Easy Access to 1H-Pyrrolo[3′,4′:5,6]pyrido[2,3-d]pyrimidine-2,4,6,8(3H,7H)-tetraone and Selectively N7-Substituted Analogues through Key Synthons

Article abstract of DOI:10.1002/ejoc.201500971

To synthesize unsubstituted pyrrolo[3′,4′:5,6] pyrido[2,3-d]pyrimidine-2,4,6,8-tetraone, we have developed new synthon 4-formyl-3-hydroxy-2,5-dioxo-2,5-dihydro-1H-pyrrole, which was then treated under mild conditions with 6-aminouracil. This new synthetic pathway could be extended to the preparation of N⁷-selectively substituted heterocycles by starting either from this new synthon or from its N-substituted analogues. Examples of N¹,N⁷-disubstituted and N¹,N³,N⁷-trisubstituted derivatives are also described. We have thus developed new synthons that lead to easy access to the unsubstituted pyrrolo[3′,4′:5,6]pyrido[2,3-d]pyrimidine-2,4,6,8-tetraone skeleton and to selectively N⁷-substituted analogues. New key synthons, 4-formyl-3-hydroxy-2,5-dioxo-2,5-dihydro-1H-pyrrole and its N-substituted analogues, have been developed for easy and versatile syntheses of heterocyclic skeletons, such as unsubstituted pyrrolo[3′,4′:5,6]pyrido[2,3-d]pyrimidine-2,4,6,8-tetraone.

Full text of DOI:10.1002/ejoc.201500971

FULL PAPER
DOI: 10.1002/ejoc.201500971
Easy Access to 1H-Pyrrolo[3Ј,4Ј:5,6]pyrido[2,3-d]pyrimidine-2,4,6,8(3H,7H)-
tetraone and Selectively N7-Substituted Analogues through Key Synthons
Aurélien Tourteau,[a] Eric Merlet,[a] Alexis Bontemps,[a] Mathilde Leland,[a]
Philippe Helissey,[a] Sylviane Giorgi-Renault,*[a] and Stéphanie Desbène-Finck*[a]
Keywords: Synthetic methods / Multicomponent reactions / Fused-ring systems / Nitrogen heterocycles
To synthesize unsubstituted pyrrolo[3Ј,4Ј:5,6] pyrido[2,3-d]-
pyrimidine-2,4,6,8-tetraone, we have developed new syn-
thon 4-formyl-3-hydroxy-2,5-dioxo-2,5-dihydro-1H-pyrrole,
which was then treated under mild conditions with 6-amino-
uracil. This new synthetic pathway could be extended to the
preparation of N7-selectively substituted heterocycles by
starting either from this new synthon or from its N-substi-
tuted analogues. Examples of N1,N7-disubstituted and
N1,N3,N7-trisubstituted derivatives are also described. We
have thus developed new synthons that lead to easy access
to the unsubstituted pyrrolo[3Ј,4Ј:5,6]pyrido[2,3-d]pyrimid-
ine-2,4,6,8-tetraone skeleton and to selectively N7-substi-
tuted analogues.
Introduction
In connection with their similarities to DNA bases, pyr-
imidinediones constitute a major class of heterocyclic com-
pounds, which have various pharmaceutical applications[1].
N1,N3-Unsubstituted pyrimidinediones possess antineo-
plastic and antiviral activities, for example.[2] The bicyclic
N1,N3-unsubstituted pyrido[2,3-d]pyrimidinedione struc-
tural motif has also received much attention and shows bio-
logical activity as antineoplastic,[3] antiviral,[4] antiasth-
matic and antiallergics.[5]
Many tricyclic heterocycles in which a pyrido[2,3-d]pyr-
imidine-2,3(1H,3H)-dione nucleus is fused with a six-mem-
bered ring have been described, particularly in the 5-de-
azaflavin series. Despite the potential biological interest of
analogues fused with a five-membered cycle or heterocycle,
few papers concerning these linear tricyclic heterocyclic
series have been published.[6] These observations and our
interest in active molecular design for drugs led us to at-
tempt an efficient synthetic pathway to the synthesis of 1H-
pyrrolo[3Ј,4Ј:5,6]pyrido[2,3-d]pyrimidine-2,4,6,8(3H,7H)-
tetraone (1) and selectively N7-substituted derivatives (Fig-
ure 1).
Figure 1. Structure of compounds 1 and 2.
state microwave irradiation[6] or under classical thermal
conditions in benzene[6] by reacting N-phenylmaleimide (5)
with 6-amino-1,3-dimethyl-5-formyluracil (4), which was
prepared from commercially available 6-amino-1,3-dimeth-
yluracil (3;[7] Scheme 1).
To the best of our knowledge, only one publication re-
ports the synthesis of this heterocyclic skeleton. 7-Phenyl-
1,3-dimethyl derivative 6 has been obtained under solid-
Scheme 1.
This pathway is very efficient for the preparation of tri-
substituted heterocycles. However, a classical approach is
not appropriate for the synthesis of the unsubstituted core
that involves very insoluble starting materials. A solvent-
less approach requires particular materials and cannot be
used for the preparation of N1,N3-dimethyl-substituted het-
erocycles (vide infra).
[a] Université Paris Descartes, Faculté de Pharmacie de Paris,
Laboratoire de Chimie Thérapeutique, UMR CNRS 8638,
Sorbonne Paris Cité
4 avenue de l’Observatoire, 75270 Paris Cedex 06, France
E-mail: sylviane.giorgi-renault@parisdescartes.fr
stephanie.desbene@parisdescartes.fr
www.comete.cnrs.fr
Supporting Information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201500971.
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Complex Nitrogen heterocycles and N7-Substituted Analogues
In this paper, we describe an original and easy access to imide (11) was prepared by dibromination of maleimide
unsubstituted heterocyclic skeleton 1 and to selectively N7- (12) and subsequent elimination of hydrobromhydric acid
substituted analogues. N7-Benzyl compound 2, which was in accordance with the method previously described by
chosen as a model, was synthesized by two different routes. Baker.[12] However, replacement of chloroform by dichloro-
Furthermore, we have also investigated the possibility that methane in the first step and modification of the work up
these new processes could be extended to the preparation of allowed us to improve the yield to 86% from 59%.
N1,N7-disubstituted and N1,N3,N7-trisubstituted analogues.
