 300 MHz) δ 9.75 (s, 1 H), 7.61 (s, 1 H), 7.50-7.40
(m, 6 H), 4.97 (s, 1 H), 1.31 (s, 6 H); 13C NMR (DMSO-d6, 75
MHz) δ 164.2, 154.0, 151.2, 133.7, 128.5, 126.7, 126.3, 119.6,
109.6, 70.1, 28.8; IR (Nujol mull) 1730 (s, CdO), 1713 (s, Cd
O), 1668 (s), 1641 (s). Anal. Calcd for C14H15N5O2: C, 58.94;
H, 5.29; N, 24.55. Found: C, 58.57; H, 5.22; N, 24.29.
1
of a single NH, which appears in the H NMR spectrum
as a singlet at δ 12.95 ppm. The presence of a cyano group
2-(4′-Meth oxyph en yl)-8-oxo-9-ph en yl-1,2-dih ydr opu r in e-
6-ca r boxa m id e (12b). Triethylamine (0.1 mL) was added to
is confirmed by a signal at δ114.58 ppm in the 13C NMR

8440 J . Org. Chem., Vol. 66, No. 25, 2001
Booth et al.
a suspension of diaminomaleonitrile urea 2a (0.25 g, 1.01
mmol) and anisaldehyde (0.28 g, 2.05 mmol) in methanol (20
mL). The solution was stirred at room temperature, and 10
min later, a solid precipitate started to form. Stirring was
continued for another 19 h at room temperature, when the
solid was filtered and washed with ethanol and diethyl ether
to give the title compound (0.30 g, 0.83 mmol, 82%) as a off-
white solid. Characterization: mp 330-331 °C; 1H NMR
(DMSO-d6, 300 MHz) δ 9.85 (s, 1 H), 7.53 (d, J ) 8.5 Hz, 2 H),
7.42 (t, J ) 9.0 Hz, 2 H), 7.32 (t, J ) 9.0 Hz, 1 H), 6.90 (d, J
) 9.0 Hz, 2 H) 5.67 (d, J ) 4.5 Hz, 1H), 5.34 (d, J ) 4.5 Hz,
1H), 3.72 (s, 3H); 13C NMR (DMSO-d6, 75 MHz) δ 164.1, 158.9,
154.0, 153.1, 134.6, 133.5, 128.6, 128.1, 126.9, 126.2, 121.5,
113.4, 112.0, 69.7, 51.1; IR (Nujol mull) 1745 (s, CdO), 1697
(s, CdO). Anal. Calcd for C19H17N5O3: C, 62.80; H, 4.72; N,
19.27. Found: C, 62.51; H, 4.55; N, 19.30.
2,2-Tet r a h yd r ot h iop yr a n yl-8-oxo-9-p h en yl-1,2-d ih y-
d r op u r in e-6-ca r boxa m id e (12c). Triethylamine (0.1 mL)
was added to a suspension of diaminomaleonitrile urea 2a
(0.23 g, 1.01 mmol) and thiopyranone (0.13 g, 1.12 mmol) in
methanol (20 mL). The solution was stirred at room temper-
ature, and 30 min later, a solid precipitate started to form.
Stirring was continued for another 19 h at room temperature,
when the solid was filtered and washed with methanol and
diethyl ether to give the title compound (0.18 g, 0.55 mmol,
50%) as a cream solid. Characterization: mp 252-253 °C; 1H
NMR (DMSO-d6, 300 MHz) δ 9.87 (s, 1 H), 7.63 (s, 1H), 7.54
(s, 1 H) 7.31 (t, J ) 6.6 Hz, 1 H), 7.50-7.42 (m, 4 H), 4.61 (s,
1 H), 2.79-2.59 (m, 4 H), 2.00-1.91 (m, 4 H); 13C NMR
(DMSO-d6, 75 MHz) δ 164.6, 154.1, 151.1, 133.6, 128.6, 126.8,
126.1, 117.9, 111.7, 70.2, 37.3, 23.4; IR (Nujol mull) 1735 (s,
CdO), 1713 (s, CdO), 1668 (s), 1642 (s). Anal. Calcd for
solid which was filtered and washed with cold ethanol was
identical to the product isolated in the first crop, giving a total
of 0.04 g (0.11 mmol, 41%). Characterization: mp 330-332
1
°C; H NMR (DMSO-d6, 300 MHz) δ 11.70 (s, 1 H), 8.49 (s, 1
H), 8.37 (d, J ) 9.3 Hz, 2 H), 7.96 (s, 1 H), 7.71 (d, J ) 7.2 Hz,
2 H), 7.60 (t, J ) 7.5 Hz, 2 H), 7.47 (t, J ) 7.2 Hz, 1 H), 6.98
(d, J ) 9.3 Hz, 2 H), 3.80 (s, 3 H); 13C NMR (DMSO-d6, 75
MHz) δ 165.7, 161.0, 154.7, 152.9, 152.8, 133.0, 132.7, 129.4,
129.2, 128.9, 127.8, 126.3, 119.3, 113.8, 55.3; IR (Nujol mull)
1745 (s, CdO), 1696 (s, CdO). Anal. Calcd for C19H15N5O3‚0.2
H2O: C, 62.53; H, 4.14; N, 19.19. Found: C, 62.46; H, 4.25; N,
19.06.