Results and Discussion
In 1882, Hantzsch described the synthesis of symmetrical
1,4-dihydropyridines under mild conditions by condensa-
tion of two equivalents of a β-dicarbonyl compound with
one equivalent of an aldehyde in the presence of ammo-
nia.[8] Subsequent oxidation afforded the corresponding
pyridines. Later, it was shown that same products can been
prepared by using an aldehyde, an α-methylenic ketone and
a ketimine, and that the scope of this synthesis can be ex-
tended to asymmetrical dihydropyridines.[9a,9b] The syn-
thetic potential of the unsymmetrical Hantzsch reaction has
been recognized and illustrated by the synthesis of numer-
ous polyhydroquinolines.[9c,9d] Enantioselective organocata-
lytic syntheses have also been described.[9e] Based on these
extensions of the Hantzsch reaction, our group has devel-
oped simple and convenient reactions for the synthesis of
various tricyclic nitrogen heterocycles[10] and specially pyr-
imido[4,5-b]quinoline-2,4(1H,3H)-diones, which have been
obtained by a three-component one-pot reaction that in-
volves barbituric acid, paraformaldehyde, and anilines.[11]
In continuation to this work, two “three-component one-
pot” strategies have been envisaged for the preparation of
unsubstituted compound 1 (Scheme 2).
Scheme 3.
With the aminomaleimide in hand, it was used in the
three-component reaction with paraformaldehyde (8) and
barbituric acid (7). However, regardless of the conditions
used [reflux temperatures in AcOH, DMF or dimethyl sulf-
oxide (DMSO)], several inseparable derivatives were ob-
tained. Replacement of the latter by 6-chlorouracil was also
unsuccessful.
Route B. According to the literature 6-aminouracil could
react either as an enamine or as a classical amine.[13] Conse-
quently, we expected that in the first step of the envisaged
one-pot reaction, the amino group of 10 would substitute
the bromine of 11. Unfortunately, in an equimolar mixture
of compounds 10, 8 and 11 in acetic acid at reflux tempera-
Scheme 2.
Route A, in which aniline has been replaced by amino-
maleimide (9), and Route B, which uses commercially avail-
able 6-aminouracil (10) and bromomaleimide (11), which is
more easily accessible than the hydroxymaleimide.
Route A. The synthesis of aminomaleimide (9) was real-
ized in two steps and 61% overall yield from bromomale-
imide (11) by reaction with sodium azide in dimethylform-
amide (DMF) at room temperature and catalytic reduction
of resulting azido derivative 14 (Scheme 3). Bromomale- Scheme 4.
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S. Giorgi-Renault, S. Desbène-Finck et al.
FULL PAPER
tures, the 6-aminouracil reacted as an enamine on the para- two signals (δ = 9.20 and 10.07 ppm). It is well known that
formaldehyde to give a small amount of bis(4-amino-2,6- several isomeric forms could co-exist in this type of hetero-
dioxo-5-tetrahydropyrimidinyl)methane[14] (15; Scheme 4).
cycle and that interpretation of the 13C NMR spectroscopic
In an attempt to carry out the synthesis in a two-step data is not easy.[15]
procedure, compounds 10 and 11 were heated in DMF.
For compound 18, partial assignment could be achieved
Only a small amount of 16 was isolated from the multi- by analysis of the HSQC and HMBC spectra that show a
compound reaction mixture (Scheme 5).
1J coupling between the proton at δ = 9.20 ppm and the
carbonyl at δ = 179.7 ppm, a J coupling between the pro-
2
ton at δ = 9.20 ppm and the carbon at δ = 102.1 ppm and
3
a J coupling between the proton at δ = 9.20 ppm and the
carbonyl at δ = 167.6 ppm. Other signals have been attrib-
uted by analysis with similar structures described in the lit-
erature (Figure 2).[16]
Scheme 5.
Therefore, we envisaged a multi-step synthesis in which
the formyl group was first introduced on the maleimide
moiety. Compound 1 was obtained in accordance to this
procedure through key synthon 18, isolated as its sodium
salt (Scheme 6). Direct Vilsmeier formylation on bromo-
maleimide (11) was not possible. To increase the reactivity
of the pyrrolidinedione toward electrophilic substitution,
bromomaleimide (11) was substituted by morpholine and
the Vilsmeier reaction was performed on resulting morphol-
ino derivative 17. During classical alkaline work-up for the
hydrolysis of the iminium intermediate, the vinylamide
function was also hydrolyzed to give 18 in 85% yield.
Figure 2. NMR data for compound 18 compared to literature data.
It is noteworthy that the carbonyl at δ = 179.7 ppm ap-
pears as a strong signal and carbonyls at 177.4 and
173.5 ppm as very weak signals. However, it is well known
that relaxation times of carbon atoms tend to vary more
widely than those for protons and that consequently their
signals may be missed or not fully accumulated specially for
quaternary carbons.[17] The ultimate proof of the structure
was the synthesis of desired heterocycle 1 by condensation
of synthon 18 with 6-aminouracil (10) in trifluoroacetic
acid (TFA; Scheme 6).
Derivative 1 was isolated in pure 94% yield by simple fil-
tration. According to this procedure, 1H-pyrrolo[3Ј,4Ј:5,6]-
pyrido[2,3-d]pyrimidine-2,4,6,8(3H,7H)-tetraone (1) has
been synthesized in four steps and in 67% overall yield from
commercially available maleimide (12) and aminouracil
(10).
The pKa of the three NH of 1 are of the same order of
magnitude (calculated pKa in water[18] = 7.05, 7.38, 8.42 for
N1, N3 and N7, respectively). Consequently, selective N7-
alkylation of 1 was believed to be difficult. To obtain the
N7-substituted heterocycles, two synthetic pathways were
explored (Scheme 7).
In a first classical sequential one-pot procedure, N-
benzyl derivative 2, chosen as a model, was synthesized in
82% yield from 1. The imide ring of compound 1 was
Scheme 6.
The structure of sodium salt 18 was confirmed by ele- opened by reaction with two equivalents of benzylamine in
mental analysis (C5H2N NaO4·H2O), a strong molecular DMF at reflux temperatures, and then resulting diamide 19
ion peak at m/z = 140 [M – Na]–, and NMR spectroscopic was cyclized with two equivalents of p-toluenesulfonic acid
data. As expected, the 1H NMR spectrum presents only (PTSA).
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Complex Nitrogen heterocycles and N7-Substituted Analogues
Figure 3. Compound 23 (potassium salt).
erocycle 2 by condensation with 6-aminouracil (10) in TFA
(Scheme 7).
According to these procedures, 7-benzyl-1H-pyrrolo-
[3Ј,4Ј:5,6]pyrido[2,3-d]pyrimidine-2,4,6,8(3H,7H)-tetraone
(2) has been synthesized either in five steps and 55% overall
yield from maleimide (12) or in four steps with 58% overall
yield from N-benzylmaleimide (20). For the preparation of
N7-benzylated analogue, the two synthetic pathways gave
similar overall yields. However, the first route is more versa-
tile because the N7-substituent is introduced in the last step.
We have shown that the scope of the reaction could be
extended to the synthesis of other N7-selectively substituted
heterocycles (Figure 4). Good yields have been obtained by
reaction of 1 with various benzylamines (unsubstituted,
electron-rich and electron-poor substituted benzylamines),
with phenylethylamine (compound 27) and with an alicyclic
amine (compound 28). Attempts with aniline have not given
good results so far.
Scheme 7.
Figure 4. Other N-substituted derivatives.
Alternatively, compound 2 was obtained from N-benzyl-
To investigate the possibility of extending these reaction
maleimide (20) by the same sequence as used for compound schemes to the preparation of di- or trisubstituted deriva-
1: bromination of 20 into 21 in accordance with the pro- tives, 1-methyl-7-benzyl compound 33 and 1,3-dimethyl-7-
cedure previously described,[19] substitution by morpholine benzyl derivative 34 were synthesized in accordance with
to give 22, Vilsmeier reaction and condensation with 6- the two synthetic pathways by using either 1-methyl-6-
aminouracil (10). Compound 2 was obtained from synthon aminouracil (29) or 1,3-dimethyl-6-aminouracil (30) as
23 as the sodium salt, without isolation.
starting materials (Scheme 8).
To characterize 23, a small amount of potassium salt has
Interestingly, for the preparation of 1,3-dimethyl hetero-
been prepared (hydrolysis of the iminium intermediate with cycle 32, we have tried to use the methods previously de-
KOH/MeOH) and purified. Contrary to N-unsubstituted scribed in the literature[6] for the synthesis of compound 6
synthon 18, the 13C NMR spectrum of compound 23 does (Scheme 1). However, no reaction occurred when carb-
not present any signal for the enol carbon and one of the aldehyde 4 and maleimide (12) were heated to reflux in
carbonyl of the imide group even if a Bruker AC 600 Spec- tetrahydrofuran (THF). Under microwave irradiation in the
trometer is used (Figure 3).
same solvent, several products were obtained. To increase
The structure of compound 23 was confirmed by elemen- the solubility of the starting materials, THF was replaced
tal analysis (C12H8KNO4) and by isolation of desired het- by DMF, but without success.
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S. Giorgi-Renault, S. Desbène-Finck et al.
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under reduced pressure. To eliminate the last traces of bromine, the
resulting solid was stirred in CH2Cl2 and the solvent was removed
under reduced pressure (three times). The crude 2,3-dibromosuc-
cinimide was dissolved in THF (80 mL) and Et3N (6 mL, 40 mmol)
in THF (40 mL) was added over a 5 min period at 0 °C. The reac-
tion mixture was warmed to room temperature and stirred for 18 h.
The solid was removed by filtration and the solvent removed under
vacuum. The crude product was purified by silica-gel column
chromatography (cyclohexane/EtOAc, 8:2) to afford a pale yellow
powder (6.21 g, 0.0344 mol) in 86% yield, m.p. 152 °C (ref.[12] 148–
151 °C).
3-Azido-1H-pyrrole-2,5-dione (14): A solution of 3-bromomale-
imide (11; 1.0 g, 5.70 mmol) and sodium azide (2.22 g, 34.2 mmol)
in DMF (5 mL) was stirred for 3 h at room temperature. After ad-
dition of H2O (50 mL) to the reaction mixture and extraction with
CH2Cl2, the organic layers were dried with anhydrous sodium sulf-
ate, and the solvent removed under vacuum. The residue was
washed with ligroin to give a crude brown solid (0.51 g, 65%). Un-
stable azide 14 was used without purification. 1H NMR
(300 MHz): δ = 6.14 (s, 1 H, CH), 11.02 (s, 1 H, NH) ppm. 13C
NMR (75 MHz): δ = 109.3 (CH), 144.2 (C-N3), 167.8 (C=O), 171.0
(C=O) ppm. IR (solid): ν = 3215, 3124, 2294, 2133, 2094, 1774,
˜
1697, 1605, 1370, 1330, 1303, 1247, 1133, 1043 cm–1.
3-Amino-1H-pyrrole-2,5-dione (9): A solution of azide 14 (0.24 g,
1.74 mmol) in EtOH (20 mL) was hydrogenated for 2 h at room
temperature in the presence of Pd/C (10 %; 56 mg) under a
hydrogen atmosphere. After filtration through a pad of Celite, the
solvent was removed under reduced pressure to afford quite pure
compound 9 as an orange powder (0.91 g, 94%) which was used
without further purification in the next step. 1H NMR (400 MHz):
δ = 4.71 (s, 1 H, CH), 7.10 (br. s, 2 H, NH2), 10.02 (s, 1 H,
NH) ppm. 13C NMR (75 MHz): δ = 86.1 (CH), 151.3 (H2N-C),
169.7 (C=O), 174.1 (C=O) ppm. IR (solid): ν = 3380, 3171, 3101,
˜
Scheme 8.
2736, 1761, 1705, 1629, 1603, 1400, 1345, 1271, 1186, 1116 cm–1.
Bis(4-amino-2,6-dioxo-5-tetrahydropyrimidinyl)methane (15): A
solution of paraformaldehyde (8; 15 mg, 0.5 mmol), 3-bromomale-
imide (11; 88 mg, 0.5 mmol), and 6-aminouracil (10; 64 mg,
0.5 mmol) was heated to reflux in glacial AcOH (5 mL) for 18 h.
Conclusions
In order to synthesize pyrrolo[3Ј,4Ј:5,6] pyrido[2,3-d]pyr-
imidine-2,4,6,8-tetraone (1), we have developed new syn-
thon 4-formyl-3-hydroxy-2,5-dioxo-2,5-dihydro-1H-pyrrole After filtration of the hot solution, the purple precipitate was puri-
fied by sequential heating to reflux in AcOH and in H2O. The
resulting precipitate was filtered off to give compound 15 (46 mg,
27%) as a white powder, m.p. 352 °C (ref.[14] 360 °C). 1H NMR
(300 MHz): δ = 3.02 (s, 2 H, CH2), 6.73 (br. s, 4 H, 2NH2), 10.24
(s, 2 H, 2NH), 10.48 (s, 2 H, 2NH) ppm. 13C NMR (75 MHz): δ =
16.30 (CH2), 85.3 (2C=C-N), 150.3 (2C=O), 154.1 (2C=C-N),
(18). We have shown that this new synthetic pathway could
be extended to the preparation of N7-selectively substituted
derivatives starting from 18 or its N-substituted analogues.