Meth od B. A suspension of diaminomaleonitrile urea 2a
(0.20 g, 0.88 mmol) in dry acetonitrile (8 mL) was stirred in
an ice bath. Addition of DBU (three drops) caused the white
suspension to evolve to a dark yellow suspension, which was
stirred in the ice bath for 2 h. A brown solution was formed
and was stirred for a further 19 h at 4 °C. The dark suspension
was removed by filtration, and anisaldehyde (0.23 g, 1.70
mmol) was added to the clear, brown solution. An orange
precipitate had been formed after 25 min at room temperature,
and the mixture was stirred for a further 6 h. The solid was
filtered and washed with acetonitrile to give the title compound
(0.15 g, 0.42 mmol, 47%) as an orange solid.
2-(4′-Cya n op h en yl)-9-p h en yl-8-oxop u r in e-6-ca r boxa m -
id e (13c). Triethylamine (0.1 mL) was added to a suspension
of diaminomaleonitrile urea 2a (0.23 g, 1.01 mmol) and
4-cyanobenzaldehyde (0.26 g, 1.98 mmol) in methanol (20 mL).
The solution was stirred at room temperature, and after 15
min, a solid precipitate started to develop. The mixture was
stirred for another 18 h, when the product was filtered and
washed with methanol and diethyl ether to give the title
compound (0.25 g, 0.70 mmol, 69%) as a cream solid. Char-
acterization: mp above 340 °C; 1H NMR (DMSO-d6, 300 MHz)
δ 11.90 (s, 1 H), 8.63 (s, 1 H), 8.61 (d, J ) 8.1 Hz, 2 H), 8.01
(s, 1 H), 7.92 (d, J ) 8.1 Hz, 2 H), 7.70 (d, J ) 7.8 Hz, 2 H),
7.61 (t, J ) 8.4 Hz, 2 H), 7.48 (t, J ) 7.2 Hz, 1 H); 13C NMR
(DMSO-d6, 75 MHz) δ 165.4, 152.97, 152.94, 152.7, 141.0,
132.9, 132.5, 129.1, 128.2, 128.1, 126.4, 120.7, 118.9, 112.2;
IR (Nujol mull) 2229 (m, CN), 1754 (s, CdO), 1685 (s, CdO).
2-(4′-Nitr op h en yl)-9-p h en yl-8-oxop u r in e-6-ca r boxa m -
id e (13d ). Triethylamine (0.1 mL) was added to a suspension
of diaminomaleonitrile urea 2a (0.18 g, 0.80 mmol) and
4-nitrobenzaldehyde (0.19 g, 1.25 mmol) in methanol (20 mL).
The solution was stirred at room temperature, and after 5 min,
a yellow/orange solid precipitate started to develop. The
mixture was stirred for another 18 h, when the product was
filtered and washed with methanol and diethyl ether to give
the title compound (0.27 g, 0.72 mmol, 90%) as a greenish
yellow solid. Characterization: mp 218-220 °C; 1H NMR
(DMSO-d6, 300 MHz) δ 11.97 (s, 1 H), 8.65 (d, J ) 8.7 Hz, 2
H), 8.61 (s, 1 H), 8.26 (d, J ) 9.0 Hz, 2 H), 8.02 (s, 1H), 7.69
(d, J ) 8.4 Hz, 2 H), 7.60 (t, J ) 7.2 Hz, 2 H), 7.49 (t, J ) 7.2
Hz, 1 H); 13C NMR (DMSO-d6, 75 MHz) δ 165.4, 153.02, 152.95,
152.3, 148.3, 142.8, 132.9, 132.5, 129.1, 128.7, 128.1, 126.5,
123.7, 120.9; IR (Nujol mull) 1754 (s, CdO), 1684 (s, CdO).