The use of these synthons for easy and versatile syntheses
of other heterocyclic skeletons is now under investigation.
166.2 (2C=O) ppm. IR (solid): ν = 3343, 3160, 2985, 2787, 1707,
˜
1592, 1527, 1456, 1387, 1161, 1092, 1018 cm–1.
Experimental Section
6-Amino-5-(2,5-dioxo-2,5-dihydro-1H-pyrrol-3-yl)pyrimidine-
2,4(1H,3H)-dione (16): A solution of 3-bromomaleimide (11;
88 mg, 0.5 mmol) and 6-aminouracil (10; 64 mg, 0.5 mmol) in
DMF (5 mL) was stirred at 120 °C for 48 h. The solvent was re-
moved under reduced pressure and the crude product was purified
by silica-gel column chromatography (CH2Cl2/MeOH, 9:1) to af-
ford compound 16 (17 mg, 15%) as a yellow powder, m.p. 364 °C.
1H NMR (300 MHz): δ = 6.85 (s, 1 H, CH), 7.35 (s, 2 H, NH2),
10.67 (s, 1 H, NH), 10.80 (br. s, 2 H, 2NH) ppm. 13C NMR
(75 MHz): δ = 79.8 (-C=C-NH2), 125.1 (-C=CH-), 141.7 (-C=C-
General Remarks: Melting points were measured with a Stuart
SMP3 melting point apparatus. TLC was carried out with Merck
1
GF 254 silica-gel plates. H and 13C NMR spectra were recorded
with a Bruker AC 300 or AC 400 spectrometers with [D6]DMSO
as both solvent and internal standard. IR spectra were obtained
with a Perkin–Elmer 1600 spectrophotometer. Mass spectra were
recorded with a Q-TOF Waters spectrometer. Elemental analyses
were performed at the C.N.R.S. Analysis Laboratory, Gif-sur-
Yvette.
Bromomaleimide (11): To maleimide (4.00 g, 40 mmol) in CH2Cl2 NH2), 150.0 (-C=CH), 154.4 (C=O), 163.2 (C=O), 173.0 (C=O),
(80 mL) was added bromine (2.5 mL, 50 mmol) in CH2Cl2 (20 mL) 174.1 (C=O) ppm. IR (solid): ν = 3407, 3239, 3024, 2921, 1762,
˜
dropwise. The reaction mixture was heated to reflux for 2.5 h and
left to cool to room temperature over 1 h. The solvent was removed
1698, 1612, 1541, 1512, 1453, 1400, 1339, 1287, 1225, 1125,
1028 cm–1. MS (ESI–): m/z = 221 [M – H]–.
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Complex Nitrogen heterocycles and N7-Substituted Analogues
3-Morpholino-1H-pyrrole-2,5-dione (17): To a solution of 3-bromo-
maleimide (11; 0.78 g, 4.44 mmol) in THF (29 mL), triethylamine
(682 μL, 4.88 mmol) and morpholine (427 μL, 4.88 mmol) were
added dropwise. After 1 h of stirring at room temperature, the sol-
vent was removed under reduced pressure. The residue was washed
with EtOH (13 mL) and filtered off to give 17 as a yellow powder
(Cq), 150.6 (-C=C-N), 167.0 (C=O), 170.4 (C=O) ppm. IR (solid):
ν = 2994, 2877, 1747, 1698, 1617, 1587, 1497, 1454, 1432, 1406,
˜
1390, 1346, 1304, 1282, 1255, 1240, 1209, 1133, 1120, 1100, 1077,
1043, 1028 cm–1. C15H16N2O3 (272.30): calcd. C 66.16, H 5.92, N
10.29; found C 66.01, H 5.96, N 10.35.
1-Benzyl-4-formyl-3-hydroxy-2,5-dioxo-2,5-dihydro-1H-pyrrole,
Potassium Salt (23): Under vigorous stirring, POCl3 (2 mL,
21.5 mmol) was added dropwise to a suspension of compound 22
(1.0 g, 3.68 mmol) in DMF (8 mL) over a period of 4 min to avoid-
ing the temperature of the reaction mixture rising above 20 °C. The
reaction mixture was stirred at room temperature for 1 h. After
removal of the solvent under reduced pressure, H2O (20 mL) was
added and the reaction mixture was stirred at room temperature
for 20 h. The resulting precipitate was filtered off and vacuum-
dried with P2O5. To a suspension of iminium salt in MeOH (3 mL)
a methanolic KOH solution (536 mg in 15 mL, 9.5 mmol) was
added. The mixture was then stirred at room temperature over-
night. The precipitate was filtered off, washed with cold MeOH
(2 mL) and vacuum-dried with P2O5 to give 23 potassium salt
(446 mg, 45 %) as a white powder, m.p. 238–240 °C. 1H NMR
(400 MHz): δ = 4.55 (s, 2 H, CH2), 7.20–7.25 (m, 5 H, 5Har), 9.27
(s, 1 H, O=CH) ppm. 13C NMR (75 MHz): δ = 39.8 (CH2), 100.8
(-C=C-O), 127.5 (CH), 127.7 (2CH), 128.9 (2CH), 138.3 (Cq),
1
(0.797 g, 97%), m.p. 239 °C. H NMR (400 MHz): δ = 3.64 (m, 8
H, 4CH2), 5.11 (s, 1 H, CH), 11.30 (s, 1 H, NH) ppm. 13C NMR
(75 MHz): δ = 47.3 (2CH2), 66.1 (2CH2), 91.0 (-C=CH-), 150.8
(-C=C-N), 169.0 (C=O),171.8 (C=O) ppm. IR (solid): ν =
˜
3117, 3036, 2994, 2925, 2871, 2747, 1710, 1621, 1597, 1466,
1452, 1432, 1348, 1303, 1261, 1238, 1111, 1065, 1034 cm–1
.
C8H10N2O3·0.25H2O: calcd. C 51.47, H 5.67, N 15.01; found C
51.39, H 5.49, N 14.75.
4-Formyl-3-hydroxy-2,5-dioxo-2,5-dihydro-1H-pyrrole, Sodium Salt
(18): Under vigorous stirring, POCl3 (0.4 mL, 4.3 mmol) was added
dropwise to a suspension of compound 17 (400 mg, 2.15 mmol) in
DMF (0.7 mL) over a 4 min period to avoid the temperature of the
reaction mixture rising above 20 °C. The reaction mixture was
stirred at room temperature for 2 h. After cooling and addition of
H2O (2 mL), the suspension was basified with an aqueous NaOH
(8 m) to pH of 9–10. The mixture was then stirred at 40 °C over-
night. The precipitate was filtered off, washed with a 1:1 H2O/
EtOH mixture (10 mL) and vacuum-dried with P2O5 to give salt
18 (339 mg, 85%) of as a light yellow powder, m.p. 313 °C. 1H
NMR (400 MHz): δ = 9.20 (s, 1 H, O=CH), 10.07 (s, 1 H, NH or
OH) ppm. 13C NMR (75 MHz): δ = 102.1 (-C=C-O), 167.6 (C=O),
173.5 (C=O), 177.4 (-C=C-O), 179.7 (HC=O strong signal) ppm.
165.7 (C=O), 178.9 (C=O strong signal) ppm. IR (solid): ν = 3030,
˜
2797, 2728, 1766, 1709, 1661, 1569, 1542, 1495, 1455, 1428, 1398,
1342, 1273, 1108, 925 cm–1. C12H8KNO4 (269.30): calcd. C 53.52,
H 2.99, N 5.20; found C 53.20, H 2.96, N 4.99.
7-Benzyl-1H-pyrrolo[3Ј,4Ј:5,6]pyrido[2,3-d]pyrimidine-2,4,6,8-
(3H,7H)-tetraone (2). Synthesis from 1: To a suspension of 1
(70 mg, 0.30 mmol) in DMF (444 μL) benzylamine (66 μL,
0.60 mmol) was added. The reaction mixture was heated to reflux
temperatures for 2 h. To the solution, PTSA (115 mg, 0.6 mmol)
was added and reflux temperatures were maintained for 10 min.
The resulting precipitate was filtered off and washed with water
(3ϫ 2 mL) to give pure 2 as a white powder (80 mg, 82%).
IR (solid): ν = 3404, 3181, 3077, 2695, 1790, 1744, 1720, 1676,
˜
1653, 1626, 1590, 1468, 1401, 1365, 1329, 1231, 1095 cm–1. MS
(ESI–): m/z = 140 [M – Na]–. C5H2NNaO4·H2O (181.1): calcd. C
33.16, H 2.23, N 7.74; found C 33.18, H 2.00, N 7.74.
1H-Pyrrolo[3Ј,4Ј:5,6]pyrido[2,3-d]pyrimidine-2,4,6,8(3H,7H)-tetra-
one (1): To a solution of 6-aminouracil (10; 221 mg, 1.74 mmol) in
TFA (11 mL) was added synthon 18 sodium salt (315 mg,
1.58 mmol). After stirring overnight at room temperature, the re-
sulting precipitate was filtered off, washed with EtOH (5ϫ 1 mL)
and Et2O (5ϫ 2 mL). To eliminate the last traces of TFA, the re-
sulting solid was stirred in EtOH and the solvent was removed
under reduced pressure (five times) to give pure compound 1
(347 mg, 94 %) as a yellow powder, m.p. Ͼ 410 °C. 1H NMR
(300 MHz): δ = 8.45 (s, 1 H, H5), 11.82 (s, 1 H, H1 or H3 or H7),
11.84 (s, 1 H, H1 or H3 or H7), 12.44 (s, 1 H, H1 or H3 or
H7) ppm. 13C NMR (75 MHz): δ = 113.2 (Cq), 122.5 (Cq), 131.9
(CH), 150.5 (C=O), 157.1 (Cq), 157.4 (Cq), 162.0 (C=O), 166.9
Synthesis from 22: POCl3 (0.2 mL, 2.15 mmol) was added dropwise
under vigorous stirring to a suspension of compound 22 (500 mg,
1.83 mmol) in DMF (6 mL) over a period of 4 min to avoid the
temperature of the reaction mixture rising above 20 °C. The reac-
tion mixture was stirred at room temperature for 30 min. After re-
moval of the solvent under reduced pressure, H2O (40 mL) was
added. The resulting suspension was basified with an aqueous
NaOH (8 m) to pH of 9–10. The mixture was then stirred at room
temperature for 48 h. The solvent was removed under reduced pres-
sure and crude product 23 was used without further purification.
A solution of crude compound 23 and 6-aminouracil (10; 234 mg,
1.83 mmol) in TFA (12 mL) was stirred for 48 h at room tempera-
ture. The solvent was removed under reduced pressure. Addition of
EtOH (25 mL) to the oily residue gave a precipitate, which was
filtered and washed with EtOH (5ϫ 1 mL) and then with Et2O
(5ϫ 2 mL). To eliminate the last traces of TFA, the resulting solid
was stirred in EtOH and the solvent was removed under reduced
(C=O), 167.0 (C=O) ppm. IR (solid): ν = 3300, 3067, 3003, 2916,
˜
2800, 1782, 1729, 1706, 1671, 1606, 1534, 1470, 1407, 1372, 1300,
1279, 1106, 1042, 1010, 890, 850, 817, 790, 740, 726 cm–1
.
C9H4N4O4·0.25H2O (236.7): calcd. C 45.68, H 1.92, N 23.67; found
C 45.47, H 1.85, N 23.39.
1-Benzyl-3-morpholino-1H-pyrrole-2,5-dione (22): To a solution of
1-benzyl-3-bromomaleimide (21;[19] 3.41 g, 12.8 mmol) in CH2Cl2 pressure (five times) to give pure compound 2 (426 mg, 72%) as a
1
(50 mL), Et3N (1.79 mL, 12.8 mmol) and morpholine (1.23 mL, white powder, m.p. 352 °C. H NMR (300 MHz): δ = 4.81 (s, 2 H,
14.1 mmol) were added dropwise. After 3 h of stirring at room tem-
perature, the organic layer was washed with H2O (3ϫ 30 mL),
dried with anhydrous sodium sulfate, and the solvent was removed
under vacuum. The resulting residue was washed with MeOH
(40 mL) to give 22 (2.87 g, 82%) as a yellow powder, m.p. 133 °C.