Anal. Calcd for C18H12N6O4: C, 57.45; H, 3.21. Found: C,
57.32; H, 3.51.
C
16H17N5O2S‚0.2 H2O: C, 55.38; H, 4.94; N, 20.18; S, 9.24.
Found: C, 55.24; H, 4.97; N, 19.94; S, 9.37.
2,2-Cycloh exa n yl-8-oxo-9-p h en yl-1,2-d ih yd r op u r in e-6-
ca r boxa m id e (12d ). Triethylamine (0.1 mL) was added to a
suspension of diaminomaleonitrile urea 2a (0.30 g, 1.30 mmol)
in cyclohexanone (10 mL), and the solution was stirred at room
temperature. A solid precipitate started to be formed after 10
min, and stirring was continued for another 19 h. The solid
was filtered and washed with diethyl ether to give the title
compound (0.27 g, 0.83 mmol, 64%) as a cream solid. Char-
acterization: mp 218-219 °C; 1H NMR (DMSO-d6, 300 MHz)
δ 9.78 (brs, 1 H), 7.61 (s, 1 H), 7.50-7.39 (m, 5 H), 7.29 (t, J
) 6.9 Hz, 1 H), 4.51 (s, 1 H), 1.80-1.30 (m 5 H); 13C NMR
(DMSO-d6, 75 MHz) δ 164.8, 154.2, 151.0, 133.8, 128.7, 126.8,
126.1, 118.4, 111.5, 71.4, 41.5, 36.9, 26.6, 25.5, 24.4; IR (Nujol
mull) 1738 (s, CdO), 1715 (s, CdO), 1670 (s), 1645 (s). Anal.
Calcd for C17H19N5O2‚0.2 H2O: C, 62.07; H, 5.82; N, 21.29.
Found: C, 62.49; H, 6.01; N, 20.91.
2,9-Dip h en yl-8-oxop u r in e-6-ca r boxa m id e (13a ). Tri-
ethylamine (0.1 mL) was added to a suspension of diaminoma-
leonitrile urea 2a (0.25 g, 1.01 mmol) and benzaldehyde (0.23
g, 2.20 mmol) in methanol (20 mL), and the solution was
stirred at room temperature. A solid precipitate started to be
formed after 30 min, and stirring was continued for another
30 min. The solid was filtered and washed with diethyl ether
to give the title compound (0.25 g, 0.75 mmol, 68%) as a pale
yellow solid. Characterization: mp 323-324 °C; 1H NMR
(DMSO-d6, 300 MHz) δ 11.80 (s, 1 H), 8.50 (s, 1 H), 8.45-8.42
(m, 2 H), 7.98 (s, 1 H), 7.71 (d, J ) 7.8 Hz, 2 H), 7.60 (t, J )
2-Meth yl-9-p h en yl-8-oxop u r in e-6-ca r boxa m id e (13e).
Triethylamine (0.1 mL) was added to a suspension of diami-
nomaleonitrile urea 2a (0.23 g, 1.01 mmol) in acetylacetone
(10 mL), and the mixture was stirred at room temperature.
After 10 min a solid precipitate started to develop and stirring
was continued for another 19 h. The product was filtered and
washed with methanol and diethyl ether to give the title
compound (0.21 g, 0.78 mmol, 78%) as a white solid. Charac-
terization: mp 310 °C dec; Anal. Calcd for C13H11N5O2: C,
57.99; H, 4.12; N, 26.01. Found: C, 57.85; H, 4.29; N, 25.87;
8.1 Hz, 2 H), 7.47 (t, J ) 7.8 Hz, 1 H), 7.46-7.44 (m, 3 H); 13
C
NMR (DMSO-d6, 75 MHz) δ 165.6, 154.6, 152.87, 152.85, 136.8,
132.9, 132.7, 130.1, 129.0, 128.5, 127.9, 127.6, 126.4, 119.9;
IR (Nujol mull) 1753 (s, CdO), 1702 (s, CdO). Anal. Calcd for
C
18H13N5O2: C, 65.25; H, 3.95; N, 21.14. Found: C, 65.01; H,
4.06; N, 21.15.