1H NMR (400 MHz): δ = 3.67 (m, 8 H, 4CH2), 4.53 (s, 2 H, CH2-
CH2), 7.29–7.35 (m, 5 H, Har), 8.52 (s, 1 H, H5), 11.88 (s, 1 H, H1
or H3), 12.51 (s, 1 H, H1 or H3) ppm. 13C NMR (75 MHz): δ =
41.6 (CH2), 113.2 (Cq), 121.6 (Cq), 127.9 (2CH), 128.0 (Cq), 129.0
(2CH), 132.0 (CH), 136.7 (CH), 150.5 (C=O), 156.5 (Cq), 157.5
(Cq), 161.9 (C=O), 165.6 (C=O), 165.7 (C=O) ppm. IR (solid): ν
˜
= 3207, 3033, 1709, 1661, 1626, 1609, 1533, 1496, 1471, 1457, 1433,
Ph), 5.26 (s, 1 H, CH), 7.20–7.35 (m, 5 H, Har) ppm. 13C NMR 1414, 1391, 1355, 1339, 1303, 1283, 1249, 1208, 1186, 1153, 1117,
(75 MHz): δ = 40.5 (CH2-Ph), 47.4 (2CH2), 66.0 (2CH2), 89.1 - 1102, 1077, 1039, 1030, 1002 cm–1. C16H10N4O4·0.5H2O (331.3):
(-C=CH-), 127.7 (2CHar), 127.8 (CHar), 129.0 (2CHar), 137.7
calcd. C 58.01, H 3.35, N 16.91; found C 58.39, H 3.11, N 16.92.
Eur. J. Org. Chem. 2015, 7028–7035
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7033

S. Giorgi-Renault, S. Desbène-Finck et al.
FULL PAPER
1H-7-(2,4-Dimethoxybenzyl)-pyrrolo[3Ј,4Ј:5,6]pyrido[2,3-d]pyrimid-
ine-2,4,6,8(3H,7H)-tetraone (24): Compound 24 was prepared by
using 2,4-dimethoxybenzylamine (90 μL, 0.60 mmol) in accordance
with the same procedure and work up as described for compound
2 (from 1). Reaction time: 2 h and 15 h, yield 89%, m.p. 295 °C.
1H NMR (300 MHz): δ = 3.73 (s, 3 H, OMe), 3.78 (s, 3 H, OMe),
4.69 (s, 2 H, CH2-N), 6.43 (dd, JH5Ј-H6Ј = 8.1, JH5Ј-H3Ј = 2.1 Hz, 1
(CO), 155.8 (Cq), 157.0 (Cq), 161.5 (CO), 165.0 (CO), 165.1
(CO) ppm. IR (solid): ν = 3604, 3478, 3164, 3028, 3055, 2817, 1778,
˜
1740, 1697, 1674, 1604, 1540, 1497, 1466, 1455, 1437, 1398, 1383,
1338, 1287, 1241, 1188, 1150, 1116, 1107, 1040, 1028, 987, 905,
866, 807 cm–1. C17H12N4O4·0.75H2O: calcd. C 58.62, H 3.86, N
16.09; found C 58.48, H 3.89, N 16.13.
7-Cyclohexylmethyl-1H-pyrrolo[3Ј,4Ј:5,6]pyrido[2,3-d]pyrimidine-
2,4,6,8(3H,7H)-tetraone (28): Compound 28 was prepared in ac-
cordance with the same procedure and work up as described for
compound 2 by using cyclohexylmethylamine (78 μL, 0.60 mmol).
Reaction times: 2 h and 17 h, yield 97 %, m.p. 390–392 °C. 1H
NMR (400 MHz): δ = 0.87–1.00 (m, 2 H, CH2), 1.07–1.23 (m, 3 H,
CH, CH2), 1.55–1.74 (m, 6 H, 3CH2), 3.43 (d, JCH2N-CH = 5.2 Hz, 2
H, CH2-N), 8.46 (s, 1 H, H5), 11.84 (s, 1 H, H1), 12.46 (s, 1 H,
H3) ppm. 13C NMR (100 MHz): δ = 25.2 (2CH2), 25.8 (CH), 30.3
(2CH2), 36.6 (CH2), 43.9 (CH2-N), 112.6 (Cq), 121.1 (Cq), 131.3
(CH), 150.0 (CO), 155.9 (Cq), 157.0 (Cq), 161.5 (CO), 165.4 (CO),
H, H5Ј), 6.55 (d, JH3Ј-H5Ј = 2.1 Hz, 1 H, H3Ј), 7.09 (d, JH6Ј-H5Ј
=
8.1 Hz, 1 H, H6Ј), 8.50 (s, 1 H, H5), 11.87 (s, 1 H, H1), 12.50 (s, 1
H, H3) ppm. 13C NMR (75 MHz): δ = 36.5 (CH2-N), 55.3 (OMe),
55.6 (OMe), 98.3 (CH), 104.5 (CH), 112.8 (Cq), 115.7 (Cq), 121.2
(Cq), 128.8 (CH), 131.4 (CH), 150.0 (Cq), 156.0 (Cq), 157.0 (CO),
157.5 (Cq), 160.1 (CO), 161.5 (CO), 165.0 (CO), 165.1 (Cq) ppm.
IR (solid): ν = 3232, 3101, 3030, 2813, 1775, 1735, 1708, 1689,
˜
1606, 1589, 1528, 1511, 1450, 1435, 1369, 1382, 1335, 1272, 1295,
1211, 1185, 1161, 1136, 1062, 1035, 1027, 966, 943, 933, 918, 853,
817 cm–1. C18H14N4O6·0.5H2O (391.3): calcd. C 55.24, H 3.86, N
14.32; found C 55.14, H 3.79, N 14.24.
165.6 (CO) ppm. IR (solid): ν = 3208, 2925, 2849, 1775, 1703, 1660,
˜
1625, 1610, 1533, 1468, 1449, 1387, 1362, 1336, 1304, 1282, 1242,
1187, 1164, 1078, 1041, 1012, 955, 936, 916, 866, 836, 813 cm–1.
C16H16N4O4·0.5H2O (337.3): calcd. C 56.97, H 5.09, N 16.61;
found C 57.30, H 4.78, N 16.61.
7-(3,4-Methylenedioxybenzyl)-1H-pyrrolo[3Ј,4Ј:5,6]pyrido[2,3-d]pyr-
imidine-2,4,6,8(3H,7H)-tetraone (25): Compound 25 was prepared
in accordance with the same procedure and work up as described
for compound 2 by using 3,4-methylenedioxybenzylamine (83 mg,
0.60 mmol). Reaction times: 2 h and 17 h, yield 79%, m.p. 352 °C.
1H NMR (300 MHz): δ = 4.70 (s, 2 H, CH2-N), 5.98 (s, 2 H, O-
1-Methyl-1H-pyrrolo[3Ј,4Ј:5,6]pyrido[2,3-d]pyrimidine-2,4,6,8-
(3H,7H)-tetraone (31): Compound 31 was prepared in accordance
with the same procedure and work up as described for compound 1
by using 6-amino-1-methyluracil (29; 117 mg, 0.829 mmol) in TFA
(6 mL) and synthon 18 (150 mg, 0.753 mmol). Reaction time: 24 h
at room temperature. Compound 31 (105 mg, 57%) was isolated as
CH2-O), 6.83 (d, JH5Ј-H6Ј = 7.8 Hz, 1 H, H6Ј), 6.86 (d, JH5Ј-H6Ј
=
7.8 Hz, 1 H, H5Ј), 6.91 (s, 1 H, H2Ј), 8.49 (s, 1 H, H5), 11.93 (s, 1
H, H1), 12.41 (s, 1 H, H3) ppm. 13C NMR (75 MHz): δ = 41.0
(CH2-N), 101.1 (O-CH2-O), 108.3 (2CH), 112.7 (Cq), 121.2 (CH,
Cq), 130.0 (Cq), 131.5 (CH), 146.6 (Cq), 147.4 (Cq), 150.1 (CO),
156.1 (Cq), 157.1 (Cq), 161.5 (CO), 165.1 (CO), 165.2 (CO) ppm.
1
a yellow powder, m.p. 312 °C. H NMR (400 MHz): δ = 3.57 (s, 3
H, Me), 8.52 (s, 1 H, H5), 11.86 (s, 1 H, H3 or H7), 12.12 (s, 1 H,
H3 or H7) ppm. 13C NMR (75 MHz): δ = 29.6 (Me), 114.5 (Cq),
122.3 (Cq), 132.0 (CH), 150.7 (C=O), 156.4 (Cq), 157.0 (Cq), 160.9
IR (solid): ν = 3204, 3045, 2895, 2859, 1947, 1804, 1742, 1707,
˜
1678, 1618, 1533, 1500, 1491, 1442, 1428, 1384.1366, 1337, 1320,
1282, 1244, 1196, 1152, 1111, 1097, 1032, 976, 947, 934, 924, 848,
839, 808 cm–1. C17H10N4O6·0.25H2O (370.8): calcd. C 55.07, H
2.85, N 14.24; found C 55.84, H 3.00, N 15.45.
(C=O), 166.8 (C=O), 166.9 (C=O) ppm. IR (solid): ν = 3515, 3304,
˜
3187, 3061, 2803, 1786, 1754, 1738, 1692, 1615, 1602, 1505, 1472,
1416, 1397, 1381, 1346, 1313, 1292, 1181, 1121, 1074, 993, 947,
849, 818 cm–1. C10H6N4O4·H2O (264.2; 246.18): calcd. C 45.46, H
3.05, N 21.21; found C 45.09, H 2.63, N 20.80.
7-(2,4-Dichlorobenzyl)-1H-pyrrolo[3Ј,4Ј:5,6]pyrido[2,3-d]pyrimidine-
2,4,6,8(3H,7H)-tetraone (26): Compound 26 was prepared in ac-
cordance with the same procedure and work up as described for
compound 2 by using 2,4-dichlorobenzylamine (80 μL, 0.60 mmol).
Reaction times: 2 h and 17 h, yield 84%, m.p. 367 °C. 1H NMR
(300 MHz): δ = 4.85 (s, 2 H, CH2-N), 7.39 (dd, JH5Ј-H6Ј = 8.3, JH5Ј-
7-Benzyl-1-methyl-1H-pyrrolo[3Ј,4Ј:5,6]pyrido[2,3-d]pyrimidine-
2,4,6,8(3H,7H)-tetraone (33): Compound 33 was prepared by the
same procedures as used for compound 2.
Synthesis from 31: N3,N7-unsubstituted heterocycle 31 (50 mg,
0.203 mmol), DMF (1 mL), benzylamine (45 μL, 0.406 mmol) and
PTSA (77 mg, 0.406 mmol). Reaction times: 2 h and 21 h to give a
white powder (32 mg, 47%).
= 1.5 Hz, 1 H, H5Ј), 7.47 (d, JH5Ј-H6Ј = 8.3 Hz, 1 H, H6Ј), 7.68
H3Ј
(d, JH3Ј-H5Ј = 1.5 Hz, 1 H, H3Ј), 8.52 (s, 1 H, H5), 11.82 (s, 1 H,
H1), 12.52 (s, 1 H, H3) ppm. 13C NMR (75 MHz): δ = 55.0 (CH2-
N), 112.8 (Cq), 121.2 (Cq), 127.5 (CH), 128.9 (CH), 130.5 (CH),
131.6 (Cq), 132.4 (CH), 132.7 (Cq), 133.0 (Cq), 150.1 (CO), 156.1
(Cq), 157.1 (Cq), 161.5 (CO), 165.0 (CO), 165.1 (CO) ppm. IR (so-
Synthesis from 22: Step 1, compound 22 (500 mg, 1.83 mmol),
POCl3 (0.2 mL, 2.15 mmol), DMF (6 mL). Step 2, crude com-
pound 23 (sodium salt), 6-amino-1-methyluracil (29; 258 mg,
1.8 mmol) and TFA (18 mL). Reaction time: 18 h at room tempera-
ture; purification by silica-gel column chromatography (CH2Cl2/
EtOAc, 8.5:1.5 to 7.5:2.5) to give compound 33 (303 mg, 50%) as
lid): ν = 3049, 2930, 2786, 1784, 1722, 1682, 1646, 1605, 1566, 1535,
˜
1474, 1450, 1414, 1398, 1378, 1340, 1318, 1287, 1254, 1197, 1187,
1151, 1119, 1102, 1072, 1045, 998, 989, 959, 934, 858, 831,
813 cm–1. C16H8Cl2N4O4·DMF: calcd. C 49.15, H 3.26, N 15.09;
found C 48.72, H 3.30, N 14.85.