2-(4′-Meth oxyp h en yl)-9-p h en yl-8-oxop u r in e-6-ca r box-
a m id e (13b). Meth od A. A suspension of the corresponding
1,2-dihydropurine 12a (0.10 g, 0.27 mmol) in ethanol (6 mL)
was refluxed for 1 h. The reaction mixture was cooled to room
temperature, leading to a white solid that was filtered and
washed with cold ethanol. The product was identified as the
title compound (0.01 g). A second crop was obtained concen-
trating the mother liquour in the rotary evaporator, and the
1
IR (Nujol mull) 1750 (s, CdO), 1703 (s, CdO). The H and 13C
NMR spectra of compound 13e could not be obtained due to
the poor solubility of this compound in DMSO-d6.
2-(4′-Meth oxyp h en yl)-9-ben zyl-8-oxop u r in e-6-ca r box-
a m id e (13f). Meth od A. Anisaldehyde (0.08 g, 0.58 mmol)
was added to a suspension of diaminomaleonitrile urea 2b
(0.07 g, 0.28 mmol) in ethanol (5 mL) kept stirring at room

Reactions of Diaminomaleonitrile with Isocyanates
J . Org. Chem., Vol. 66, No. 25, 2001 8441
temperature. Triethylamine (0.03 g, 0.29 mmol) was added to
the reaction mixture after 10 min. A homogeneous solution
was obtained after 3 h at room temperature, and shortly after
a white solid started to precipitate out. After 18 h, TLC
indicated that the reaction was almost complete. The solid was
filtered after another 2 days, washed with ethanol and diethyl
ether and identified as the title compound (0.07 g, 0.20 mmol,
70%). Characterization: mp above 300 °C dec; 1H NMR
(DMSO-d6, 300 MHz) δ 11.60 (brs, 1 H), 8.47 (d, J ) 8.7 Hz,
2 H), 8.44 (brs, 1 H), 7.92 (brs, 1 H), 7.40-7.20 (m, 5 H), 7.02
(d, J ) 8.7 Hz, 2 H), 5.08 (s, 2 H), 3.82 (s, 2 H); 13C NMR
(DMSO-d6, 75 MHz) δ 165.6, 161.0, 154.7, 153.7, 152.8, 136.5,
132.7, 129.5, 129.3, 128.6, 127.8, 127.6, 119.2, 113.8, 55.3, 42.7;
IR (Nujol mull) 1723 (s, CdO), 1665 (s, CdO). Anal. Calcd for
with water to give the title compound (0.36 g, 1.80 mmol, 98%)
as a pale yellow solid. Characterization: mp 206-208 °C; H
NMR (DMSO-d6, 300 MHz) δ 8.26 (s, 1 H), 8.00-8.05 (m, 2
H), 7.94 (s, 2 H), 7.50-7.40 (m, 3 H); 13C NMR (DMSO-d6, 75
MHz) δ 155.1, 135.5, 131.5, 129.0, 128.7, 127.0, 126.9, 114.3,
113.7, 102.6; IR (Nujol mull) 2239 (m, CN), 2204 (s, CN), 1608
(s), 1579 (s).
1
Rea ction of 1-Ben zylid en ea m in o-2-a m in o-1,2-d icya -
n oeth ylen e 5 w ith P h en yl Isocya n a te. Triethylamine (3
drops) was added to a suspension of 1-benzylideneamino-2-
amino-1,2-dicyanoethylene 5 (1.00 g, 5.10 mmol) and phenyl
isocyanate (0.70 g, 5.88 mmol) in acetonitrile (20 mL). The
reaction mixture was warmed gently in a water bath, and after
15 min, the white precipitate that had been formed was filtered
and washed with acetonitrile. The product was identified as
the substituted imidazole 20 (1.49 g, 4.73 mmol, 93%).
Characterization of imidazole 20, present in the NMR specta
as two isomeric forms A and B, in a 3:1 ratio: mp 241-242
C
20H17N5O3: C, 64.00; H, 4.53; N, 18.67. Found: C, 63.63; H,
4.58; N, 18.52.
Meth od B. Anisaldehyde (0.10 g, 0.74 mmol) was added to
a suspension of 19b (0.06 g, 0.23 mmol) in ethanol (10 mL),
and the mixture was stirred at room temperature for 18 h. A
new white solid had been formed in a yellow/orange solution,
and the mixture was stirred at room temperature for another
2 days. The solid was filtered and washed with ethanol and
diethyl ether. The product was identified as the title compound
(0.05 g, 0.13 mmol, 58%).
1
°C; H NMR (DMSO-d6, 300 MHz) δ 12.06 (s, 1 H, B), 11.91
(s, 1 H, A), 8.93 (s, 1 H, B), 8.78 (s, 1 H, A), 8.56 (s, 1 H, B),
8.52 (s, 1 H, A), 8.19 (d, J ) 6.9 Hz, 2 H, A+B), 7.60-7.39 (m,
8 H, A+B); 13C NMR (DMSO-d6, 75 MHz) δ 159.4 (B), 158.4
(A), 152.7 (B), 152.4 (A), 151.9 (B), 150.6 (A), 139.8, 136.2 (B),
135.4 (A), 130.9, 129.7, 129.5, 128.9, 128.7, 128.1, 127.9, 112.1,
98.7; IR (Nujol mull) 2210 (m, CN), 1736 (s, CdO). Anal. Calcd
for C18H13N5O: C, 68.56; H, 4.16; N, 22.21. Found: C, 68.53;
H, 4.03; N, 22.29.
5-Am in o-1-b en zyl-4-cya n ofor m im id oyl-im id a zole-2-
on e (19). A catalytic amount of DBU (70 µL) was added to a
suspension of diaminomaleonitrile urea 2b (0.15 g, 0.62 mmol)
in dry acetonitrile (2 mL), and the mixture was stirred at 4
°C for 18 h, when the TLC indicated that the reaction was
complete. The yellow solid was filtered and washed with
acetonitrile and diethyl ether. The product was identified as
the title compound (0.11 g, 0.46 mmol, 74%). Characterization
of imidazole 19, present in the NMR spectra as two isomeric
forms A and B, in a 2:1 ratio: mp above 175 °C dec; 1H NMR
(DMSO-d6, 300 MHz) δ 10.15 (brs, 2 H, A + B), 8.02 (s, 1 H,
B), 7.83 (s, 1 H, A), 7.35-7.20 (m, 5 H, A + B), 5.61 (s, 2 H,
A), 5.35 (s, 2 H, B), 4.72 (s, 2 H, B), 4.68 (s, 2 H, A); 13C NMR
(DMSO-d6, 75 MHz) δ 153.9 (B), 153.7 (B), 153.6 (A), 153.0
(A), 150.5 (B), 137.1 (B), 136.6 (A), 128.5 (B), 128.4 (A), 127.4
(B), 127.3 (B), 118.0 (B), 116.2 (A), 116.0 (A), 114.5 (A), 99.3
(A), 41.4 (A), 40.5 (B); IR (Nujol mull) 2210 (m, CN), 1758 (m,
CdO); MS (EI, 70 eV) m/z (rel int) 241 (M+, 40). Anal. Calcd
for C12H11N5O; C, 59.75; H, 4.56; N, 29.05. Found: C, 59.62;
H, 4.81; N, 28.75.
Cycliza tion of Im id a zole 20 in Acetic Acid a n d Hy-
d r ogen P er oxid e. A suspension of imidazole 20 (0.20 g, 0.66
mmol) in acetic acid (8 mL) and hydrogen peroxide 30% (2 mL)
was stirred at room temperature for 4 days. The pale yellow
suspension evolved to a white solid, which was filtered and
washed with ethanol and diethyl ether. This product was
identified as the 6-cyanopurine 22 (0.05 g, 0.16 mmol, 24%).
1
Characterization: mp 289-291 °C; H NMR (DMSO-d6, 300
MHz) δ 13.94 (brs, 1 H), 8.21-8.17 (m, 2 H), 7.71-7.47 (m, 8
H); 13C NMR (DMSO-d6, 75 MHz) δ 156.2, 152.7, 136.3, 132.1,
130.7, 129.2, 128.8, 128.4, 127.2, 126.3, 125.3, 114.7, 113.9;
IR (Nujol mull) 2254 (w, CN), 1751 (s, CdO). The mother
liquour was neutralized by ammonium hydroxide leading to a
white precipitate which was filtered and washed with water
and diethyl ether. This product was identified as the 8-oxopu-
rine-6-carboxamide 13a (0.07 g, 0.21 mmol, 32%).
1-Ben zylid en ea m in o-2-a m in o-1,2-d icya n oeth ylen e (5).
Benzaldehyde (0.20 g, 1.88 mmol) was added to a solution of
DAMN (0.20 g, 1.85 mmol) and concentrated sulfuric acid (3
drops) in dimethyldulfoxide (25 mL). The mixture was stirred
at room temperature for 15 min and poured into an ice/water
bath (250 mL). After 2 h, the solid was filtered and washed
Ack n ow led gm en t. The authors gratefully acknowl-
edge the financial support by the University of Minho
and Fundac¸a˜o para a Cieˆncia e Technologia (Project
PRAXIS/C/QUI/10101/1998).
J O010595W