1
a white powder, m.p. 294 °C. H NMR (400 MHz): δ = 3.56 (s, 3
7-Phenylethyl-1H-pyrrolo[3Ј,4Ј:5,6]pyrido[2,3-d]pyrimidine-
2,4,6,8(3H,7H)-tetraone (27): Compound 27 was prepared in ac-
cordance with the same procedure and work up as described for
compound 2 by using phenylethylamine (72 μL, 0.60 mmol). Reac-
tion times: 5 h and 17 h, yield 75 %, m.p. 360 °C 1H NMR
H, Me), 4.83 (s, 2 H, CH2), 7.29–7.35 (m, 5 H, 5Har), 8.57 (s, 1 H,
H5), 12.16 (s, 1 H, H3) ppm. 13C NMR (75 MHz): δ = 29.6 (Me),
41.7 (CH2), 114.5 (Cq), 121.4 (Cq), 128.0 (2CH, Cq), 129.0 (2CH),
132.0 (CH), 136.6 (CH), 150.7 (C=O), 155.8 (Cq), 157.0 (Cq), 160.9
(C=O), 165.5 (C=O), 165.6 (C=O) ppm. IR (solid): ν = 3182, 3128,
˜
(300 MHz): δ = 2.92 (t, J = 6.9 Hz, 2 H, CH2-Ph), 3.84 (t, J = 3068, 2838, 1775, 1698, 1614, 1599, 1508, 1494, 1473, 1456, 1431,
6.9 Hz, 2 H, CH2-N), 7.15–7.32 (m, 5 H, Har), 8.46 (s, 1 H, H5), 1390, 1373, 1350, 1307, 1273, 1210, 1197, 1158, 1122, 1111, 1101,
11.85 (s, 1 H, H1), 12.47 (s, 1 H, H3) ppm. 13C NMR (75 MHz): δ 1072, 1039, 1027, 995, 981, 952, 920, 903, 826, 817 cm–1
.
= 33.6 (CH2-Ph), 39.0 (CH2-N), 112.8 (Cq), 121.0 (Cq), 126.5 C17H12N4O4 (336.31): calcd. C 60.71, H 3.60, N 16.66; found C
(CH), 128.5 (2CH), 128.7 (2CH), 131.3 (CH), 138.2 (Cq), 150.0 60.26, H 3.64, N 16.59.
7034
www.eurjoc.org
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2015, 7028–7035

Complex Nitrogen heterocycles and N7-Substituted Analogues
Pharm. 2012, 2, 1–9; c) V. Sharma, N. Chitranshi, A. K. Agar-
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1,3-Dimethyl-1H-pyrrolo[3Ј,4Ј:5,6]pyrido[2,3-d]pyrimidine-2,4,6,8-
(3H,7H)-tetraone (32): Compound 32 was prepared in accordance
with the same procedure and work up as described for compound
1 by using 6-amino-1,3-dimethyluracil (30; 144 mg, 0.928 mmol) in
TFA (6 mL) and synthon 18 (168 mg, 0.844 mmol). Reaction time:
72 h at room temperature. Compound 32 (160 mg, 73%) was iso-
lated as a yellow powder, m.p. 327 °C. 1H NMR (400 MHz): δ =
3.34 (s, 3 H, Me), 3.65 (s, 3 H, Me), 8.58 (s, 1 H, H5), 11.87 (s, 1
H, NH) ppm. 13C NMR (75 MHz): δ = 28.9 (Me), 30.5 (Me), 113.6
(Cq), 122.5 (Cq), 132.4 (CH), 151.1 (C=O), 155.6 (Cq), 156.4 (Cq),
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160.6 (C=O), 166.7 (C=O), 166.8 (C=O) ppm. IR (solid): ν = 3365,
˜
3171, 3056, 2755, 1778, 1711, 1651, 1612, 1599, 1507, 1464, 1414,
1399, 1386, 1357, 1317, 1290, 1190, 1159, 1140, 1105, 1067, 1041,
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Comb. Sci. 2012, 14, 631–635.
1,3-Dimethyl-7-benzyl-1H-pyrrolo[3Ј,4Ј:5,6]pyrido[2,3-d]pyrimidine-
2,4,6,8(3H,7H)-tetraone (34): Compound 34 was prepared by the
same procedures as used for compound 2.
Synthesis from 32: N-unsubstituted heterocycle 32 (50 mg,
0.192 mmol), DMF (1 mL), benzylamine (41 μL, 0.384 mmol) and
PTSA (77 mg, 0.406 mmol). Reaction times: 2 h and 46 h to give a
white powder (32 mg, 47%).
Synthesis from 22: Step 1, compound 22 (500 mg, 1.83 mmol),
POCl3 (0.2 mL, 2.15 mmol) and DMF (6 mL). Step 2, crude com-
pound 23 (sodium salt), 6-amino-1,3-dimethyluracil (30; 284 mg,
1.83 mmol) and TFA (12 mL). Reaction time: 48 h at room tem-
perature. Purification by silica-gel column chromatography
(CH2Cl2/EtOAc, 10:0 to 9.7:0.3) to give a white powder (277 mg,
44%), m.p. 243 °C. 1H NMR (400 MHz): δ = 3.34 (s, 3 H, Me),
3.66 (s, 3 H, Me), 4.84 (s, 2 H, CH2), 7.28–7.36 (m, 5 H, 5Har),
8.65 (s, 1 H, H5) ppm. 13C NMR (75 MHz): δ = 28.9 (Me), 30.6
(Me), 41.7 (CH2), 113.6 (Cq), 121.6 (Cq), 128.0 (2CH, Cq), 129.0
(2CH), 132.4 (CH), 136.7 (CH), 151.1 (C=O), 155.6 (Cq), 155.8
(Cq), 160.6 (C=O), 165.5 (C=O), 165.6 (C=O) ppm. IR (solid): ν
˜
= 3061, 3036, 2960, 1780, 1717, 1661, 1615, 1602, 1514, 1497, 1471,
1456, 1427, 1415, 1385, 1364, 1349, 1337, 1313, 1286, 1208, 1108,
1094, 1074, 1055, 1027, 990, 970, 934, 923, 906, 843, 818, 805 cm–1.
C18H14N4O4 (350.33): calcd. C 61.71, H 4.03, N 15.99; found C
61.41, H 4.05, N 16.02.
Supporting Information (see footnote on the first page of this arti-
cle): 1H, 13C and J-MOD NMR spectra for all new compounds are
available. Spectra recorded with a Bruker AC 600 spectrometer are
also available
Acknowledgments
[17] D. G. Watson, Pharmaceuticals analysis, 3rd ed., Churchill Lev-
ingston Elsevier, 2012, p. 194.
We are grateful to Prof. Brigitte Deguin for helpful discussions and
to Dr Serge Bouaziz for NMR experiments at 600 MHz.
[18] http://archemcalcd.com/sparc/Logiciel,
Automated Reasoning in Chemistry.
SPARC
Performs
[19] L. J. Jiang, H. Q. Lan, J. F. Zheng, J. L. Ye, P. Q. Huang, Syn-
lett 2009, 2, 297–301.
[1] a) S. D. Arikkatt, B. Mathew, J. Joseph, M. Chandran, A. R.
Bhat, K. Krishnakumar, Int. J. Org. Biol. Chem. 2014, 4, 1–5;
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Received: July 23, 2015
Published Online: October 8, 2015
Eur. J. Org. Chem. 2015, 7028–7035
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7035